Download New techniques that could make germline genetic

The Economist
Genome editing
The age of the red pen
It is now easy to edit the genomes of
plants, animals and humans
Aug 22nd 2015



IN THE summer of 2005 Karen Aiach and her husband received heartbreaking news about their fourmonth-old daughter, Ornella: she had a rare disorder known as Sanfilippo syndrome. The prognosis was
that, from about the age of three, the disorder would gradually rob her of most of her cognitive abilities.
She would probably develop a severe sleep disorder and become hyperactive and aggressive. She was
unlikely to live into her teens; she certainly would not survive them.
The problem was that Ornella lacked a working copy of a specific gene. It is a gene that tells the body how
to make a particular protein which is involved in clearing up cellular debris. Without that protein the cells
of her body were unable to break down a complex sugar molecule, heparan sulphate. It is the build-up of
that molecule in brain cells that lies behind the symptoms of the syndrome. If her cells could make that
protein, the situation might, in principle, be reversed. Learning this, Ms Aiach embarked on a ten-year
search for a way to correct the error in her daughter’s genome.
In almost every cell in Ornella’s body, as in every human body, there are two copies of the human genome,
one from her mother, one from her father. In each of those genomes there are about 20,000 genes, each of
which contains the recipe for a specific protein in the form of a sequence of chemical “letters”. To date,
medicine has recognised about 6,000 diseases that can be traced to a problem with one or another of those
genes—a disorder in which a missing or garbled sequence of DNA leaves the body unable to make a
particular protein, or causes it to be made in an abnormal form. Some of these single-gene disorders are
well known: Tay Sachs; sickle-cell anaemia; haemophilia. Others, such as Sanfilippo syndrome, are the sort
of thing you learn of only when a child you care about turns out to be the one in 70,000 that it afflicts.
Since genetic engineers assembled their first tool kits in the 1970s heart-broken parents and medical
researchers have longed to use such technologies to fix these faulty genes. The first clinical attempts at
such “gene therapy” began in the 1990s, with viruses used to add needed genes to cells that lacked them.
But this was crude stuff. The new genes could not be guaranteed to slot into the right place in the genome;
this often meant they did not in practice produce much protein; it also meant there was a risk that, by
disrupting other genes, they could cause cancer. There were indeed cancers in some early trials; there was
also a case in which a patient died of a lethal immune reaction to the virus used to carry the gene.
Powered by the desire to do something for children like Ornella, the gene therapists have soldiered on. And
in the past few years they have found themselves helped by the most impressive piece of kit yet—a system
called CRISPR-Cas9.
Some years ago, biologists discovered an odd feature in the genomes of some bacteria that they described
as “clustered, regularly interspaced short palindromic repeats”—CRISPR for short. Bacteria use them to
make little bits of RNA, a molecule that can store sequences of letters like those that make up genes in
DNA. A CRISPR RNA will bind to a piece of DNA that has a complementary sequence. A protein called
Cas9, which is a sort of pair of molecular scissors, recognises the structure made when a CRISPR RNA
binds to a piece of DNA and responds by cutting through the DNA at precisely that point (see diagram).
Beating bugs into scalpels
Bacteria make CRISPR RNAs that recognise the DNA of viruses which prey on them, marking that DNA
for destruction by Cas9 and thus protecting the bacteria from infection. Scientists can make RNAs that
target any sequence they want. And because of the way that cells repair broken DNA, if they put a new
gene into a cell along with the CRISPR-Cas9 system, they can get that new gene to replace an old one. The
effect is to give scientists something that works like the find-and-replace function on a word processor.
Because it is so simple and easy to use, CRISPR has generated huge excitement in the worlds of molecular
biology, medical research, commercial biotechnology—and gene therapy, where it may make it possible to
make changes with profound consequences. To date gene therapies have been designed to fix everyday
sorts of cells, such as those of the blood, or the retina, or the pancreas. CRISPR makes it possible to think
about aiming at the special cells that make sperm and eggs, or the genome of a fertilised embryo awaiting
implantation in the womb. In either case the changes made would pass from one generation to the next, and
the one after that, in perpetuity.
This sort of “germ-line” editing is widely seen as a bourn no ethical traveller should cross. Some scientists
and research organisations want a moratorium on any work aimed at engineering the germ line; others say
basic research on such things should continue, but any moves to use it in the clinic should at the very least
be widely debated by society as a whole. America’s National Academies of Science are convening a
gathering in December to look at the options. Genetics is a peculiarly personal science, but it is also one
very prone to politics. The power of CRISPR looks sure to exacerbate that propensity.
When Jennifer Doudna of the University of California, Berkeley, Emmanuelle Charpentier, who is now at
the Helmholtz Centre for Infection Research in Germany, and colleagues worked out how to turn the
bacterial CRISPR system into a genome editor three years ago there were already two other techniques for
making specific and precise changes to genomes. But the other techniques were time-consuming and often
finicky. The new technique was as good if not better, and far quicker and easier to use. Matthew Porteus, a
pioneer in gene editing at Stanford University, says research that required a sophisticated molecular biology
lab three years ago can now be done by a high-school student.
All of the species, all the time
By the beginning of 2015 the regular analysis of “hot” research in biology put out by Thomson Reuters,
which looks at what papers are being cited most by other scientists, had three CRISPR papers in its top ten.
The technique has been applied to dozens of species, including zebrafish (much favoured by developmental
biologists), yeast, fruit flies, rabbits, pigs, rats, mice and macaques—the first primates to be genetically
engineered with the technique. It has been used to cure mouse versions of muscular dystrophy and a rare
liver disease. Ways have been found to make the technique more reliable, more versatile and less likely to
make cuts where it is not supposed to; further improvements are on the way, not least at the startup
companies built around the technology.
One of CRISPR’s great attractions is that it can be used to introduce, or remove, a number of different
genes at a time. Most disorders are not caused by just one gene going wrong; being able to manipulate
many different genes in a cell line, plant or animal opens new avenues for the study of conditions such as
diabetes, heart disease and autism where a number of genes are involved, along with the environment. In
the past a mouse with as few as three genes knocked out would have taken as many years to create; now it
can be done in three weeks.
CRISPR is also letting researchers get more out of other technological breakthroughs—notably the ability
to make stem cells which can then be turned into the cells typical of any sort of tissue. George Church at
Harvard is using CRISPR to edit the genomes of stem cells before turning them into nerve cells, so as to
find the mechanisms behind a range of neurological disorders. Feng Zhang, a scientist at the nearby Broad
Institute, has been using CRISPR to model Angelman syndrome, a neurological disorder.
Previous genetic-engineering technologies have tended to be species-specific; there have been lots of tools
for manipulating E. coli and yeast, but they have often not been broadly applicable. This is another area
where CRISPR excels; it can be used in organisms that have resisted previous attempts at engineering. This
could be a big help in agriculture, spreading modification techniques to new grains, roots and fruits—
Monsanto has already begun working with CRISPR to design plants with useful traits. Another biotech
application is the use of CRISPR to build a “kill switch” which allows any genetic modifications made to
bacteria to be removed after they have been used, either for safety or to protect intellectual property.
One particularly impressive—and potentially worrying—application is in the creation of genes that can
spread themselves quickly through a population with blithe disregard for the constraints of natural
selection. Engineering the CRISPR-Cas9 system itself into a creature’s genome makes it possible for an
organism to edit its own genes, and there are ways that this ability can be used to “drive” a gene through a
population (see article). Such a technology might, proponents say, be used to make the mosquitoes that
carry malaria, or dengue fever, unable to spread the organisms responsible for causing the disease.
The applications seem limited only by the imagination. Dr Zhang says CRISPR has enormous potential for
treating previously intractable diseases. For example, genome editing may make it possible to eliminate
viral infections within the body, creating entirely new antiviral treatments. He also speculates that it might
be possible to make red meat that is less harmful, or to engineer pig organs so that they could be
transplanted into humans with much less risk of rejection. Dr Church, for his part, has speculated about
using gene editing to turn elephants into mammoths—or to recreate Neanderthals.
There has been a flurry of commercial activity and investment. Large pharmaceutical companies are eyeing
the technology for research. AstraZeneca has plans to use it in cell cultures to explore the function of every
gene in the human genome. Among the startups, Caribou, which was founded by Dr Doudna in 2011, has
raised $11m in funding and will focus on cell engineering for drug screening, agricultural and industrial
biotechnology. Caribou has also formed, with pharma company Novartis and a venture-capital firm, a
startup called Intellia. With $15m raised in 2014 Intellia will focus its work on gene therapies in which
cells are taken from patients, edited and put back.
Crispr Therapeutics, co-founded by Dr Charpentier in Switzerland, which has raised $25m, is aiming at a
similar market, as is Editas Medicine, co-founded by Dr Zhang. In early August, Editas raised $120m from
a group of investors that includes Bill Gates. This comes on top of $43m the company raised in 2013.
Although Dr Doudna and Dr Charpentier filed the first patent for CRISPR’s use in gene editing, Dr Zhang
was granted a patent on its use in plants and animals after his institution paid for an accelerated review.
This would seem to give him and the Broad Institute control over the key commercial uses of CRISPR in
humans and research animals. The applicants for the other patent are challenging the ruling.
The easiest sorts of gene therapy will be those that can be done outside the body—ex vivo, in lab speak.
The appeal of ex vivo work is the level of control; cells can be extracted, have their genes manipulated, and
have their new genes tested before being put back. To see the sort of things that this makes possible take a
look at the work being done by Sangamo Biosciences, based in Richmond, California, which has been
working for a decade on an earlier, more cumbersome gene-editing technology that makes use of what are
known as “zinc fingers”. It is trying to apply that technology to beta-thalassaemia, sickle-cell disease,
haemophilia and HIV infection.
In clinical trials of its HIV treatment, Sangamo takes the immune cells that the virus infects out of the
patient’s bloodstream and edits in a mutation that makes them highly resistant to infection. It then grows up
a large number of the edited cells and infuses them back into the patient, where it is hoped they will
flourish. A similar sort of approach can also be used in blood disorders such as beta-thalassaemia and
sickle-cell disease which are caused by mutations in the globin gene. The idea is to extract blood stem cells
from bone marrow, edit them so as to switch on the production of fetal haemoglobin (which the body stops
producing shortly after birth, even if it cannot make the adult stuff) and return the stem cells to the body. It
would be like a bone-marrow transplant—except that since the new genetically improved cells come from
the patient’s own body there is no danger of rejection.
Similar ex vivo approaches could make gene editing a powerful tool for fighting cancer. A currently
promising approach to the disease is to retrofit the immune system’s T cells with what is called a chimeric
antigen receptor (CAR)—a protein that recognises tumours. This CAR-T approach is likely to evolve as
CRISPR makes it possible to add more, or subtler, genetic changes to the T cells. Given the ease and speed
with which RNA guides can be designed and tested, it seems only a matter of time until T cells are tailored
to mutations specific to a particular patient’s cancer.
With blood cells ex vivo approaches work fine, and they may have applications in other diseases, too. But
when it comes, say, to a brain disease there is no way to take the cells out, fiddle about and put them back.
Instead you have to deliver your molecular editing suites to the cells where they live—to do the editing in
vivo. So far attempts at therapeutic in vivo gene editing have been limited in scope. Sangamo has done a
little work in mouse brains, where it has been able to repress the expression of the gene that causes
Huntington’s disease. Intellia has plans to look at in vivo applications that include diseases of the eyes and
nerves, as well as haemophilia and some infectious diseases.
The easiest in vivo applications of gene editing will be diseases where the damaged cells are easy to get
at—for example diseases of the eye. But gene-therapy companies also have strategies for getting at harderto-reach cells, with years of work that could now be applied to the delivery of gene-editing packages. Take
Lysogene, the company Karen Aiach founded after her daughter’s diagnosis with Sanfilippo syndrome. It
has a viral vector which, injected directly into the central nervous system, puts copies of the gene that
children like Ornella lack directly into brain cells.
And then there is the most controversial form of editing—editing the genome of a newly created embryo,
or of the cells that produce sperm and eggs. If this could be done safely it would offer the possibility of
acting once and for all. By changing a gene in an early-stage embryo, or in the cell that makes an egg, you
could ensure that the change is found in every cell in the adult body—including its own eggs or sperm,
which would pass it to the next generation and thus on down through the ages. No one is pursuing such
avenues in the clinic as yet. But the announcement in April that a Chinese group had engineered changes
into non-viable human embryos as part of their research into beta-thalassaemia set alarm bells ringing
Even before that a group of scientists, which included the boss of Sangamo, had published an article in
Nature calling for a voluntary moratorium on all experiments involving germ-line modification. The Centre
for Genetics and Society, a non-profit in Berkeley, California, that supports responsible use of genetic
technologies, opposes using CRISPR to conduct even basic research on embryos. It says that the prospect
of people modified in ways that would be transmitted to their children raises grave safety, social and ethical
concerns, running the risk not just of producing children with unforeseen difficulties because of side-effects
but of opening the door to new forms of social inequality, discrimination and conflict.
Dr Doudna and a number of other eminent molecular biologists, such as David Baltimore of Caltech, have
called for scientists to avoid any attempts at human germ-line modification, even if they are in countries
where regulation might allow it, before there has been a much fuller discussion of the implications. This
would not preclude using the technology for research purposes on embryos created as part of an in-vitro
fertilisation programme and not intended for implantation (in Britain and a number of other countries such
research is allowed on embryos up to 14 days old). Dr Baltimore was part of a group that called, in 1975,
for scientists to refrain from using some of the earliest tools of genetic engineering until rules had been
established; that moratorium is often touted as a worthy example of scientists thinking a new technology’s
implications through before running into a thicket of practical and philosophical issues.
Crossing a line, again
Francis Collins, who runs the National Institutes of Health, America’s main government funder of
biomedical research, said in April that altering the human germ-line for clinical purposes is viewed “almost
universally as a line that should not be crossed”. However this may not be strictly true. Mitochondrial DNA
donation, an in-vitro fertilisation technique that replaces a specific form of defective DNA from the mother
with equivalent DNA from another woman, recently became legal in Britain. Like changes produced by
editing the genome of an egg or early embryo, the effects of this donation will be passed on to future
generations.
The issues surrounding mitochondrial DNA donation were widely discussed in Britain, and the procedure
voted on in parliament. The conclusion was that the risks were small and that helping people carrying
certain diseases to have healthy children mattered more than rather formless worries about “playing God”.
A debate on the merits of using CRISPR for germ-line engineering in cases where there was no alternative
might reach a similarly permissive conclusion. But that would depend on a number of factors.
On the technical front, CRISPR, though good, is not perfect—it can make cuts that are not desired as well
as the ones that are. In research it is fine just to work with the cells and animals that came out perfectly; in
the clinic you need a lower error rate. In germ-line editing, when any errors will end up in every cell in the
body, the problem is particularly worrying. What is more, in most cases where there is a risk of genetic
disease it will be safer, when using in-vitro fertilisation, to choose an embryo that does not have the defect
than edit one that does. Only when there are a number of genes to worry about would editing seem a
plausible option.
Worries about germ-line editing are fascinating, and the discussion they produce may prove important,
divisive or both. But they are far from the realities of today, where genetic disorders that CRISPR might
make amenable to uncontentious forms of gene therapy are destroying lives and parents are fighting to save
their children.
The gene therapy Ornella eventually received from Lysogene came too late to prevent her cognitive
decline. But she smiles and she is gentle, and her nights are almost normal—an improvement over her
earlier years that Ms Aiach puts down to the therapy. In decades to come, the prognosis for others like her
will almost certainly improve. However much the well worry about the nefarious applications of gene
editing, the needs of the sick will continue to drive science and medicine forward—as they should.
SA
Biotech
Money from Genes: CRISPR Goes
Commercial
The new DNA-changing tech has attracted millions of dollars from AstraZeneca, DuPont and other big
companies

By Katrina Megget, ChemistryWorld on January 22, 2016
It was only a matter of time before the technique moved beyond academia, and in
2015 a number of companies have invested in Crispr technology.
Credit: ©iStock
Within just three years since the discovery of its gene-editing potential, the new technique Crispr has
become the hottest, and most controversial, development in genomics research. And now it’s more than just
a science – it’s big business too.
First discovered in bacteria, Crispr (clustered regularly interspaced short palindromic repeats) is a genomeediting tool that can target specific genes in any organism based on RNA–DNA base pairing and then
precisely cut the gene through the activities of the enzyme known as Crispr-associated protein 9 or Cas9.
The technology can delete, repair or replace genes, and is faster, easier, cheaper and – in principle – more
precise than other gene-editing techniques. With potential benefits across human health, agriculture and
industrial biotechnology, it’s no surprise Crispr has entered the biological hall of fame.
Genetic goldrush
It was only a matter of time before the technique moved beyond academia, and in 2015 a number of
companies have invested in Crispr technology. First it was pharma heavyweight Novartis, which signed
two separate deals with gene-editing start-ups Intellia Therapeutics and Caribou Biosciences. It plans to use
Crispr for engineering immune cells and blood stem cells, and as a research tool for drug discovery.
Just weeks after Novartis, fellow drugmaker AstraZeneca sealed four deals with the Wellcome Trust
Sanger Institute, the Innovative Genomics Initiative, the Broad and Whitehead Institutes in Massachusetts,
and Thermo Fisher Scientific. Complementing the company’s in-house Crispr programme, the technology
will identify and validate new targets in preclinical models across a range of disease areas.
Then immunotherapy firm Juno Therapeutics shook hands with gene-editing start-up Editas to create
anticancer immune cell therapies; Vertex Pharmaceuticals and Crispr Therapeutics, another start-up, inked
an agreement that could be valued at $2.6 billion; while Regeneron Pharmaceuticals formed a patent
licence agreement with ERS Genomics, which holds the rights to the foundational Crispr intellectual
property from Emmanuelle Charpentier, one of the Crispr pioneers. The space isn’t only confined to
pharma either, as science company DuPont also formed alliances with Lithuania’s Vilnius University and
Caribou Biosciences, with a specific interest in plant breeding and agricultural applications.
‘Interest from the pharmaceutical industry in Crispr-Cas9 gene editing has really taken off in the last year,’
says Bill Lundberg, chief scientific officer at Crispr Therapeutics. ‘A considerable amount of my time is
spent in discussions with companies and organisations that are interested in working with us.’
Besides these deals, there has also been rapid investment in the start-up firms that aim to commercialise the
Crispr technology and its related products, both through pharma and other sources of funding. Caribou,
founded by Crispr pioneer Jennifer Doudna, has raised $15 million; Crispr Therapeutics, set up by
Charpentier, has raised $89 million since April 2014, plus $105 million through the deal with Vertex; and
Editas, founded by current Crispr patent holder Feng Zhang, has brought in more than $160 million.
While it’s still early days, one analyst tells Chemistry World the technology could be transformative for
companies. ‘The fact a single deal was valued at a potential $2.6 billion tells you something about the
overall size the technology could reach,’ says Anette Breindl, senior science editor at Thomson Reuters
BioWorld.
The commercial potential of Crispr has not been lost on AstraZeneca. It believes the technology offers a
powerful solution to the research and development challenges that plague the pharmaceutical industry, says
company spokeswoman Karen Birmingham. From accelerating the identification and validation of novel
therapeutic targets, to creating better animal models of human diseases in a shorter time frame, to reducing
the number of failed products, Crispr looks set to shave millions off R&D costs and boost drug discovery,
she says. ‘Ultimately, through the application of Crispr we hope to increase productivity in the
pharmaceutical R&D process.’
Likewise in the agricultural space, Crispr promises to develop solutions for growers with greater precision
and accelerated timelines, says Neal Gutterson, vice president of research and development at DuPont
Pioneer. The current average development time for agricultural products ranges from 10 to 20 years, which
makes forecasting grower needs challenging, and the rate of change is accelerating, he says. ‘Crispr-Cas9
genome editing can allow us to respond more rapidly to grower needs and to increase our ability to deliver
higher-yielding crops with the same or fewer resources.’
Patent battle
But amid the surge in research and commercial opportunities, a patent battle over Crispr simmers in the
background, which is casting a shadow over the technology’s future commercial potential. In 2012, Doudna
and Charpentier filed a patent application after working together on Crispr, followed seven months later by
a separate patent application by Zhang. Despite being second to submit, Zhang was awarded the patent
based on his claimed invention date. Now Doudna and Charpentier’s team has been granted an
‘interference review of competing claims’ by the US Patent and Trademark Office to determine who
invented the technology.
It is unclear which way the result will go, says Mari Serebrov, regulatory editor at Thomson Reuters
BioWorld. ‘If the courts rule the technology isn’t patentable, it could chill investment. On the other hand, if
one group is allowed the patent, it could result in a monopoly and will probably make licences more
expensive or discourage research because the patents could lock up the field, depending on how broadly
they are written.’ With such uncertainty, there may be a lull, she says, as people wait to see how the battle
pans out. Already, biotech giant Monsanto has limited Crispr’s applications until a decision is made.
But Greg Aharorian, director of the Centre for Global Innovation/Patent Metrics, believes the dispute won’t
have any serious impact on science and R&D, though he warns the longer the patent battle continues
without a deal the greater the chance new types of gene editing will be discovered, which will ‘potentially
undercut their future profits’. But, ‘if Crispr proves to be useful,’ he adds, ‘it will be used and people will
make money’.
This article is reproduced with permission from Chemistry World. The article was first published on
January 21, 2016
SA
Where to Draw the Line on Gene-Editing
Technology
New techniques that could make germline genetic engineering unprecedentedly easy are forcing
policymakers to confront the ethical implications of moving forward
By Jonathan D. Moreno | November 30, 2015
©iStock.com
The biologists have done it again. Not so long ago it was cloning and embryonic stem cells that challenged
moral imagination. These days all eyes are on a powerful new technique for engineering or “editing” DNA.
Relatively easy to learn and to use, CRISPR has forced scientists, ethicists and policymakers to reconsider
one of the few seeming red lines in experimental biology: the difference between genetically modifying an
individual’s somatic cells and engineering the germline that will be transmitted to future generations.
Instead of genetic engineering for one person why not eliminate that disease trait from all of her or his
descendants?
This week, the U.S. National Academy of Sciences, the Chinese Academy of Sciences, and the U.K. Royal
Society are trying to find ways to redraw that red line. And redraw it in a way that allows the technology to
help and not to hurt humanity. Perhaps the hardest but most critical part of the ethical challenge: doing that
in a way that doesn’t go down a dark path of “improvements” to the human race.
Compared to previous strategies, the technique known as CRISPR (clustered interspaced short palindromic
repeats) is faster, more reliable and cheaper than previous methods for modifying the base pairs of genes.
CRISPR is made up of scissors in the form of an enzyme that cuts DNA strands and an RNA guide that
knows where to make the cut, so the traits expressed by the gene are changed. Already, labs are applying
gene editing in pluripotent stem cells. Older methods are being used to help the human immune system’s T
cells resist HIV, which might be done better with CRISPR. Gene editing trials are also in the offing for
diseases like leukemia. It looks very much like these genies are out of the bottle.
Since the 1960s, technical limitations, the prospect of unintended consequences, and the “eugenic”
implications of deliberate alterations of future generations weighed heavily against germline engineering.
Many countries, including many in Europe, have laws that forbid human germline modification. The
National Institutes of Health won’t pay for such research but there’s no law against using private funds.
China also doesn’t prohibit it.
But over the past 20 years, advances in laboratory techniques, genetic screening for disease traits, and the
prospective fruits of the Human Genome Project have smudged the red line. Gradually, the public health
benefits of changing the human germline have gained as much emphasis as the risks. Some observers have
noted that, aside from the efficiencies that could be realized with germline engineering, the ethical
distinction between germline and somatic cell modification may already be moot, since even somatic cell
modifications can “leak” into effects on gametes. The emergence of CRISPR has made it impossible to
delay more definitive guidance.
Even apart from risks and benefits, are we prepared to modify our genetic heritage with all the implications
for humanity’s relationship to the rest of the natural world? Following a wave of publicity about CRISPR,
last spring a number of scientists and researchers called for a voluntary moratorium on its use. Their
proposal was reminiscent of the Asilomar moratorium on recombinant DNA research in 1975. Asilomar is
commonly (but not universally) thought to have been an effective response on the part of the scientific
community to public fears about biohazards.
But the world of life sciences research is far different now than it was 40 years ago, when the community
was much smaller and more intimate. Sophisticated experimental biology is now a globalized affair.
Funding pressures, the virtually instantaneous availability of experimental procedures and results, and the
fact that researchers may have limited face-to-face contact make self-policing far more challenging than it
once was. Indeed, within weeks of the calls for a moratorium, a Chinese team performed a modification of
non-viable embryos, a proof-of-concept experiment that fell smack into the ethical grey zone and further
shook confidence in the prospects for an effective moratorium.
With events moving so quickly, the summit organized by the U.S. National Academies, along with its
British and Chinese counterparts, will need to face a few key ethical issues. How can technical risks, like
“off target” effects that change an important gene instead of the one intended, be avoided? Are there any
diseases that could justify attempts to diffuse genetic changes in a human population? And who is to make
such monumental decisions on behalf of unborn generations? Recommendations from the Academies aren’t
law but they can establish guiding principles for legitimate scientific practices.
Ten years ago a National Academy of Sciences committee that I co-chaired set rules for doing human
embryonic stem cell research that were voluntarily adopted in many parts of the world. When it comes to
the ethics of science, the scientific community needs to lead but also needs to listen to non-scientists.
Especially in the case of the human germline, one principle worth defending is that between therapy and
enhancement. Even if population-wide disease prevention is sometimes acceptable, attempts to otherwise
“improve” the human race should be banned.
Other principles will apply mainly to agricultural research. Genetically modified plants and animals are the
focus of a parallel National Academies study on the ecological risks of gene drive experiments that might
someday lead to deliberate changes of non-human populations in the wild. New techniques like CRISPR
will make the recently approved fast growing salmon look old fashioned.
The experiments that are both the most promising and the most risky are that those that involve rapidly
propagating species like insects, like eliminating the ability of mosquitoes to carry the malaria parasite.
And accidents are always possible so best biosafety practices will have to be reviewed and strengthened,
including perhaps inbred biological barriers like the “suicide genes” that will cause modified organisms to
die if they escape the lab.
One thing is clear: CRISPR and its descendants will have lives beyond the laboratory.
Jonathan D. Moreno is the David and Lyn Silfen University Professor at the University of Pennsylvania
where he teaches bioethics and the history of science. He is the author of "The Body Politic: The Battle
Over Science in America."
Genome Editing: 7 Facts About a
Revolutionary Technology
What everyone should know about cut-and-paste genetics
By Lucy Odling-Smee, Heidi Ledford, Sara Reardon and Nature magazine |
November 30, 2015
CRISPR-CAS9 gene editing complex from Streptococcus pyogenes.
©iStock.com
The ethics of human-genome editing is in the spotlight again as a large international meeting on the topic
is poised to kick off in Washington DC. Ahead of the summit, which is being jointly organized by the US
National Academy of Sciences, the US National Academy of Medicine, the Chinese Academy of Sciences
and Britain’s Royal Society and held on December 1–3, we bring you seven key genome-editing facts.
1. Just one published study describes genome editing of human germ cells
In April, a group led by Junjiu Huang at Sun Yat-sen University in Guangzhou, China, described their use
of the popular CRISPR–Cas9 technology to edit the genomes of human embryos. Only weeks before the
researchers’ paper appeared in Protein & Cell, rumours about the work had prompted fresh debate over the
ethics of tinkering with the genomes of human eggs, sperm or embryos, known collectively as germ cells.
Huang and colleagues used non-viable embryos, which could not result in a live birth. But in principle,
edits to germ cells could be passed to future generations.
2. The law on editing human germ cells varies wildly across the world
Germany strictly limits experimentation on human embryos, and violations can be a criminal offence. By
contrast, in China, Japan, Ireland and India, only unenforceable guidelines restrict genome editing in
human embryos. Many researchers long for international guidelines, and some hope that the upcoming
summit in Washington DC could be the start of the process to create them.
3. You don’t have to be a pro to hack genomes
The CRISPR–Cas9 technology has made modifying DNA so cheap and easy that amateur biologists
working in converted garages or community laboratories are starting to dabble.
4. Cas9 is not the only enzyme in town
A key ingredient in the CRISPR–Cas9 system is the DNA-cutting enzyme Cas9. But in September,
synthetic biologist Feng Zhang at the Broad Institute of MIT and Harvard in Cambridge,
Massachusetts, reported the discovery of a protein called Cpf1, which may make it even easier to edit
genomes. (Zhang is one of those who pioneered the use of CRISPR-Cas9 for genome editing in
mammalian cells).
5. Pigs are on the front line of genome-editing experiments
Dogs, goats and monkeys are all part of the growing CRISPR zoo. But pigs in particular have been at the
heart of several eye-catching announcements—from micropigs that weigh about six times less than many
farm pigs, to super-muscly pigs, to a pig whose genome has been edited in 62 places (the aim being to
produce a suitable non-human organ donor).
6. Gates, Google and DuPont want a piece of the genome-editing action
In August, several high-profile investors, including the Bill & Melinda Gates Foundation and Google
Ventures, pumped US$120 million into the genome-editing firm Editas Medicine of Cambridge,
Massachusetts. Big Agriculture is following suit: DuPont forged an alliance with the genome-editing firm
Caribou Biosciences of Berkeley, California, in October, and announced its intention to use CRISPR–Cas9
technology to engineer crops.
7. The CRISPR–Cas9 system is at the centre of a patent row
Zhang was granted a US patent on CRISPR–Cas9 in April 2014. But several months before he filed his
application in 2012, molecular biologists Jennifer Doudna at the University of California (UC), Berkeley,
and Emmanuelle Charpentier, now at the Max Planck Institute for Infection Biology in Berlin, had filed
their own patent. UC Berkeley has since requested that the United States Patent and Trademark Office
determine who should get credit for harnessing the CRISPR–Cas9 system, in particular for its application
in human cells. And a similar debate is playing out in Europe, where oppositions to a patent that Zhang and
his colleagues won in February have been filed. All three scientists co-founded companies that make use of
CRISPR–Cas9.
This article is reproduced with permission and was first published on November 30, 2015.
NYT
A Pause to Weigh Risks of Gene Editing
By THE EDITORIAL BOARDDEC. 18, 2015
Photo
A model of a protein used in gene-editing research. Credit Evan Oto/Science Source
The technology for altering defects in the human genome has progressed so rapidly in the last three years
that it has outstripped the ability of scientists and ethicists to understand and cope with the consequences.
An international panel of experts has wisely called for a pause in using the technique to produce genetic
changes that could be inherited by future generations. That would allow time to assess risks and benefits,
they said, and develop a “broad societal consensus” on the work.
The revolutionary new technology, known as Crispr-Cas9, allows scientists to easily eliminate or replace
sections of DNA with great precision, much as a word processing program can edit or replace words in a
text. The issue is whether to use the technique to alter human eggs, sperm or early embryos in ways that
would be passed on, a process that is called germline editing.
Related Coverage

Scientists Seek Moratorium on Edits to Human Genome That Could Be
InheritedDEC. 3, 2015
The technology has the potential to prevent devastating hereditary diseases that are caused by a single
defective gene that can be edited out of the germline and replaced with a correct version. In the case of
Huntington’s disease, which causes a progressive breakdown of nerve cells in the brain, the technology
could protect all children in the family, who would otherwise face a 50/50 chance of inheriting the disease.
The technique is not considered to be of value for diseases like cancer and diabetes, or for altering traits
like intelligence, in which the hereditary component is caused by many different genes.
The international panel calling for a pause met in Washington this month at the National Academy of
Sciences and was jointly convened by the Chinese Academy of Sciences and the Royal Society of London.
The academies have no regulatory power, but their recommendations are expected to be followed by most
scientists.
The technology is a tremendous accomplishment, but there are dangers in rushing to use it before the risks
are understood. Chinese scientists attempted to alter genes in human embryos that cause a blood disorder,
beta thalassemia, in an experiment deemed ethical by a Chinese national committee because the embryos
were not viable. The editing technique ran amok and cut the DNA at many unintended sites. That may be a
temporary setback as subsequent advances have reduced off-target editing.
The panel left a path for the technology to move forward once a vigorous program of basic research has
resolved lingering questions. That seems sensible given that many biomedical advances, like in vitro
fertilization and stem cell research, raised concerns at the start but ultimately proved valuable and became
widely accepted.
SA
The Embarrassing, Destructive Fight
over Biotech's Big Breakthrough
The gene-editing technology known as CRISPR has spawned an increasingly unseemly brawl over who
will reap the rewards

By Stephen S. Hall on February 4, 2016
Illustration by Scott Brundage
A defining moment in modern biology occurred on July 24, 1978, when biotechnology pioneer Robert
Swanson, who had recently co-founded Genentech, brought two young scientists to dinner with Thomas
Perkins, the legendary venture capitalist. As they stood outside Perkins’s magnificent mansion in Marin
County, with its swimming pool and garden and a view of the Golden Gate Bridge, Swanson turned to his
two young colleagues and said, “This is what we’re all working for.”
That scene came to mind as I sorted through the tawdry verbal wreckage on social media and in print of the
“debate” over CRISPR, the revolutionary new gene-editing technology. The current brouhaha, triggered by
Eric Lander’s now-infamous essay in Cell called “The Heroes of CRISPR,” is the most entertaining food
fight in science in years.
The stakes are exceedingly high. CRISPR is the most important new technology to hit biology since
recombinant DNA, which launched Genentech, made Swanson, along with his colleagues and investors,
rich and brought molecular biology, long the province of academia, into the realm of celebrity and big
money. In this context, the Cell essay has huge patent and prize implications. Lander has been accused of
writing an incomplete and inaccurate history of the CRISPR story, burnishing the patent claims of the
Broad Institute in Cambridge, Mass., (he is its director) and minimizing the contributions of rival scientists.
A blogger has referred to him as “an evil genius at the height of his craft.” And George Church, a colleague
at the Broad Institute, likens Lander to a figure out of a Greek tragedy. “The only person that could hurt
him was himself,” he says. “He was invulnerable to anybody else’s sword.” And you thought scientists
couldn’t talk smack.
Spectators, scientific and otherwise, have followed this bitter dispute with fascination but the fight is
destructive--and far from over. In waging a nasty public battle over CRISPR, the protagonists have given
science a black eye for the reason Swanson suggested on that long-ago night in Marin County: money and
glory. In waging a nasty public fight over CRISPR, they have already attracted the scrutiny of the
mainstream press (The Washington Post and the Boston Globe Media’s STAT, to name two avid voyeurs),
the scientific press and, oh boy, the Internet. The trash talking has undermined the public image of science,
raised unflattering questions about the motives of scientists and institutions and, less obviously, fueled
doubts about the judgment of leading scientific journals, which act as unofficial auditors of the billions of
taxpayer dollars spent on biological research. The spat is like an escalating and increasingly ugly domestic
dispute: no one wants outsiders to get involved but the screaming has gotten so loud that somebody has to
call the cops. The fight over CRISPR is getting to that point. Woe be it to science if the politicians step in
and use the fight as an excuse to rethink funding or the rules of technology transfer.
The scientific story has deep roots. Scientists glimpsed the first hint of CRISPR biology in the 1980s and
primitive forms of gene-editing arose in the 1990s. But a crucial leap occurred in 2012 when a group led by
Jennifer Doudna of the University of California, Berkeley, and Emmanuelle Charpentier, now at the Max
Planck Institute for Infection Biology in Berlin, demonstrated the possibility of simple CRISPR-based
gene-editing to a broad audience of scientists with a paper in Science. The University of California and the
University of Vienna filed for a patent, listing Doudna, Charpentier and other individuals. But the U.S.
Patent and Trademark Office issued a patent in 2014 to Feng Zhang of the Broad Institute, which filed its
application after Berkeley but requested expedited consideration. The University of California has
challenged the validity of all the Broad patents (now numbering about a dozen) and the ensuing
“interference” proceedings may allow another year of trash talking by scientists and bloggers alike.
Meanwhile the protagonists—and their institutional proxies—continue to jockey for priority, prizes and
reputation.
Against this backdrop, Lander’s piece came as a shock. Lander is director of the Broad Institute and
therefore someone with a very big dog in the patent fight. Maybe by calling it a “Perspective” the editors of
Cell were signaling Lander’s obvious conflict of interest; nothing else in the article did.
Let me note, first, that “The Heroes of CRISPR” is beautifully written. In addition to being a fabulous
scientist and truly visionary thinker, Lander is a terrific communicator. His history reads at times like highend magazine journalism (the story begins in Spain’s Costa Blanca, “where the beautiful coast and vast salt
marshes have for centuries attracted vacationers, flamingoes and commercial salt producers”) with almost
novelistic detail (Zhang, born in China and reared in Des Moines, has his eureka moment while “holed up”
in a Miami hotel)—not your average journal prose. Lander’s account of the early work on CRISPR, often
overlooked, is thorough, accurate and generous, according to people who know the history well. And it’s
written as a feel-good story with an inspirational take-home message: People who work off the beaten
track, in both the geographic and biological sense, often make dramatic contributions to the “remarkable
ecosystem underlying scientific discovery,” he notes. Scientific breakthroughs are “ensemble acts” that
unfold over many years. “It’s a wonderful lesson for the general public,” Lander concludes, “as well as for
a young person contemplating a life in science.”
Beautifully put. So why did the Twitterverse go radioactive on Lander within hours of the article’s
publication on January 14?
As I often suggest to students in my science journalism classes, just because a story is beautifully
written doesn’t mean that it is true—in whole or in part. Judging from the firestorm of criticism,
“The Heroes of CRISPR” falls short on a number of issues, beginning with this awkward moneytinged paradox: If the CRISPR story (and science in general) is such a beautiful ensemble activity,
why is there only one name on the Broad Institute’s patent? Well, patents have to do with money,
and money turns a lot of beautiful scientific stories into ugly legal narratives.
Case in point: in 1979, a year after Bob Swanson’s pep talk to his Genentech biologists, a biologist
then at Columbia University named Michael Wigler published a very clever method (called “cotransformation”) for smuggling genes into eukaryotic cells; the university filed a patent application
in 1980, with Wigler and two colleagues as inventors, and received the first of several patents in 1983.
Like CRISPR, the technique may sound esoteric but biologists (and companies) quickly recognized
its value, and Columbia ultimately reaped nearly $800 million from those patents. (Other, unofficial
estimates run between $1 billion and $1.5 billion.) Columbia became so enamored of the revenue
stream that it resorted to several controversial tactics, including having a U.S. senator try to extend
the patent by slipping language into an agricultural bill. These maneuvers prompted an uproar and
were later characterized, by historians of genomics Robert Cook-Deegan and Alessandra Colaianni,
both then at Duke University, as “behavior unbecoming a nonprofit academic institution.”
Wigler, who now runs a lab at Cold Spring Harbor Laboratory, says of the Columbia patent: “Of course it’s
had an impact on institutions, because institutions are desperate for money.” That’s why the University of
California and the Broad Institute (a joint venture of Harvard University and Massachusetts Institute of
Technology) will fight fiercely—“red in tooth and claw,” you might say—to claim intellectual property on
CRISPR.
Many readers (including me) interpreted Lander’s elegant history of CRISPR as a calculated
attempt to elevate the intellectual contribution of Zhang (the Broad Institute scientist who is
recognized, for the moment, by the patent office as the lone “inventor” of CRISPR) as it minimizes
the contributions of Doudna and Charpentier. (Zhang’s discovery narrative is long, detailed and
colorful; Doudna’s appearance comes in the middle of a paragraph, and her work doesn’t get nearly the
same star treatment.) In other words, this beautifully crafted history can also be read as a patent brief in
disguise. (A blog by science historian Nathaniel Comfort shrewdly deconstructs the rhetoric used by
Lander to advance Broad’s interests. Inexplicably, Cell didn’t even mention Lander’s flagrant conflict of
interest (an instance of editorial neglect to which we’ll return later).
Both Doudna and Charpentier quickly posted frostily brief comments to PubMed Commons; Doudna
claimed the description of her lab’s work was “factually incorrect,” and Charpentier characterized her part
of the story as “incomplete and inaccurate.” Church, whose Harvard lab published on the utility of CRISPR
gene-editing in mammalian cells at the same time as Zhang’s, disputed Lander’s history as well in press
accounts. When I spoke with Church about a week after the Cell article came out, he was not shy about
itemizing. “Normally I’m not so nitpicky about all these errors,” he said. “But as soon as I saw that they
[Lander and Cell] were not giving the young people, the people who actually did the work, and Jennifer
and Emmanuelle, adequate credit, I just said, ‘No, I have to correct what I know to be false.’” (Lander was
“delighted” to append Church’s clarifications to the Cell article). Church acknowledged that the essay was
“exquisitely crafted,” but crafted, in his view, with an ulterior motive. “It was like, ‘I’m going to prove my
point of view,’” he said. But according to Church, Lander may have achieved the exact opposite effect. “I
think Jennifer and Emmanuelle deserve a lot of credit,” he said. “And the more you try to take it from them,
the more people want to give it to them.”
In truth, there are a lot of moving parts and proxies in this messy battle. The hostilities involve institutions
(M.I.T. and Harvard versus University of California), gender (Doudna, Charpentier, Zhang), geography
(east versus west coast) and what you might call über-institutions (the Broad Institute, which has become
an empire of genomic research under Lander’s direction, especially after his leading role in the Human
Genome Project, versus the Howard Hughes Medical Institute, whose president, Robert Tjian, is based at
Berkeley and has co-authored at least one CRISPR paper with Doudna, also an HHMI investigator).
Probably because of this combustible mix of interests, the debate over the Cell article has become
especially nasty; whatever used to be the line of decorum in scientific debate, it was breached within 24
hours after the Cell article appeared.
Some viewed Lander’s history as a gender diss. The title of a post on the Web site Jezebel says it all: “How
One Man Tried to Write Women Out of CRISPR, the Biggest Biotech Innovation in Decades.” Others saw
it as shameless politicking for a Nobel Prize.
And a lot of the invective has been surprisingly personal. Michael Eisen, an HHMI researcher at Berkeley,
has been particularly outspoken in his blog. The Cell essay was “an elaborate lie,” Eisen wrote on January
25, and his attack didn’t stop there.
Lander is in Antarctica and unavailable for comment, according to a Broad Institute spokesperson. But in
an e-mail to the Broad staff on January 28 he reiterated his pride in writing the essay and added: "Needless
to say, 'Perspective' articles are personal opinions. Not everyone will fully agree with anyone else's point of
view. In the end, we come to understand science only by integrating a diverse range of thoughtfully
expressed perspectives. And, when scientific discovery is also the subject of patent disputes (as is the case
with U.C. Berkeley and Broad–M.I.T.), intellectual disagreements can, as here, give rise to vigorous online
discussion." As for the conflict-of-interest issue, Broad spokesperson Lee McGuire noted that Lander had
previously "disclosed the fact that he has no personal financial interest and that the institute he represents
does license CRISPR technologies."
The dirty truth is that long before Lander’s Cell article the scientific community has been watching this
food fight—for patent dollars, for credit, for prizes—with increasing dismay. Both Zhang and Doudna have
been subtly lobbying for recognition in what one scientist characterized to me, dismissively, as “their little
Nobel talks—they don’t give seminars anymore.” Doudna, Charpentier and Zhang are all outstanding
researchers and very likable people but they appear caught up in the vortex of scientific politics and
recognition spin. If it were your work and someone was trying to devalue it, you’d defend it to the hilt, too.
But the ongoing drama is not a good look for science, and some of the “heroes of CRISPR” are wearing out
their welcome on the public stage. “This is not David versus Goliath,” one disgusted scientist told me
recently. “This is Goliath against Goliath. These two camps deserve each other, and they can bully each
other into oblivion.”
Why would such a shrewd and strategic thinker like Lander tempt such a public backlash by writing such a
cleverly slanted history? Perhaps his ultimate audience was not Cell’s readers nor even the scientific
community at large but rather a very small (and select) group of readers in Alexandria, Va. A gifted writer,
Lander set out to produce a seemingly neutral and magnanimous history of CRISPR that even an examiner
at the U.S. Patent and Trade Office could understand. (If this sounds condescending, consider how Wigler
summarizes 35-plus years of dealing with the patent system: “My general experience with the patent office
is that they don’t get it. They don’t understand this stuff.”)
The Lander article has inflicted some surprising collateral damage, notably to scientific publishing itself.
Cell’s decision to publish the article, despite the Broad’s clear financial interest in the patent dispute,
invited withering criticism. (The journal stated that it "regularly" evaluates its policies, and "will include"
in that process the role of institutional conflicts of interest.) And if CRISPR is “the century’s biggest
biotech innovation,” as a blogger for The Washington Post recently noted, what does it say about the
quality of scientific journals that in at least 10 instances “seminal papers,” according to Lander’s Cell
article, were rejected by journals like Nature, Proceedings of the National Academy of Sciences and even
Cell itself? In many cases, editors at these journals did not even send out the articles for peer review.
Virtually all this research is paid for at least in part by public money, which raises an inconvenient
question: Is the public interest served by journals that don’t even recognize scientific excellence? Does Cell
even give a hoot about public perception? Here’s what one prominent scientist told me about Cell’s
handling of the entire episode: “All they care about is how many times the article is cited in their citation
index.” That and the traffic on Twitter.
That may hint at why the CRISPR dispute is so different, and so dangerous to the scientific community.
Trash talking has been a part of science for centuries; Newton’s seemingly magnanimous remark that he
stood “on the shoulders of giants” was, to the contrary, likely understood by his contemporaries to be a
disparaging reference to the short stature of his main rival, Robert Hooke. But invective today gets
amplified and disseminated so rapidly that it assumes a public life of its own, and scientific spats become a
reality show complete with egos, self-promotion, greed and Machiavellian stratagems dissected in blogs, on
social media and on bulletin boards.
And then there’s the influence of money. Since the summer of 1978 biotechnology has bestowed untold
riches on companies, institutions and individual biologists. It has produced thrilling science and some
wonderful (albeit pricey) new medicines. But it has also slowly eroded boundaries between appropriate and
inappropriate behavior. Scientific narratives used to be cast in the past tense, about what had been
accomplished; now the storytelling is in the future tense to raise venture capital (or, in the case of ‘Heroes,”
in what might be called the past imperfect to advance a patent claim). Hype used to be frowned on; now it
is part of every business plan. Since at least the 1990s biotech companies have tried to influence university
research, and it is a commonplace that the pharmaceutical industry dictates the terms of much academic
clinical research. Students, already demoralized by scarce funding and no jobs, fret over whether basic
research (of the sort that produced CRISPR in the first place) will be as esteemed as “patentable” work—
and if their names will even be included on the patent. And the red flags that used to signal conflicts of
interest are so frayed that you can essentially see right through them. It’s not that Cell should have had a
stricter policy about conflicts of interest, it’s that a protagonist in the patent dispute probably shouldn’t
have attempted to write a history of CRISPR in the first place. After the Lander article was published Cell
posted a statement on its Web site saying Lander had indeed communicated that his institutional
affiliations—Broad, M.I.T. and Harvard—had patents and patent applications related to CRISPR but that
the journal only considers "personal" conflicts of interest.
There is currently a lull in the CRISPR hostilities; no one has flamed anyone, by my count, in the last 72
hours. But that probably won’t last long. The patent interference, in which University of California lawyers
will probably claim that its scientists invented CRISPR gene-editing and also applied for a patent before
Broad, will be hotly contested. Maybe this little pause is an opportunity for a reset—a chance for the
scientific community to acknowledge that the CRISPR system, as some have quietly suggested all along,
was actually “invented” by bacteria eons ago as an ingenious immune response to viral infection, and that
its rediscovery was accomplished by so many heroic (if you will) hands and with so much public coin that
the technology ultimately belongs in the public commons and should not be patented and…
…Sorry, I got a little carried away there. Yes, it would be nice if the transformative power of CRISPR
remained in the public domain; maybe we could even invent a new prize—the Rashomon Prize!—that
recognizes all the key players, no matter how contradictory or self-serving their stories. But in the current
ecosystem of biology, where institutions are indeed desperate for money and the rules of the game create
winner-take-all slugfests, that is very unlikely to happen.
Stephen S. Hall is the author of Invisible Frontiers: The Race to Synthesize a Human Gene, an account of
the birth of biotechnology, and five other books. He teaches science writing (to journalism students) and
science communication (to scientists) at New York University
MIT TR

Biomedicine
The Scientific Swap Meet Behind the Gene-Editing Boom
How one nonprofit’s mailroom is making tinkering with genomes as easy as shopping at Amazon.


by Antonio Regalado
April 8, 2016
The gene-editing technology called CRISPR is probably the fastest-spreading technology in the history of
biology.
Here’s one reason why: each weekday at 8 a.m. at the offices of AddGene in Cambridge, Massachusetts,
interns start loading UPS packages containing the raw DNA material needed for gene-editing, sending it as
far away as Zimbabwe and Croatia.
AddGene is a nonprofit that exists to help scientists share their DNA inventions. Think of it as an
Amazon.com for biological parts. Anyone can submit one—or order someone else’s part for $65.
Easy access to gene-editing technology is what has allowed labs everywhere to get into the game. Last
year, there were more than 1,300 scientific papers on CRISPR, and it’s been used to do everything from
curing muscular dystrophy in mice to making super-muscled beagles.
And remember those Chinese scientists who set off an ethical firestorm by editing human embryos? They
got their ingredients by mail order from AddGene, too.
AddGene was started in 2004 by a graduate student, Melina Fan, who got tired of trying to beg and barter
for key materials she needed. Why not create a central repository to which everyone can contribute?
“Sharing is something that people don’t talk about enough,” says Patrick Hsu, a biologist at the Salk
Institute. “It dramatically sped up CRISPR adoption. In a way, AddGene shows you why it’s worth fighting
over. It’s in everyone’s hands and changing everything.”
To be sure, there’s a nasty patent battle playing out over who controls the commercial rights to CRISPR.
But that doesn’t affect sharing between labs, since patents don’t directly restrict what basic scientists can
do.
Faster sharing is part of an open science movement changing biology. Instead of keeping results under
wraps for a year waiting for a big Nature paper, biologists have started to follow the lead of physicists, who
are popping papers onto “pre-print” servers so everyone can have a look and offer feedback.
Here’s how it works: the language of DNA is a code, but it’s physical. It’s made up of strings of chemical
bases labelled A, G, C, and T. To ship it, AddGene mails out vials of E. coli bacteria with the valuable bits
of DNA spliced into mini-chromosomes, known as plasmids.
There are about 45,000 plasmids to choose from. Want to make a mouse’s brain cells react to light? That’s
plasmid number 20298, deposited by Karl Deisseroth, the famed co-inventor of optogenetics at Stanford.
Need to turn off every gene in a fruit fly, one by one? That’s number 64750.
Behind the CRISPR craze is the mailroom
at AddGene, which sends out DNA to more than 250 labs a day.
The most frequently ordered DNA of all the code is to make Cas9, the editing protein used in CRISPR.
Since 2013, the ingredients for CRISPR have been sent out more than 60,000 times, says Joanne Kamens,
AddGene’s executive director. Once a lab has bacteria harboring the gene, it can make more. It’s a
renewable resource.
Hsu, who is currently setting up his lab in California, had just ordered 10 plasmids the day I spoke to him.
He typed in his name and telephone number and hit “purchase.” AddGene made such exchanges easier by
putting in place cookie-cutter legal agreements. For research centers like Salk that sign on, ordering genetic
material from another university is a one-click affair rather than a trip to the legal department. “The
ingenious part was to get the paperwork out of the way,” says Hsu.
The sharing of these genetic gadgets doesn’t extend to companies, since universities still hope to charge
them. Hsu says that when he worked at gene-editing startup Editas Medicine, also in Cambridge, he
couldn’t order from AddGene. Instead he had to laboriously re-create long stretches of DNA he needed. “I
was synthesizing DNA with VC dollars,” he says.
The idea of synthetic biology—mixing and matching biological parts to make stuff —has led to a lot of
heavy breathing in the media. “Biological Legos” we’re told, will turn life into mere “plug-and-play.” A
well-known annual synthetic biology competition, iGEM, asks students to build things like flashing
bacteria using defined DNA parts that come in a kit.
In reality, biology isn’t as tidy as an Ikea kit. Researchers say AddGene became biology’s de facto parts
store by solving practical problems. “[It’s] for practicing scientists,” says Bruce Shay, a genetic engineer at
Carnegie Mellon University, who submitted DNA this year so others can use a technique he created to
make cells glow. “They love the chaos. They are about collecting disorder.”
If AddGene weren’t a nonprofit, it would be a decent business. It sold $8 million worth of DNA
instructions last year, and banked a $2 million surplus. Kamens says it will invest the extra money to
expand its efforts.
Science
Researchers still have a ways to go before using CRISPR to repair genes in patients.
iStock
The gene editor CRISPR won’t fully fix
sick people anytime soon. Here’s why
By Jocelyn KaiserMay. 3, 2016 , 3:15 PM
This week, scientists will gather in Washington, D.C., for an annual meeting devoted to gene therapy—a
long-struggling field that has clawed its way back to respectability with a string of promising results in
small clinical trials. Now, many believe the powerful new gene-editing technology known as CRISPR will
add to gene therapy’s newfound momentum. But is CRISPR really ready for prime time? Science explores
the promise—and peril—of the new technology.
How does CRISPR work?
Traditional gene therapy works via a relatively brute-force method of gene transfer. A harmless virus, or
some other form of so-called vector, ferries a good copy of a gene into cells that can compensate for a
defective gene that is causing disease. But CRISPR can fix the flawed gene directly, by snipping out bad
DNA and replacing it with the correct sequence. In principle, that should work much better than adding a
new gene because it eliminates the risk that a foreign gene will land in the wrong place in a cell's
genome and turn on a cancer gene. And a CRISPR-repaired gene will be under the control of that gene’s
natural promoter, so the cell won’t make too much or too little of its protein product.
What has CRISPR accomplished so far?
Researchers have published successes with using CRISPR to treat animals with an inherited liver disease
and muscular dystrophy, and there will be more such preclinical reports at this week’s annual meeting of
the American Society of Gene and Cell Therapy (ASGCT). The buzz around CRISPR is growing. This
year’s meeting includes 93 abstracts on CRISPR (of 768 total), compared with only 33 last year. What’s
more, investors are flocking to CRISPR. Three startups, Editas Medicine, Intellia Therapeutics, and
CRISPR Therapeutics, have already attracted hundreds of millions of dollars.
So why isn’t CRISPR ready for prime time?
CRISPR still has a long way to go before it can be used safely and effectively to repair—not just disrupt—
genes in people. That is particularly true for most diseases, such as muscular dystrophy and cystic fibrosis,
which require correcting genes in a living person because if the cells were first removed and repaired then
put back, too few would survive. And the need to treat cells inside the body means gene editing faces many
of the same delivery challenges as gene transfer—researchers must devise efficient ways to get a working
CRISPR into specific tissues in a person, for example.
CRISPR also poses its own safety risks. Most often mentioned is that the Cas9 enzyme that CRISPR uses
to cleave DNA at a specific location could also make cuts where it’s not intended to, potentially causing
cancer.
With these caveats, do you even need CRISPR?
Conventional gene addition treatments for some diseases are so far along that it may not make sense to start
over with CRISPR. In Europe, where one gene therapy is already approved for use for a rare metabolic
disorder, regulators are poised to approve a second for an immune disorder known as adenosine
deaminase–severe combined immunodeficiency (SCID). And in the United States, a company this year
expects to seek approval for a gene transfer treatment for a childhood blindness disease called Leber
congenital amaurosis (LCA).
At the ASCGT meeting, researchers working with the company Bluebird Bio will present interim data for a
late-stage trial showing that gene addition can halt the progression of cerebral adrenoleukodystrophy, a
devastating childhood neurological disease. Final results could help pave the way for regulatory approval.
Bluebird will also report on trials using gene transfer for two blood disorders, sickle cell disease and βthalassemia, bringing these treatments closer to the clinic.
Except for LCA, in which gene-carrying viruses are injected directly into eyes, these diseases are treated by
removing bone marrow cells from patients, adding a gene to the cells, and reinfusing the cells back into the
patient. New, safer viral vectors have reduced risks of leukemia seen in a few patients in some early trials
for immunodeficiency diseases. Researchers are seeing “excellent clinical responses,” says Donald Kohn of
the University of California, Los Angeles.
Although Kohn and other researchers have used an older gene-editing tool known as zinc finger nucleases
to repair defective genes causing sickle cell disease and a type of SCID in cells in a dish, only a tiny
fraction of immature blood cells needed for the therapy to work end up with the gene corrected—far below
the fraction altered by now standard gene transfer methods. One reason is because the primitive blood cells
aren’t dividing much (more on this below). Because gene-editing methods such as CRISPR are so much
less efficient than gene addition, for several diseases, “I don’t think there will be a strong rationale for
switching to editing,” says Luigi Naldini of the San Raffaele Telethon Institute for Gene Therapy in Milan,
Italy.
CRISPR also has other issues
Using CRISPR to cut out part of a gene—not correct the sequence—is relatively easy to do. In fact, this
strategy is already being tested with zinc finger nucleases in a clinical effort to stop HIV infection. In this
treatment, the nucleases are used to knock out a gene for a receptor called CCR5 in blood cells that HIV
uses to get into cells.
But when CRISPR is used to correct a gene using a strand of DNA that scientists supply to cells, not just to
snip out some DNA, it doesn’t work very well. That’s because the cells must edit the DNA using a process
called homology-directed repair, or HDR, that is only active in dividing cells. And unfortunately, most cells
in the body—liver, neuron, muscle, eye, blood stem cells—are not normally dividing. For this reason,
“knocking out a gene is a lot simpler than knocking in a gene and correcting a mutation,” says Cynthia
Dunbar, president-elect of ASGCT and a gene therapy researcher at the National Heart, Lung, and Blood
Institute in Bethesda, Maryland.
Researchers are working on ways to get around this limitation. The genes for HDR are present in all cells,
and it’s a matter of turning them on, perhaps by adding certain drugs to the cells, says CRISPR researcher
Feng Zhang of the Broad Institute in Cambridge, Massachusetts. Another avenue is to find alternatives to
the Cas9 system that don’t rely on the HDR process, Zhang says.
But the low rate of HDR in most cells is one reason why the first use of CRISPR in the clinic will likely
involve disrupting genes, not fixing them. For example, several labs have shown in mice that CRISPR can
remove a portion of the defective gene that causes Duchenne muscular dystrophy, so that the remaining
portion will produce a functional, albeit truncated protein. Editas hopes to start a clinical trial next year to
treat a form of LCA blindness by chopping out part of the defective gene. One proposed gene-editing
treatment for sickle cell disease would similarly snip out some DNA, so that blood cells produce a fetal
form of the oxygen-carrying protein hemoglobin.
And CRISPR still has big safety risks
The most-discussed safety risk with CRISPR is that the Cas9 enzyme, which is supposed to slice a specific
DNA sequence, will also make cuts in other parts of the genome that could result in mutations that raise
cancer risk. Researchers are moving quickly to make CRISPR more specific. For example, in January, one
lab described a tweak to Cas9 that dramatically reduces off-target effects. And in April in Nature, another
team showed how to make the enzyme more efficient at swapping out single DNA bases.
But immediate off-target cuts aren’t the only worry. Although it’s possible to deliver CRISPR’s
components into cells in a dish as proteins or RNA, so far researchers can usually only get it working in
tissue inside the body by using a viral vector to deliver the DNA for Cas9 into cells. This means that even
after Cas9 has made the desired cuts, cells will keep cranking it out. “The enzyme will still hang around
over 10, 20 years,” Zhang says. That raises the chances that even a very specific Cas9 will still make offtarget cuts and that the body will mount an immune response to the enzyme.
This may not truly be a problem, Zhang suggests. His team created a mouse strain that is born with the
gene for Cas9 turned on all the time, so it expresses the enzyme in all cells for the animal’s entire life. Even
after interbreeding these mice for about 20 generations, the mice “seem to be fine” with no obvious
abnormal health effects, Zhang says. All the same, “the most ideal case is, we want to shut off the enzyme.”
And that may mean finding nonviral methods for getting Cas9 into cells, such as ferrying the protein with
lipids or nanoparticles—delivery methods that biologists have long struggled to make work in living
animals.
Other long-standing obstacles to gene therapy will confront efforts using CRISPR, too. Depending on the
disease, any gene-edited cells may eventually die and patients could have to be treated multiple times.
Researchers using gene transfer and editing approaches are also both hindered by limits on how much DNA
a viral vector can carry. Right now CRISPR researchers often must use two different viruses to get
CRISPR’s components into cells, which is less efficient than a single vector.
So what’s the bottom line?
Gene therapists remain excited by CRISPR, in part because it could tackle many more inherited diseases
than can be treated with gene transfer. Among them are certain immune diseases where the amount of the
repaired protein must be precisely controlled. In other cases, such as sickle cell disease, patients won’t get
completely well unless a defective protein is no longer made by their cells, so just adding a gene isn’t
enough. “It opens up a lot of diseases to gene therapy because gene addition wasn’t going to work,” Dunbar
says.
After more than 2 decades of seeing their field through ups and downs, veterans of the gene therapy field
are wary of raising expectations about CRISPR for treating diseases. “Whenever there’s a new technology,
there’s a huge amount of excitement and everybody thinks it will be ready tomorrow to cure patients,” says
gene therapy researcher Mark Kay of Stanford University in Palo Alto, California. “It’s going to take some
time.”
NYT
Scientists Talk Privately About Creating a
Synthetic Human Genome
By ANDREW POLLACKMAY 13, 2016
Sixty trays can contain the entire human genome as 23,040 different fragments of
cloned DNA. Credit James King-Holmes/Science Source
Scientists are now contemplating the fabrication of a human genome, meaning they would use chemicals to
manufacture all the DNA contained in human chromosomes.
The prospect is spurring both intrigue and concern in the life sciences community because it might be
possible, such as through cloning, to use a synthetic genome to create human beings without biological
parents.
While the project is still in the idea phase, and also involves efforts to improve DNA synthesis in general, it
was discussed at a closed-door meeting on Tuesday at Harvard Medical School in Boston. The nearly 150
attendees were told not to contact the news media or to post on Twitter during the meeting.
Organizers said the project could have a big scientific payoff and would be a follow-up to the original
Human Genome Project, which was aimed at reading the sequence of the three billion chemical letters in
the DNA blueprint of human life. The new project, by contrast, would involve not reading, but rather
writing the human genome — synthesizing all three billion units from chemicals.
But such an attempt would raise numerous ethical issues. Could scientists create humans with certain kinds
of traits, perhaps people born and bred to be soldiers? Or might it be possible to make copies of specific
people?
“Would it be O.K., for example, to sequence and then synthesize Einstein’s genome?” Drew Endy, a
bioengineer at Stanford, and Laurie Zoloth, a bioethicist at Northwestern University, wrote in an essay
criticizing the proposed project. “If so how many Einstein genomes should be made and installed in cells,
and who would get to make them?”
Dr. Endy, though invited, said he deliberately did not attend the meeting at Harvard because it was not
being opened to enough people and was not giving enough thought to the ethical implications of the work.
Related Coverage

Scientists Seek Moratorium on Edits to Human Genome That Could Be
Inherited DEC. 3, 2015

British Researcher Gets Permission to Edit Genes of Human Embryos FEB.
1, 2016
George Church, a professor of genetics at Harvard Medical School and an organizer of the proposed
project, said there had been a misunderstanding. The project was not aimed at creating people, just cells,
and would not be restricted to human genomes, he said. Rather it would aim to improve the ability to
synthesize DNA in general, which could be applied to various animals, plants and microbes.
“They’re painting a picture which I don’t think represents the project,” Dr. Church said in an interview.
He said the meeting was closed to the news media, and people were asked not to tweet because the project
organizers, in an attempt to be transparent, had submitted a paper to a scientific journal. They were
therefore not supposed to discuss the idea publicly before publication. He and other organizers said ethical
aspects have been amply discussed since the beginning.
The project was initially called HGP2: The Human Genome Synthesis Project, with HGP referring to the
Human Genome Project. An invitation to the meeting at Harvard said that the primary goal “would be to
synthesize a complete human genome in a cell line within a period of 10 years.”
Photo
George Church, one of the organizers of the proposed project, at his lab at Harvard
Medical School in 2013. Credit Jessica Rinaldi/Reuters
But by the time the meeting was held, the name had been changed to “HGP-Write: Testing Large Synthetic
Genomes in Cells.”
The project does not yet have funding, Dr. Church said, though various companies and foundations would
be invited to contribute, and some have indicated interest. The federal government will also be asked. A
spokeswoman for the National Institutes of Health declined to comment, saying the project was in too early
a stage.
Besides Dr. Church, the organizers include Jef Boeke, director of the institute for systems genetics at NYU
Langone Medical Center, and Andrew Hessel, a self-described futurist who works at the Bay Area software
company Autodesk and who first proposed such a project in 2012.
Scientists and companies can now change the DNA in cells, for example, by adding foreign genes or
changing the letters in the existing genes. This technique is routinely used to make drugs, such as insulin
for diabetes, inside genetically modified cells, as well as to make genetically modified crops. And scientists
are now debating the ethics of new technology that might allow genetic changes to be made in embryos.
But synthesizing a gene, or an entire genome, would provide the opportunity to make even more extensive
changes in DNA.
For instance, companies are now using organisms like yeast to make complex chemicals, like flavorings
and fragrances. That requires adding not just one gene to the yeast, like to make insulin, but numerous
genes in order to create an entire chemical production process within the cell. With that much tinkering
needed, it can be easier to synthesize the DNA from scratch.
Right now, synthesizing DNA is difficult and error-prone. Existing techniques can reliably make strands
that are only about 200 base pairs long, with the base pairs being the chemical units in DNA. A single gene
can be hundreds or thousands of base pairs long. To synthesize one of those, multiple 200-unit segments
have to be spliced together.
But the cost and capabilities are rapidly improving. Dr. Endy of Stanford, who is a co-founder of a DNA
synthesis company called Gen9, said the cost of synthesizing genes has plummeted from $4 per base pair in
2003 to 3 cents now. But even at that rate, the cost for three billion letters would be $90 million. He said if
costs continued to decline at the same pace, that figure could reach $100,000 in 20 years.
J. Craig Venter, the genetic scientist, synthesized a bacterial genome consisting of about a million base
pairs. The synthetic genome was inserted into a cell and took control of that cell. While his first synthetic
genome was mainly a copy of an existing genome, Dr. Venter and colleagues this year synthesized a more
original bacterial genome, about 500,000 base pairs long.
Dr. Boeke is leading an international consortium that is synthesizing the genome of yeast, which consists of
about 12 million base pairs. The scientists are making changes, such as deleting stretches of DNA that do
not have any function, in an attempt to make a more streamlined and stable genome.
But the human genome is more than 200 times as large as that of yeast and it is not clear if such a synthesis
would be feasible.
Jeremy Minshull, chief executive of DNA2.0, a DNA synthesis company, questioned if the effort would be
worth it.
“Our ability to understand what to build is so far behind what we can build,” said Dr. Minshull, who was
invited to the meeting at Harvard but did not attend. “I just don’t think that being able to make more and
more and more and cheaper and cheaper and cheaper is going to get us the understanding we need.”
WP
Companies rush to build ‘bio-factories’ for medicines, flavorings and fuels
View Photo Gallery — Bio-factories bring new drugs, flavorings and fuels: Scientists are using newly
created life-forms to produce new medicines and other products, but environmental groups are worried
about unforeseen risks.
By Ariana Eunjung Cha, Published: October 24 E-mail the writer
For scientist Jack Newman, creating a new life-form has become as simple as this: He types out a DNA
sequence on his laptop. Clicks “send.” And a few yards away in the laboratory, robotic arms mix together
some compounds to produce the desired cells.
Newman’s biotech company is creating new organisms, most forms of genetically modified yeast, at the
dizzying rate of more than 1,500 a day. Some convert sugar into medicines. Others create moisturizers that
can be used in cosmetics. And still others make biofuel, a renewable energy source usually made from
corn.
“You can now build a cell the same way you might build an app for your iPhone,” said Newman, chief
science officer of Amyris.
Some believe this kind of work marks the beginning of a third industrial revolution — one based on using
living systems as “bio-factories” for creating substances that are either too tricky or too expensive to grow
in nature or to make with petrochemicals.
The rush to biological means of production promises to revolutionize the chemical industry and transform
the economy, but it also raises questions about environmental safety and biosecurity and revives ethical
debates about “playing God.” Hundreds of products are in the pipeline.
Laboratory-grown artemisinin, a key anti-malarial drug, went on sale in April with the potential to help
stabilize supply issues. A vanilla flavoring that promises to be significantly cheaper than the costly extract
made from beans grown in rain forests is scheduled to hit the markets in 2014.
On Wednesday, Amyris announced another milestone — a memorandum of understanding with Brazil’s
largest low-cost airline, GOL Linhas Aereas, to begin using a jet fuel produced by yeast starting in 2014.
Proponents characterize bio-factories as examples of “green technology” that are sustainable and immune
to fickle weather and disease. Backers say they will reshape how we use land globally, reducing the
cultivation of cash crops in places where that practice hurts the environment, break our dependence on
pesticides and result in the closure of countless industrial factories that pollute the air and water.
But some environmental groups are skeptical.
They compare the spread of bio-factories to the large-scale burning of coal at the turn of the 20th century
— a development with implications for carbon dioxide emissions and global warming that weren’t
understood until decades later.
Much of the early hype surrounding this technology was about biofuels — the dream of engineering
colonies of yeast that could produce enough fuel to power whole cities. It turned out that the technical
hurdles were easier to overcome than the economic ones. Companies haven’t been able to find a way to
produce enough of it to make the price affordable, and so far the biofuels have been used only in smaller
projects, such as local buses and Amyris’s experiment with GOL’s planes.
But dozens of other products are close to market, including synthetic versions of fragrances extracted from
grass, coconut oil and saffron powder, as well as a gas used to make car tires. Other applications are being
studied in the laboratory: biosensors that light up when a parasite is detected in water; goats with spider
genes that produce super-strength silk in their milk; and synthetic bacteria that decompose trash and break
down oil spills and other contaminated waste at a rapid pace.
Revenue from industrial chemicals made through synthetic biology is already as high as $1.5 billion, and it
will increase at an annual rate of 15 to 25 percent for the next few years, according to an estimate by Mark
Bünger, an analyst for Lux Research, a Boston-based advisory firm that focuses on emerging technologies.
Since it was founded a decade ago, Amyris has become a legend in the field that sits at the intersection of
biology and engineering, creating more than 3 million organisms. Unlike traditional genetic engineering,
which typically involves swapping a few genes, the scientists are building entire genomes from scratch.
Keeping bar-code-stamped vials in giant refrigerators at minus-80 degrees, the company’s repository in
Emeryville, Calif., is one of the world’s largest collections of living organisms that do not exist in nature.
Ten years ago, when Newman was a postdoctoral student at the University of California at Berkeley, the
idea of being able to program cells on a computer was fanciful.
Newman was working in a chemical engineering lab run by biotech pioneer Jay Keasling and helping
conduct research on how to rewrite the metabolic pathways of microorganisms to produce useful
substances.
Their first target was yeast.
The product of millions of years of evolution, the single-celled organism was capable of a miraculous feat:
When fed sugar, it produced energy and excreted alcohol and carbon dioxide. Humans have harnessed this
power for centuries to make wine, beer, cheese and other products. Could they tinker with some genes in
the yeast to create a biological machine capable of producing medicine?
Excited about the idea of trying to apply the technology to a commercial product, Keasling, Newman and
two other young post-docs — Keith Kinkead Reiling and Neil Renninger — started Amyris in 2003 and set
their sights on artemisinin, an ancient herbal remedy found to be more than 90 percent effective at curing
those infected with malaria.
It is harvested from the leaves of the sweet wormwood plant, but the supply of the plant had sometimes
fluctuated in the past, causing shortages.
The new company lined up high-profile investors: the Bill & Melinda Gates Foundation, which gave
$42.6 million to a nonprofit organization to help finance the research, and Silicon Valley luminaries John
Doerr and Vinod Khosla, who as part of a group invested $20 million.
As of this month, Amyris said its partner, pharmaceutical giant Sanofi, has manufactured 70 metric tons of
artemisinin — roughly equivalent to 140 million courses of treatment. The World Health Organization gave
its stamp of approval to the drug in May, and the pills are being used widely.
Concerns about risks
The early scientific breakthroughs by the Amyris founders paved the way for dozens of other companies to
do similar work. The next major product to be released is likely to be a vanilla flavoring by Evolva, a Swiss
company that has laboratories in the San Francisco Bay area.
Cultivated in the remote forests of Madagascar, Mexico and the West Indies, natural vanilla is one of the
world’s most revered spices. But companies that depend on the ingredient to flavor their products have long
struggled with its scarcity and the volatility of its price.
Its chemically synthesized cousins, which are made from petrochemicals and paper pulp waste and are
three to five times cheaper, have 99 percent of the vanilla market but have failed to match the natural
version’s complexity.
Now scientists in a lab in Denmark believe they’ve created a type of vanilla flavoring produced by yeast
that they say will be more satisfying to the palate and cheaper at the same time.
In Evolva’s case, much of the controversy has focused on whether the flavoring can be considered
“natural.” Evolva boasts that it is, because only the substance used to produce the flavoring was genetically
modified — not what people actually consume.
“From my point of view it’s fundamentally as natural as beer or bread,” said Evolva chief executive Neil
Goldsmith, who is a co-founder of the company. “Neither brewer’s or baker’s yeast is identical to yeast in
the wild. I’m comfortable that if beer is natural, then this is natural.”
That justification has caused an uproar among some consumer protection and environmental groups. They
say that representing Evolva’s laboratory-grown flavoring as something similar to vanilla extract from an
orchid plant is deceptive, and they have mounted a global campaign urging food companies to boycott the
“vanilla grown in a petri dish.”
“Any ice-cream company that calls this all-natural vanilla would be committing fraud,” argues Jaydee
Hanson, a senior policy analyst at the Center for Food Safety, a nonprofit public interest group based in
Washington.
Jim Thomas, a researcher for the ETC Group, said there is a larger issue that applies to all organisms
produced by synthetic biology techniques: What if they are accidentally released and evolve to have
harmful characteristics?
“There is no regulatory structure or even protocols for assessing the safety of synthetic organisms in the
environment,” Thomas said.
Then there’s the potential economic impact. What about the hundreds of thousands of small farmers who
produce these crops now?
Artemisinin is farmed by an estimated 100,000 people in Kenya, Tanzania, Vietnam and China and the
vanilla plant by 200,000 in Madagascar, Mexico and beyond.
Evolva officials say they believe there will still be a strong market for artisan ingredients like vanilla from
real beans and that history has shown that these products typically attract an even higher premium when
new products hit the market.
Other biotech executives say they are sympathetic, but that it is the price of progress. Amyris’s Newman
says he is confused by environmental groups’ criticism and points to the final chapter of Rachel Carson’s
“Silent Spring” — the seminal book that is credited with launching the environmental movement. In it,
Carson mentions ways that science can solve the environmental hazards we have endured through years of
use of fossil fuels and petrochemicals.
“The question you have to ask yourself is, ‘Is the status quo enough?’ ” Newman said. “We live in a world
where things can be improved upon.”
NYT
Gene Editing to Alter Whole Species Gets
Limited Backing
By AMY HARMONJUNE 8, 2016
Female mosquitoes that have been altered as part of a gene drive experiment. Credit
Anthony James
The National Academies of Sciences, Engineering and Medicine on Wednesday endorsed research on a
technology known as “gene drive,” which gives humans the power for the first time to alter or eliminate
entire populations of organisms in the wild — like mosquitoes, mice or plants — through deliberate genetic
manipulation.
For centuries, people have tinkered in ever more precise ways with the genetic makeup of living things
already well under our control: pets, farm animals, crops and assorted species of laboratory animals. But
modifying wild animals has been stymied by the inability to choreograph the mating of organisms not
under our dominion.
Gene drives overcome this limitation by ensuring that the chunk of genetic code containing them is
transmitted to all of an individual’s offspring, even if it reduces their fitness or causes their annihilation. By
linking pieces of DNA to the gene driver with new editing tools that make them easy to insert, scientists
think they can spread desired traits through an entire wild species.
But the report by an advisory panel of ethicists, biologists and others for the N.A.S., which advises the
federal government, underscores that there is not enough evidence about gene drives to justify the release
of an altered living thing beyond the laboratory or controlled field experiments. Scientists and
environmental advocates alike noted that while the report did a good job of laying out the many questions
raised by gene drives, it did not provide many answers.
Some independent scientists say the report strikes a good balance by permitting more gene drive research
while limiting the use of the technology. But opponents of widespread genetic engineering argue that the
panel should have demanded a halt to this type of genetic editing, which has become feasible only in the
last few years with the advent of the Crispr-Cas9 tool.
Some biologists have called for using gene drive to eradicate the Aedes aegypti mosquito that transmits the
Zika virus as well as other pathogens, by spreading a gene that determines whether mosquitoes become
male, reducing the number of females until the species can no longer reproduce.
The Bill and Melinda Gates Foundation, which helped pay for the report, has spent some $40 million on a
gene drive project aimed at eradicating the species of mosquitoes that spread malaria. In agriculture, gene
drive systems could destroy or modify insect pests. Other proposals involve using gene drives to squelch
populations of harmful invasive species like rodents on islands, or to combat Lyme disease.
The panel also acknowledged how daunting it may be to ethically obtain consent from people whose
environments might be affected by such a release. “There are few avenues for such participation,” the
report noted, “and insufficient guidance on how communities can and should take part.”
Anthony James, a mosquito researcher at the University of California, Irvine, said the
academies’ report was “reasonable.” Credit Jake Michaels for The New York Times
In addition, the panel cautioned that “after release into the environment, a gene drive knows no political
boundaries.”
The technology also falls through the cracks of the existing regulatory systems for genetically engineered
organisms in the United States and globally, the committee noted.
And it cautioned that officials should not resort to the gene drive technique under the pressure of a public
health crisis like the one posed by the emergence of the Zika virus without the “phased testing” system
recommended in the report.
The committee considered six case studies, including using gene drive to control mice destroying
biodiversity on islands, mosquitoes infecting native Hawaiian birds with malaria, and a weed called Palmer
amaranth that has become resistant to herbicides and a scourge for some farmers.
Dr. James’s research demonstrated how a gene drive might prevent mosquitoes
from transmitting malaria. Credit Jake Michaels for The New York Times
Each case carries its own risks, including the possibility that a gene drive might jump to another species, or
that the suppression of one undesirable organism will lead to the emergence of another that is even worse.
The report cites the difficulty in modeling the “cascade of population dynamics and evolutionary processes
that could have numerous reverberating effects.”
Still, the possible benefits of the technology, the report concludes, make it important to pursue.
“The potential to reduce human suffering and ecological damage demands scientific attention,” said
Elizabeth Heitman, a medical ethicist at Vanderbilt University who helped lead the committee. “Gene drive
is a fascinating area of science that has promise if we can study it appropriately.”
So far, gene drive research has focused largely on mosquitoes that transmit infectious diseases to humans.
Anthony James, a mosquito researcher at the University of California, Irvine, who published a paper last
year demonstrating how a gene drive might prevent mosquitoes from transmitting malaria, called the
panel’s report “reasonable.”
“The key thing is there’s no moratorium,” he said.
But Kevin Esvelt, a Massachusetts Institute of Technology evolutionary biologist who has also pioneered
the technology, said the report failed to adequately flag its key risk. “They assume you can safely run a
contained field trial,” he said. “But anytime you release an organism with a gene drive system into the wild
you must assume there is a significant chance that it will spread — globally — and factor that in.”
And environmental watchdog groups that have traditionally opposed genetic engineering argued that, in
light of the risks identified in the report, it should have recommended the research be halted. Jim Thomas,
the program director of the ETC Group in Montreal, said the report gave short shrift to how to prevent
commercial and military interests from misusing the technology, which he said should be placed under the
control of the United Nations.
“We believe that at this point it would be prudent to halt gene drive development until such safety concerns
are formally addressed and clarified,” he said.
Gene drives spread a trait through a population by ensuring that it is passed to virtually all of an
individual’s offspring as it reproduces, rather than the usual half. In laboratory experiments, the desired
change has appeared in 99 percent of the offspring of flies and mosquitoes.
But James Bull, a researcher at the University of Texas, Austin, recently posted a draft paper outlining
another risk: that the species might evolve to undermine the spread of the gene drive, making it less
effective than researchers had hoped.
“There may be multiple mechanisms by which a species responds and blocks the harmful effects of these
drives,” Dr. Bull said. “It’s going to depend on a lot of details, and the only way we’re going to find out is
to try it.”
SA
Fast-Spreading Genetic Mutations Pose
an Ecological Risk
U.S. science academies advise caution in experimenting with gene drives

By Heidi Ledford, Nature magazine on June 8, 2016
Gene drives could be used to combat mosquito-borne diseases such as malaria.
Credit: MARVIN RECINOS/AFP/Getty Images
A technique that allows particular genes to spread rapidly through populations is not ready to be set loose
in the wild, warns a committee convened by the US National Academies of Sciences, Engineering, and
Medicine.
In a report released on June 8, the committee argued that such ‘gene drives’ pose complex ecological risks
that are not yet fully understood. “It is not ready—and we are not ready—for any kind of release,” says
Elizabeth Heitman, co-chair of the committee and a research integrity educator at Vanderbilt University
School of Medicine in Nashville, Tennessee. “There is a lot of work that needs to be done.”
Even so, Heitman and other members of the committee felt that the potential of gene drives, for example to
combat insect-borne diseases, is compelling enough to warrant additional laboratory and field studies.
Gene drives have been studied for more than half a century, and have long been postulated as a way to
eradicate mosquito-borne diseases such as malaria. But the field was hampered by technical challenges
until the recent advent of sophisticated—and easy-to-use—tools for engineering genomes. In the past two
years, researchers have used a popular gene-editing technique called CRISPR–Cas9 to develop gene drives
that spread a given gene through a population almost exponentially faster than normal in yeast, fruit flies
and two species of mosquitoes.
But as molecular biology research on gene drives has surged forward, it has outpaced our understanding of
their ecological consequences, says Heitman. Even a small, accidental release from a laboratory holds the
potential to spread around the globe: “After release into the environment, a gene drive knows no political
boundaries,” the committee wrote.
As a result, oversight of gene drive projects should be coordinated across countries, the committee argued,
and best practices should be openly shared among laboratories. The committee also detailed multiple
phases of testing that should be used to assess the effects of a gene drive, and stressed the need to involve
researchers' home institutions, regulators and even the public in decision-making.
It is a good overall strategy, says Todd Kuiken, who studies science policy at the Wilson International
Center for Scholars, a think tank in Washington DC. But the committee missed an opportunity to set out the
infrastructure and safety measures that would be needed to conduct field trials of gene drives, he adds.
“They don’t talk about how you would actually do this and where the money is going to come from.”
A gene drive could have unintended effects on the environment if it is unleashed in wild populations:
removing one species of insect, for example, could endanger the animals that feed on it. Given this risk, the
report also stressed the importance of layering multiple methods of containment to prevent accidental
release of engineered species, and of consulting with the public even before gene drive experiments are
undertaken in the laboratory. It’s a message that evolutionary engineer Kevin Esvelt worries may not come
through strongly enough to individual researchers.
“If you were to accept that there is a risk that building it in the laboratory could lead to its release, then that
demands that you tell the world what you’re doing before you do the experiments,” says Esvelt, who works
at the Massachusetts Institute of Technology in Cambridge.
Heitman notes that researchers lack tried and tested ways of soliciting input from the public at large about
their work. For Esvelt, the bigger barrier is a scientific culture that often discourages researchers from
sharing their experiments before they are published, for fear of being beaten to the finishing line by another
group. “No one would rationally design the current scientific enterprise,” he says. “And right now it’s
easier to engineer biology than culture.”
Science


Credit: angellodeco/Shutterstock
Genetic counseling: A growing area of
opportunity
By Elisabeth Pain
Jun. 13, 2016 , 1:30 PM
For scientists who want to use their genetics knowledge to help patients while also potentially keeping a
foot in research, genetic counseling can offer uniquely rewarding career opportunities. It is still a young
profession, with few Ph.D. holders having made the transition thus far, but it presents exciting options to
those who make the leap.
A small but growing profession
Today, the number of genetic counselors remains small across the globe. In 2014, 2400 genetic counselors
were employed in the United States, according to the U.S. Bureau of Labor Statistics, and the American
Board of Genetic Counseling (ABGC) currently counts more than 4000 certified professionals in the
United States and Canada. (The United States was the first country to train genetic counseling
professionals, with the introductory class graduating in 1971.) In the United Kingdom, where the job first
emerged in the early 1980s, there were just 300 genetic counselors as of 2011, according to a paper
produced by a European Society of Human Genetics (ESHG) working group. And the profession is even
smaller elsewhere in Europe, the authors of that paper report, with 75 genetic counselors in France; 65 in
the Netherlands; 17 in Norway; 15 in Denmark; 10 in Sweden; a handful each in Ireland, Spain, and
Switzerland; and none in Germany, Italy, and many other countries.
But several signs bode well for the profession’s future growth. Major research efforts that aim to broaden
our understanding of how genetic variations may cause rare inherited disorders and cancer or interact with
environmental and lifestyle factors to influence more common, complex diseases, such as the 100,000
Genomes Project in the United Kingdom and the Precision Medicine Initiative in the United States, are
underway. Meanwhile, DNA analysis technologies are becoming ever more affordable, with companies
offering an increasing number of genetic sequencing and testing services, sometimes directly to consumers.
In this evolving landscape, the demand for professionals who can make sense of genetic information and
help translate it into clinical practice while navigating the psychological, ethical, and legal pitfalls is likely
to grow.
This expansion is already underway in the United States, and the need for these trained professionals will
continue growing into the foreseeable future, the U.S. Bureau of Labor Statistics forecasts. It predicts a
29% growth rate for genetic counseling jobs between 2014 and 2024, as compared to an average rate of 7%
across all occupations. “So we’re in a position at the moment where people who graduate with genetic
counseling [master’s] degrees essentially have their pick of what they would like to do,” says National
Society of Genetic Counselors (NSGC) President Jehannine Austin.
Employment opportunities are also on the rise in some parts of Europe. In the United Kingdom, says Sue
Kenwrick, a principal genetic counselor at Addenbrooke’s Hospital in Cambridge and chair of the training
panel of the Association of Genetic Nurses and Counsellors (AGNC), “my experience … is that referrals
are going up rapidly and genetic counseling roles are growing and growing, and there are not enough of us
… to meet workforce needs.” (The AGNC also offers a helpful document explaining the genetic counseling
career structure in the United Kingdom.) Similarly, the 75 trained professionals currently in France aren’t
enough to fill all its vacant positions, says Christophe Cordier, a French genetic counselor who was the first
author on the ESHG working group paper. In contrast, the seven counselors in the French-speaking part of
Switzerland are sufficient to meet the local demand, which is unlikely to increase until more funding
becomes available to create new positions, Cordier adds.
Genetic counseling positions are also becoming available in many different medical areas and work
environments. “Genetic counselors can work in multiple specialty areas, including prenatal, cardiovascular
disease, cancer, metabolic disease, neurology, pediatrics, infertility, pharmacogenetics, genomic medicine,
and others,” according to the 2016 NSGC Professional Status Survey (PSS) of genetic counselors in the
United States and Canada. And although genetic counselors have traditionally worked in clinical settings,
today they are also finding work in commercial diagnostic laboratories and, to a lesser extent, in nonprofit
organizations and government agencies. Genetic counselors’ possible roles are also growing to include new
applications and responsibilities. “These include working in administration, research, public and
professional education, web content development, public health, laboratory support, public policy, and
consulting,” the PSS report says.
Many genetic counselors also have the option to get involved in academic research at one point or another
in their career. In the United Kingdom, some do so as research assistants in university labs. In the United
States and Canada, they may hold research genetic counselor positions. This title, Austin says, “recognizes
the greater autonomy and responsibility that these individuals often have beyond what would traditionally
be expected of other types of research employees like a research assistant.” In addition, some genetic
counselors conduct research as part of a Ph.D. or a part-time postdoctoral position.
There are also opportunities for genetic counselors to hold higher-ranking academic positions. In fact, 22%
of the more than 2000 respondents to the PSS have research, teaching, or clinical faculty appointments—
though only 11 of these faculty members are tenure track. Pursuing a tenure-track academic position as a
genetic counselor is a challenge, notes Gillian Hooker—who earned a Ph.D. in molecular, cellular, and
developmental biology before training and working as a genetic counselor—because many genetic
counselors want to continue seeing patients, which can be hard to balance with the duties of a tenure-track
professor.
But regardless of title, “there are a lot of really big research questions out there” about patients’ experiences
and how to best deliver information to them, Hooker says. “For Ph.D.s who do want to [stay] in research
but maybe want to do something that’s more clinical or work more directly with patients, it’s a great time
to think about making that move.”
Getting the training
A career in genetic counseling requires a deep understanding of genetics, extensive medical knowledge and
clinical experience, and excellent communication and counseling skills. Specific training requirements vary
across the world, but in many countries, these skills can—and must—be learned through a 2- to 3-year
master’s degree program. However, while job opportunities have expanded, training options remain more
limited and admission is quite competitive. Currently, there are 33 accredited genetic counseling master’s
programs in the United States and three in Canada, and in 2010, just over 30% of the applicants to these
programs were accepted. (Most employers in North America want applicants to win or at least be eligible
for ABGC certification, which requires graduating from an accredited program.)
Across the pond, genetic counseling master’s programs can be found in the United Kingdom, France,
Spain, Portugal, Romania, the Netherlands, Norway, and Turkey, though there is significant variation in the
training they provide. In an attempt to improve and harmonize the provision of both genetic counseling
training and services across the continent, the European Board of Medical Genetics has recently put in
place a pan-European professional certification system that recognizes six approved programs. And the
United Kingdom, which in 1992 became the first in Europe to offer formal training, is overhauling its
system with the introduction of a new 3-year master’s program in genomic counseling to begin in
September 2016.
The admissions committees for most of these master’s programs want to see evidence that applicants know
what they are getting into, so candidates should demonstrate a good understanding of the profession, Austin
says. Good places to start are websites like the NSGC's, which has a section that introduces the job and
includes videos of simulated counseling sessions, she adds. Hooker suggests getting in touch with master’s
program directors and practicing genetic counselors to gather information about the training requirements
and what the job is like, which will also help potential applicants develop a sense for whether genetic
counseling is really for them.
But nothing replaces the real-life experience of helping people. To even be considered for admission, most
programs require that applicants have experience providing one-on-one counseling support or working in a
clinical or caring environment. Often, applicants have volunteered with crisis hotlines, which sometimes
offer some degree of training, or in domestic abuse shelters, Hooker says. If possible, shadowing genetic
counselors is also a good option because it allows aspiring counselors to see if they feel comfortable being
with patients and working in a clinical setting, she adds.
Balancing trade-offs
Investing another 2 to 3 years of your life into getting yet another degree may be a potential turn-off for
Ph.D. scientists considering the genetic counseling path. But, Austin advises, do “not … be held back by
thinking that doing a master’s degree would be taking a step backwards in some way. It’s not. You’re
learning an entirely different set of skills.” Obtaining her master’s degree, for example, broadened her
scientific knowledge and put it into the context of patient needs, she says. A master’s degree in genetic
counseling can also be useful if you ultimately decide to pursue a research career, adds Austin, who is an
associate professor of medical genetics and psychiatry at the University of British Columbia, Vancouver, in
Canada. She credits her academic success at least in part to the extra training she gained by completing her
genetic counseling master’s degree, which allowed her to tackle clinical questions that had previously
received little attention.
Another drawback for Ph.D. scientists thinking about a genetic counseling career may be the financial cost
of further training, though tuition fees vary across programs and countries. “Once you’ve finished a Ph.D.,
you don’t want to go back and pay for more school,” says Hooker, who trained at and later spent a couple
of years working as the associate program director at The Johns Hopkins University/National Human
Genome Research Institute Genetic Counseling Training Program. But, she continues, in the United States
at least, “some of the [programs] do have good tuition benefits and various financial deals, so … I wouldn’t
rule out [further training] immediately for anyone without exploring the question first.” And in the United
Kingdom, the new master’s program will offer salaries and cover trainees’ tuition fees, which will create
“more of a level playing field” for anyone who might want to enter the profession, Kenwrick says.
The field is likely to continue evolving as it becomes increasingly possible to interrogate larger tracks of
DNA and decipher what genetic variations might mean for rare inherited disorders and common complex
diseases alike. As more companies offer genetic and genomic services directly to consumers, the landscape
of where and how genetic counseling is done is also likely to undergo some profound changes. All of this
presents big adaptation challenges—and opportunities. “The great thing,” Hooker says, “is that it’s a part of
our ethos already to respond to technology. … So hopefully the field will continue to grow to meet demand
and then at the same time develop new, interesting models to reach more patients.”
Interested in entering the field? Look for our final installment for the stories of how Kenwrick, Austin,
Hooker, and Cordier each carved their own unique professional paths. And if you missed it, check out the
first installment introducing the rewards—and challenges—of a career in genetic counseling.
Further reading

“Evolving Roles for Physicians and Genetic Counselors in Managing Complex
Genetic Disorders,” by Celeste A. Shelton and David C. Whitcomb (Clinical and
Translational Gastroenterology, November 2015)









“Genetic counselors and Genomic Counseling in the United Kingdom,” by
Anna Middleton et al. (Molecular Genetics & Genomic Medicine, March 2015)
“The Angelina Jolie effect: how high celebrity profile can have a major impact
on provision of cancer related services,” by D. Gareth R. Evans et al. (Breast
Cancer Research, September 2014)
“The role of the genetic counsellor: a systematic review of research
evidence,” by Heather Skirton et al. (European Journal of Human Genetics,
June 2014)
“Teaching Genomic Counseling: Preparing the Genetic Counseling Workforce
for the Genomic Era,” by Gillian W. Hooker et al. (Journal of Genetic
Counseling, February 2014)
“From genetic counseling to ‘genomic counseling,’” by Kelly E. Ormond
(Molecular Genetics & Genomic Medicine, November 2013)
“Implementing genomic medicine in the clinic: the future is here,” by Teri A.
Manolio et al. (Genetics in Medicine, January 2013)
“Defining the Role of Laboratory Genetic Counselor,” by Susan Christian et al.
(Journal of Genetic Counseling, November 2011)
Ethical Issues in Genetic Testing, by the American Congress of Obstetricians
and Gynecologists Committee of Ethics and Committee of Genetics (June
2008)
Maps & Genes: [A] sounding board for prospective & current genetic
counseling students
SCIENCE
Biologists are transforming the proteinmaking instructions of Escherichia coli.
C. Bickel/Science
Biologists are close to reinventing the
genetic code of life
By John BohannonAug. 18, 2016 , 2:00 PM
The term "life hacking" usually refers to clever tweaks that make your life more productive. But this week
in Science, a team of scientists comes a step closer to the literal meaning: hacking the machinery of life
itself. They have designed—though not completely assembled—a synthetic Escherichia coli genome that
could use a protein-coding scheme different from the one employed by all known life. Requiring a
staggering 62,000 DNA changes, the finished genome would be the most complicated genetic engineering
feat so far. E. coli running this rewritten genome could become a new workhorse for laboratory
experiments and a factory for new industrial chemicals, its creators predict.
Such a large-scale genomic hack once seemed impossible, but no longer, says Peter Carr, a bioengineer at
the Massachusetts Institute of Technology Lincoln Laboratory in Lexington who is not involved with the
project. "It's not easy, but we can engineer life at profound scales, even something as fundamental as the
genetic code."
The genome hacking is underway in the lab of George Church at Harvard University, the DNA-sequencing
pioneer who has become the most high-profile, and at times controversial, name in synthetic biology. The
work takes advantage of the redundancy of life's genetic code, the language that DNA uses to instruct the
cell's protein-synthesizing machinery. To produce proteins, cells "read" DNA's four-letter alphabet in
clusters of three called codons. The 64 possible triplets are more than enough to encode the 20 amino acids
that exist in nature, as well as the "stop" codons that mark the ends of genes. As a result, the genetic code
has multiple codons for the same amino acid: the codons CCC and CCG both encode the amino acid
proline, for example.
Church and others hypothesized that redundant codons could be eliminated—by swapping out every CCC
for a CCG in every gene, for instance—without harming the cell. The gene that enables CCC to be
translated into proline could then be deleted entirely. "There are a number of 'killer apps'" of such a
"recoded" cell, says Farren Isaacs, a bioengineer at Yale University, who, with Church and colleagues,
showed a stop codon can be swapped out entirely from E. coli.
The cells could be immune to viruses that impair bioreactors, for example, if crucial viral genes include
now untranslatable codons. The changes could also allow synthetic biologists to repurpose the freed
redundant codons for an entirely different function, such as coding for a new, synthetic amino acid.
For this study, Church's team decided to eliminate seven of the microbe's 64 codons. That target seemed
like "a good balance" between the number of changes that appeared technically achievable and the number
that might be too many for a cell to survive, says Matthieu Landon, one of Church's Ph.D. students. And
the seven spare codons could eventually be repurposed to code up to four different unnatural amino acids.
But making so many changes, even with the latest DNA editing techniques such as CRISPR, still appeared
impossible. Luckily, the cost of synthesizing DNA has plummeted over the past decade. So instead of
editing the genome one site at a time, Church's team used machines to synthesize long stretches of the
recoded genome from scratch, each chunk containing multiple changes.
The team has now turned to the laborious job of inserting these chunks into E. coli one by one and making
sure that none of the genomic changes is lethal to the cells. The researchers have only tested 63% of the
recoded genes so far, but remarkably few of the changes have caused trouble, they say.
Does this progress report from Church's lab put biologists on the doorstep of a new era of virus-free
bioengineered cells? "More likely on the driveway than the doorstep," Isaacs says. Carr agrees. "The
upcoming phases of synthesis, testing, and assembly are likely to take several years," he says. "The
toughest 5% of the design may end up requiring 95% of the effort."
In the meantime, another issue is likely to dominate discussions: safety. One concern is that many of the
"unnatural" proteins that the recoded E. coli could be engineered to produce may be toxic, and the cells'
resistance to viruses would give them a competitive edge if they escaped into the environment—or into our
own guts. "As we get closer to full multivirus resistance, this becomes more critical," Church
acknowledges.
The failsafe that Church plans to build into the microbes is superficially similar to the one used to control
the bioengineered dinosaurs in the film Jurassic Park. Those resurrected creatures couldn't survive without
a special nutrient supplied by their human masters—that is, until they found a source of the nutrient in the
wild. In a study published in Nature last year, Church demonstrated a failsafe system for engineered
microbes that should be far more robust. Not only does the required nutrient not occur naturally, but it
appears to be virtually impossible for the cells to overcome the barrier through mutation or mating with
normal cells in the wild.
Whether others will agree with Church that his failsafe is unbeatable remains to be seen. "The term 'safe'
needs a lot more scrutiny," Carr says. "Instead of the all-or-nothing connotations of 'safe' or 'not safe,' it is
more useful to describe degrees of risk."
MIT Technology Review
Rewriting Life
Engineering the Perfect Baby
Scientists are developing ways to edit the DNA of tomorrow’s children. Should they stop before it’s too
late?

by Antonio Regalado

March 5, 2015

If anyone had devised a way to create a genetically engineered baby, I figured George Church would know
about it.
At his labyrinthine laboratory on the Harvard Medical School campus, you can find researchers giving E.
Coli a novel genetic code never seen in nature. Around another bend, others are carrying out a plan to use
DNA engineering to resurrect the woolly mammoth. His lab, Church likes to say, is the center of a new
technological genesis—one in which man rebuilds creation to suit himself.
When I visited the lab last June, Church proposed that I speak to a young postdoctoral scientist named
Luhan Yang. A Harvard recruit from Beijing, she’d been a key player in developing a powerful new
technology for editing DNA, called CRISPR-Cas9. With Church, Yang had founded a small biotechnology
company to engineer the genomes of pigs and cattle, sliding in beneficial genes and editing away bad ones.
This story is part of our May/June 2015 Issue
See the rest of the issue
Subscribe
As I listened to Yang, I waited for a chance to ask my real questions: Can any of this be done to human
beings? Can we improve the human gene pool? The position of much of mainstream science has been that
such meddling would be unsafe, irresponsible, and even impossible. But Yang didn’t hesitate. Yes, of
course, she said. In fact, the Harvard laboratory had a project under way to determine how it could be
achieved. She flipped open her laptop to a PowerPoint slide titled “Germline Editing Meeting.”
Here it was: a technical proposal to alter human heredity. “Germ line” is biologists’ jargon for the egg and
sperm, which combine to form an embryo. By editing the DNA of these cells or the embryo itself, it could
be possible to correct disease genes and pass those genetic fixes on to future generations. Such a
technology could be used to rid families of scourges like cystic fibrosis. It might also be possible to install
genes that offer lifelong protection against infection, Alzheimer’s, and, Yang told me, maybe the effects of
aging. Such history-making medical advances could be as important to this century as vaccines were to the
last.
That’s the promise. The fear is that germ-line engineering is a path toward a dystopia of superpeople and
designer babies for those who can afford it. Want a child with blue eyes and blond hair? Why not design a
highly intelligent group of people who could be tomorrow’s leaders and scientists?
Just three years after its initial development, CRISPR technology is already widely used by biologists as a
kind of search-and-replace tool to alter DNA, even down to the level of a single letter. It’s so precise that
it’s expected to turn into a promising new approach for gene therapy in people with devastating illnesses.
The idea is that physicians could directly correct a faulty gene, say, in the blood cells of a patient with
sickle-cell anemia (see “Genome Surgery”). But that kind of gene therapy wouldn’t affect germ cells, and
the changes in the DNA wouldn’t get passed to future generations.
In contrast, the genetic changes created by germ-line engineering would be passed on, and that’s what has
made the idea seem so objectionable. So far, caution and ethical concerns have had the upper hand. A
dozen countries, not including the United States, have banned germ-line engineering, and scientific
societies have unanimously concluded that it would be too risky to do. The European Union’s convention
on human rights and biomedicine says tampering with the gene pool would be a crime against “human
dignity” and human rights.
But all these declarations were made before it was actually feasible to precisely engineer the germ line.
Now, with CRISPR, it is possible.
The experiment Yang described, though not simple, would go like this: The researchers hoped to obtain,
from a hospital in New York, the ovaries of a woman undergoing surgery for ovarian cancer caused by a
mutation in a gene called BRCA1. Working with another Harvard laboratory, that of antiaging specialist
David Sinclair, they would extract immature egg cells that could be coaxed to grow and divide in the
laboratory. Yang would use CRISPR in these cells to correct the DNA of the BRCA1 gene. They would try
to create a viable egg without the genetic error that caused the woman’s cancer.
Yang would later tell me that she dropped out of the project not long after we spoke. Yet it remained
difficult to know if the experiment she described was occurring, canceled, or awaiting publication. Sinclair
said that a collaboration between the two labs was ongoing, but then, like several other scientists whom I’d
asked about germ-line engineering, he stopped replying to my e-mails.
Regardless of the fate of that particular experiment, human germ-line engineering has become a burgeoning
research concept. At least three other centers in the United States are working on it, as are scientists in
China, in the U.K., and at a biotechnology company called OvaScience, based in Cambridge,
Massachusetts, that boasts some of the world’s leading fertility doctors on its advisory board.
All this means that germ-line engineering is much further along than anyone imagined.
The objective of these groups is to demonstrate that it’s possible to produce children free of specific genes
involved in inherited disease. If it’s possible to correct the DNA in a woman’s egg, or a man’s sperm, those
cells could be used in an in vitro fertilization (IVF) clinic to produce an embryo and then a child. It might
also be possible to directly edit the DNA of an early-stage IVF embryo using CRISPR. Several people
interviewed by MIT Technology Review said that such experiments had already been carried out in China
and that results describing edited embryos were pending publication. These people, including two highranking specialists, didn’t wish to comment publicly because the papers are under review.
All this means that germ-line engineering is much further along than anyone imagined. “What you are
talking about is a major issue for all humanity,” says Merle Berger, one of the founders of Boston IVF, a
network of fertility clinics that is among the largest in the world and helps more than a thousand women get
pregnant each year. “It would be the biggest thing that ever happened in our field.” Berger predicts that
repairing genes involved in serious inherited diseases will win wide public acceptance but says the idea of
using the technology beyond that would cause a public uproar because “everyone would want the perfect
child”: people might pick and choose eye color and eventually intelligence. “These are things we talk about
all the time,” he says. “But we have never had the opportunity to do it.”
Editing embryos
How easy would it be to edit a human embryo using CRISPR? Very easy, experts say. “Any scientist with
molecular biology skills and knowledge of how to work with [embryos] is going to be able to do this,” says
Jennifer Doudna, a biologist at the University of California, Berkeley, who in 2012 co-discovered how to
use CRISPR to edit genes.
To find out how it could be done, I visited the lab of Guoping Feng, a biologist at MIT’s McGovern
Institute for Brain Research, where a colony of marmoset monkeys is being established with the aim of
using CRISPR to create accurate models of human brain diseases. To create the models, Feng will edit the
DNA of embryos and then transfer them into female marmosets to produce live monkeys. One gene Feng
hopes to alter in the animals is SHANK3. The gene is involved in how neurons communicate; when it’s
damaged in children, it is known to cause autism.
Feng said that before CRISPR, it was not possible to introduce precise changes into a primate’s DNA. With
CRISPR, the technique should be relatively straightforward. The CRISPR system includes a gene-snipping
enzyme and a guide molecule that can be programmed to target unique combinations of the DNA letters, A,
G, C, and T; get these ingredients into a cell and they will cut and modify the genome at the targeted sites.
But CRISPR is not perfect—and it would be a very haphazard way to edit human embryos, as Feng’s
efforts to create gene-edited marmosets show. To employ the CRISPR system in the monkeys, his students
simply inject the chemicals into a fertilized egg, which is known as a zygote—the stage just before it starts
dividing.
Feng said the efficiency with which CRISPR can delete or disable a gene in a zygote is about 40 percent,
whereas making specific edits, or swapping DNA letters, works less frequently—more like 20 percent of
the time. Like a person, a monkey has two copies of most genes, one from each parent. Sometimes both
copies get edited, but sometimes just one does, or neither. Only about half the embryos will lead to live
births, and of those that do, many could contain a mixture of cells with edited DNA and without. If you add
up the odds, you find you’d need to edit 20 embryos to get a live monkey with the version you want.
That’s not an insurmountable problem for Feng, since the MIT breeding colony will give him access to
many monkey eggs and he’ll be able to generate many embryos. However, it would present obvious
problems in humans. Putting the ingredients of CRISPR into a human embryo would be scientifically
trivial. But it wouldn’t be practical for much just yet. This is one reason that many scientists view such an
experiment (whether or not it has really occurred in China) with scorn, seeing it more as a provocative bid
to grab attention than as real science. Rudolf Jaenisch, an MIT biologist who works across the street from
Feng and who in the 1970s created the first gene-modified mice, calls attempts to edit human embryos
“totally premature.” He says he hopes these papers will be rejected and not published. “It’s just a
sensational thing that will stir things up,” says Jaenisch. “We know it’s possible, but is it of practical use? I
kind of doubt it.”
For his part, Feng told me he approves of the idea of germ-line engineering. Isn’t the goal of medicine to
reduce suffering? Considering the state of the technology, however, he thinks actual gene-edited humans
are “10 to 20 years away.” Among other problems, CRISPR can introduce off-target effects or change bits
of the genome far from where scientists had intended. Any human embryo altered with CRISPR today
would carry the risk that its genome had been changed in unexpected ways. But, Feng said, such problems
may eventually be ironed out, and edited people will be born. “To me, it’s possible in the long run to
dramatically improve health, lower costs. It’s a kind of prevention,” he said. “It’s hard to predict the future,
but correcting disease risks is definitely a possibility and should be supported. I think it will be a reality.”
Editing eggs
Elsewhere in the Boston area, scientists are exploring a different approach to engineering the germ line, one
that is technically more demanding but probably more powerful. This strategy combines CRISPR with
unfolding discoveries related to stem cells. Scientists at several centers, including Church’s, think they will
soon be able to use stem cells to produce eggs and sperm in the laboratory. Unlike embryos, stem cells can
be grown and multiplied. Thus they could offer a vastly improved way to create edited offspring with
CRISPR. The recipe goes like this: First, edit the genes of the stem cells. Second, turn them into an egg or
sperm. Third, produce an offspring.
Some investors got an early view of the technique on December 17, at the Benjamin Hotel in Manhattan,
during commercial presentations by OvaScience. The company, which was founded four years ago, aims to
commercialize the scientific work of David Sinclair, who is based at Harvard, and Jonathan Tilly, an expert
on egg stem cells and the chairman of the biology department at Northeastern University (see “10
Emerging Technologies: Egg Stem Cells,” May/June 2012). It made the presentations as part of a
successful effort to raise $132 million in new capital during January.
During the meeting, Sinclair, a velvet-voiced Australian whom Time last year named one of the “100 Most
Influential People in the World,” took the podium and provided Wall Street with a peek at what he called
“truly world-changing” developments. People would look back at this moment in time and recognize it as a
new chapter in “how humans control their bodies,” he said, because it would let parents determine “when
and how they have children and how healthy those children are actually going to be.”
The company has not perfected its stem-cell technology—it has not reported that the eggs it grows in the
lab are viable—but Sinclair predicted that functional eggs were “a when, and not an if.” Once the
technology works, he said, infertile women will be able to produce hundreds of eggs, and maybe hundreds
of embryos. Using DNA sequencing to analyze their genes, they could pick among them for the healthiest
ones.
Genetically improved children may also be possible. Sinclair told the investors that he was trying to alter
the DNA of these egg stem cells using gene editing, work he later told me he was doing with Church’s lab.
“We think the new technologies with genome editing will allow it to be used on individuals who aren’t just
interested in using IVF to have children but have healthier children as well, if there is a genetic disease in
their family,” Sinclair told the investors. He gave the example of Huntington’s disease, caused by a gene
that will trigger a fatal brain condition even in someone who inherits only one copy. Sinclair said gene
editing could be used to remove the lethal gene defect from an egg cell. His goal, and that of OvaScience, is
to “correct those mutations before we generate your child,” he said. “It’s still experimental, but there is no
reason to expect it won’t be possible in coming years.”
Sinclair spoke to me briefly on the phone while he was navigating in a cab across a snowed-in Boston, but
later he referred my questions to OvaScience. When I contacted OvaScience, Cara Mayfield, a
spokeswoman, said its executives could not comment because of their travel schedules but confirmed that
the company was working on treating inherited disorders with gene editing. What was surprising to me was
that OvaScience’s research in “crossing the germ line,” as critics of human engineering sometimes put it,
has generated scarcely any notice. In December of 2013, OvaScience even announced it was putting $1.5
million into a joint venture with a synthetic biology company called Intrexon, whose R&D objectives
include gene-editing eggs to “prevent the propagation” of human disease “in future generations.”
When I reached Tilly at Northeastern, he laughed when I told him what I was calling about. “It’s going to
be a hot-button issue,” he said. Tilly also said his lab was trying to edit egg stem cells with CRISPR “right
now” to rid them of an inherited genetic disease that he didn’t want to name. Tilly emphasized that there
are “two pieces of the puzzle”—one being stem cells and the other gene editing. The ability to create large
numbers of egg stem cells is critical, because only with sizable quantities can genetic changes be stably
introduced using CRISPR, characterized using DNA sequencing, and carefully studied to check for
mistakes before producing an egg.
Tilly predicted that the whole end-to-end technology—cells to stem cells, stem cells to sperm or egg and
then to offspring—would end up being worked out first in animals, such as cattle, either by his lab or by
companies such as eGenesis, the spinoff from the Church lab working on livestock. But he isn’t sure what
the next step should be with edited human eggs. You wouldn’t want to fertilize one “willy nilly,” he said.
You’d be making a potential human being. And doing that would raise questions he’s not sure he can
answer. He told me, “‘Can you do it?’ is one thing. If you can, then the most important questions come up.
‘Would you do it? Why would you want to do it? What is the purpose?’ As scientists we want to know if
it’s feasible, but then we get into the bigger questions, and it’s not a science question—it’s a society
question.”
Improving humans
If germ-line engineering becomes part of medical practice, it could lead to transformative changes in
human well-being, with consequences to people’s life span, identity, and economic output. But it would
create ethical dilemmas and social challenges. What if these improvements were available only to the
richest societies, or the richest people? An in vitro fertility procedure costs about $20,000 in the United
States. Add genetic testing and egg donation or a surrogate mother, and the price soars toward $100,000.
Others believe the idea is dubious because it’s not medically necessary. Hank Greely, a lawyer and ethicist
at Stanford University, says proponents “can’t really say what it is good for.” The problem, says Greely, is
that it’s already possible to test the DNA of IVF embryos and pick healthy ones, a process that adds about
$4,000 to the cost of a fertility procedure. A man with Huntington’s, for instance, could have his sperm
used to fertilize a dozen of his partner’s eggs. Half those embryos would not have the Huntington’s gene,
and those could be used to begin a pregnancy.
Indeed, some people are adamant that germ-line engineering is being pushed ahead with “false arguments.”
That is the view of Edward Lanphier, CEO of Sangamo Biosciences, a California biotechnology company
that is using another gene-editing technique, called zinc fingers nucleases, to try to treat HIV in adults by
altering their blood cells. “We’ve looked at [germ-line engineering] for a disease rationale, and there is
none,” he says. “You can do it. But there really isn’t a medical reason. People say, well, we don’t want
children born with this, or born with that—but it’s a completely false argument and a slippery slope toward
much more unacceptable uses.”
Critics cite a host of fears. Children would be the subject of experiments. Parents would be influenced by
genetic advertising from IVF clinics. Germ-line engineering would encourage the spread of allegedly
superior traits. And it would affect people not yet born, without their being able to agree to it. The
American Medical Association, for instance, holds that germ-line engineering shouldn’t be done “at this
time” because it “affects the welfare of future generations” and could cause “unpredictable and irreversible
results.” But like a lot of official statements that forbid changing the genome, the AMA’s, which was last
updated in 1996, predates today’s technology. “A lot of people just agreed to these statements,” says
Greely. “It wasn’t hard to renounce something that you couldn’t do.”
The fear? A dystopia of superpeople and designer babies for those who can afford it.
Others predict that hard-to-oppose medical uses will be identified. A couple with several genetic diseases at
once might not be able to find a suitable embryo. Treating infertility is another possibility. Some men don’t
produce any sperm, a condition called azoospermia. One cause is a genetic defect in which a region of
about one million to six million DNA letters is missing from the Y chromosome. It might be possible to
take a skin cell from such a man, turn it into a stem cell, repair the DNA, and then make sperm, says
Werner Neuhausser, a young Austrian doctor who splits his time between the Boston IVF fertility-clinic
network and Harvard’s Stem Cell Institute. “That will change medicine forever, right? You could cure
infertility, that is for sure,” he says.
I spoke with Church several times by telephone over the last few months, and he told me what’s driving
everything is the “incredible specificity” of CRISPR. Although not all the details have been worked out, he
thinks the technology could replace DNA letters essentially without side effects. He says this is what makes
it “tempting to use.” Church says his laboratory is focused mostly on experiments in engineering animals.
He added that his lab would not make or edit human embryos, calling such a step “not our style.”
What is Church’s style is human enhancement. And he’s been making a broad case that CRISPR can do
more than eliminate disease genes. It can lead to augmentation. At meetings, some involving groups of
“transhumanists” interested in next steps for human evolution, Church likes to show a slide on which he
lists naturally occurring variants of around 10 genes that, when people are born with them, confer
extraordinary qualities or resistance to disease. One makes your bones so hard they’ll break a surgical drill.
Another drastically cuts the risk of heart attacks. And a variant of the gene for the amyloid precursor
protein, or APP, was found by Icelandic researchers to protect against Alzheimer’s. People with it never get
dementia and remain sharp into old age.
Church thinks CRISPR could be used to provide people with favorable versions of genes, making DNA
edits that would act as vaccines against some of the most common diseases we face today. Although he told
me anything “edgy” should be done only to adults who can consent, it’s obvious to him that the earlier such
interventions occur, the better.
Church tends to dodge questions about genetically modified babies. The idea of improving the human
species has always had “enormously bad press,” he wrote in the introduction to Regenesis, his 2012 book
on synthetic biology, whose cover was a painting by Eustache Le Sueur of a bearded God creating the
world. But that’s ultimately what he’s suggesting: enhancements in the form of protective genes. “An
argument will be made that the ultimate prevention is that the earlier you go, the better the prevention,” he
told an audience at MIT’s Media Lab last spring. “I do think it’s the ultimate preventive, if we get to the
point where it’s very inexpensive, extremely safe, and very predictable.” Church, who has a less cautious
side, proceeded to tell the audience that he thought changing genes “is going to get to the point where it’s
like you are doing the equivalent of cosmetic surgery.”
Some thinkers have concluded that we should not pass up the chance to make improvements to our species.
“The human genome is not perfect,” says John Harris, a bioethicist at Manchester University, in the U.K.
“It’s ethically imperative to positively support this technology.” By some measures, U.S. public opinion is
not particularly negative toward the idea. A Pew Research survey carried out last August found that 46
percent of adults approved of genetic modification of babies to reduce the risk of serious diseases.
The same survey found that 83 percent said genetic modification to make a baby smarter would be “taking
medical advances too far.” But other observers say higher IQ is exactly what we should be considering.
Nick Bostrom, an Oxford philosopher best known for his 2014 book Superintelligence, which raised alarms
about the risks of artificial intelligence in computers, has also looked at whether humans could use
reproductive technology to improve human intellect. Although the ways in which genes affect intelligence
aren’t well understood and there are far too many relevant genes to permit easy engineering, such realities
don’t dim speculation on the possibility of high-tech eugenics.
“The human genome is not perfect. It’s ethically imperative to positively support this technology.”
What if everyone could be a little bit smarter? Or a few people could be a lot smarter? Even a small number
of “super-enhanced” individuals, Bostrom wrote in a 2013 paper, could change the world through their
creativity and discoveries, and through innovations that everyone else would use. In his view, genetic
enhancement is an important long-range issue like climate change or financial planning by nations, “since
human problem-solving ability is a factor in every challenge we face.”
To some scientists, the explosive advance of genetics and biotech means germ-line engineering is
inevitable. Of course, safety questions would be paramount. Before there’s a genetically edited baby saying
“Mama,” there would have to be tests in rats, rabbits, and probably monkeys, to make sure they are normal.
But ultimately, if the benefits seem to outweigh the risks, medicine would take the chance. “It was the same
with IVF when it first happened,” says Neuhausser. “We never really knew if that baby was going to be
healthy at 40 or 50 years. But someone had to take the plunge.”
Wine country
In January, on Saturday the 24th, around 20 scientists, ethicists, and legal experts traveled to Napa Valley,
California, for a retreat among the vineyards at the Carneros Inn. They had been convened by Doudna, the
Berkeley scientist who co-discovered the CRISPR system a little over two years ago. She had become
aware that scientists might be thinking of crossing the germ line, and she was concerned. Now she wanted
to know: could they be stopped?
“We as scientists have come to appreciate that CRISPR is incredibly powerful. But that swings both ways.
We need to make sure that it’s applied carefully,” Doudna told me. “The issue is especially human germline editing and the appreciation that this is now a capability in everyone’s hands.”
At the meeting, along with ethicists like Greely, was Paul Berg, a Stanford biochemist and Nobel Prize
winner known for having organized the Asilomar Conference, a historic 1975 forum at which biologists
reached an agreement on how to safely proceed with recombinant DNA, the newly discovered method of
splicing DNA into bacteria.
Should there be an Asilomar for germ-line engineering? Doudna thinks so, but the prospects for consensus
seem dim. Biotechnology research is now global, involving hundreds of thousands of people. There’s no
single authority that speaks for science, and no easy way to put the genie back in the bottle. Doudna told
me she hoped that if American scientists agreed to a moratorium on human germ-line engineering, it might
influence researchers elsewhere in the world to cease their work.
Doudna said she felt that a self-imposed pause should apply not only to making gene-edited babies but also
to using CRISPR to alter human embryos, eggs, or sperm—as researchers at Harvard, Northeastern, and
OvaScience are doing. “I don’t feel that those experiments are appropriate to do right now in human cells
that could turn into a person,” she told me. “I feel that the research that needs to be done right now is to
understand safety, efficacy, and delivery. And I think those experiments can be done in nonhuman systems.
I would like to see a lot more work done before it’s done for germ-line editing. I would favor a very
cautious approach.”
Not everyone agrees that germ-line engineering is such a big worry, or that experiments should be
padlocked. Greely notes that in the United States, there are piles of regulations to keep lab science from
morphing into a genetically modified baby anytime soon. “I would not want to use safety as an excuse for a
non-safety-based ban,” says Greely, who says he pushed back against talk of a moratorium. But he also
says he agreed to sign Doudna’s letter, which now reflects the consensus of the group. “Although I don’t
view this as a crisis moment, I think it’s probably about time for us to have this discussion,” he says.
(After this article was published online in March, Doudna’s editorial appeared in Science (see “Scientists
Call for a Summit on Gene-Edited Babies”.) Along with Greely, Berg, and 15 others, she called for a
global moratorium on any effort to use CRISPR to generate gene-edited children until researchers could
determine “what clinical applications, if any, might in the future be deemed permissible.” The group,
however, endorsed basic research, including applying CRISPR to embryos. The final list of signatories
included Church, although he did not attend the Napa meeting.)
As news has spread of germ-line experiments, some biotechnology companies now working on CRISPR
have realized that they will have to take a stand. Nessan Bermingham is CEO of Intellia Therapeutics, a
Boston startup that raised $15 million last year to develop CRISPR into gene therapy treatments for adults
or children. He says germ-line engineering “is not on our commercial radar,” and he suggests that his
company could use its patents to prevent anyone from commercializing it.
“The technology is in its infancy,” he says. “It is not appropriate for people to even be contemplating germline applications.”
Bermingham told me he never imagined he’d have to be taking a position on genetically modified babies so
soon. Modifying human heredity has always been a theoretical possibility. Suddenly it’s a real one. But
wasn’t the point always to understand and control our own biology—to become masters over the processes
that created us?
Doudna says she is also thinking about these issues. “It cuts to the core of who we are as people, and it
makes you ask if humans should be exercising that kind of power,” she told me. “There are moral and
ethical issues, but one of the profound questions is just the appreciation that if germ-line editing is
conducted in humans, that is changing human evolution.” One reason she feels the research should slow
down is to give scientists a chance to spend more time explaining what their next steps could be.
“Most of the public,” she says, “does not appreciate what is coming.”
This story was updated on April 23, 2015
MIT
Rewriting Life
U.S. Panel Endorses Designer Babies to Avoid Serious Disease
Genetically modified children could be acceptable in narrow circumstances, according to National
Academy of Sciences.



by Antonio Regalado
February 14, 2017
embryo, as seen through a microscope in an IVF lab.
An early-stage human
Since its invention four years ago, a powerful and precise technology for editing DNA called CRISPR has
transformed science because of how it makes altering the genetic makeup of plants and animals easier than
ever before.
But no possibility opened by gene-editing technology has been so exciting, frightening, or as hotly
contested as its capacity to allow humanity, for the first time, to control the genetic constitution of children
by applying CRISPR to human embryos, sperm, or eggs—cells which together make up the “germ line.”
On Tuesday, in a striking acknowledgement that humanity is on the cusp of genetically modified children,
a panel of the National Academy of Sciences, the nation’s source of blue-ribbon advice on science policy,
recommended that germ-line modification of human beings be permitted in the future in certain narrow
circumstances to prevent the birth of children with serious diseases.
"Heritable germline genome editing trials must be approached with caution, but caution does not mean that
they must be prohibited," according to a 216-page report released today and which was researched and
written over the course of a year by a 22-member panel of prominent scientists and experts.
The recommendations came freighted with moral and technical caveats, however. The panel believes it will
be many years before germ-line engineering is safe enough to consider. The panel also said it should
proceed only under “stringent oversight,” and drew a bright line between preventing disease and
“enhancements” like attempting to alter genes to make people more intelligent, which it said should not be
pursued “at this time.”
Despite the cautious language, the panel’s endorsement of GM humans could prove politically explosive,
and puts the academy’s experts in conflict with existing legislation in Europe and the U.S. as well as with
swaths of the public who oppose the idea of modifying the human genome from birth out of religious
conviction or for other reasons.
Germ-line modification is already prohibited as a practical matter in the U.S. In 2015, pro-life legislators
added a rider to the U.S. Department of Health and Human Services appropriations bill, which forbids the
U.S. Food and Drug Administration from considering any proposal to create genetically modified
offspring.
The legislation, which has to be renewed periodically, means that any proposal to modify an embryo and
create a child would be ignored and could not legally proceed in the U.S.
In contrast, the academy panel argued that germ-line editing should be allowed in narrow cases where it is
the only option for “preventing a serious disease or condition.” For instance, a couple who each suffers
from beta thalassemia might only have healthy children free from the inherited blood disorder if they were
able to produce embryos in which the genetic defect was corrected using gene editing. The report
acknowledges that such circumstances might be exceedingly rare.
“They show a narrow but clear path to future clinical use,” says Tetsuya Ishii, a bioethicist at Hokkaido
University in Japan who tracks global legislation on germ-line modification. He says the report also
provides a justification for laboratory research already occurring in China, Sweden, and the U.K. in which
gene-editing is being applied to human embryos to explore its potential. “They want to show that basic
research toward severe disease prevention would be permissible,” he says.
The report’s authors struggled with how legitimate medical applications could be encouraged while still
preventing “a slippery slope toward less compelling or even antisocial uses” like enhancement of height,
looks, or intelligence. The report’s authors addressed that problem by arguing that no form of germ-line
editing should be allowed if a country’s regulators can’t also guarantee the technology won’t be misused
for “enhancement” of human beings.
“They have said there is one narrow corner, a tiny fraction of cases, where it might be the right thing to
do,” says Eric Lander, head of the Broad Institute in Cambridge, Massachusetts, which has invested heavily
in developing CRISPR technology. “What is fascinating is their argument that if we can’t control where it
goes from there, we shouldn’t do it at all.”
It’s not clear how such a policy, which Lander calls “the ‘no slippery slopes’ recommendation,” would be
implemented. Other technologies considered dangerous, like nuclear weapons, are monitored by a complex
combination of technical bodies, international diplomacy, sanctions, and military threats.
Lander says the Broad Institute is “uneasy” with germ-line therapy. It controls more than a dozen patents
on CRISPR, which it has licensed to biotech companies, but with a requirement they don’t use it for germline modification. “We didn’t want to be licensing technology for germ-line editing ahead of society
reaching consensus and we are still very far from a consensus,” Lander says.
The report draws a sharp distinction between modifying embryos and modifying the DNA of adults and
children. The latter process, known as gene therapy, is already a well-established part of medical research,
does not raise the same ethical questions, and should proceed without new restrictions. Scientists are now
racing to apply CRISPR as an even more effective way to perform gene therapy on adults, including to treat
cancer and muscular dystrophy.
In the case of editing human embryos, the line between avoiding serious disease and enhancement may
eventually prove to be a blurry one. In addition to preventing the transmission of known genetic diseases
like beta thalassemia or cystic fibrosis, the report’s authors said their positive recommendation could also
apply to genetic improvements that would act like a vaccine, making people less susceptible to HIV
infection or cancer. For instance, people with a certain version of a gene called ApoE are much less likely
to develop Alzheimer’s. The report’s authors said that swapping in a “protective” version of ApoE or
another gene to an embryo might also be considered acceptable if it prevents disease.
“We do not view prevention as a form of enhancement,” says R. Alta Charo, a University of Wisconsin
bioethicist who co-chaired the panel. “But whether it’s permissible is up to regulators.” She says the group
intentionally did not list specific diseases or situations where germ-line modification should be used.
Controlling the technology could prove difficult. One worry is that doctors and scientists will go overseas
to countries with permissive rules, or no rules, to attempt it. That is already occurring with a related
technique known as mitochondrial transfer, which involves the transfer of DNA-bearing structures between
eggs. Last year, a New York fertility doctor treated an American woman in Mexico using the procedure.
Most reports of the academy quickly end up on bookshelves and are of interest to only a few experts. But
George Annas, a bioethicist at Boston University, says this one has the potential to be politically explosive
because of how it presents the right of parents to use germ-line modification as a “procreative liberty” such
as abortion.
“The scientists are saying this is all a question of risk benefit analysis, versus saying, 'No, it’s just wrong to
do,'” says Annas. He thinks the committee “underestimates” public discomfort with the idea. “It’s like
torture—some people think we should never do it, other people say, 'No, no, if it works, then it’s okay.'
Designer babies is a lot like that.”
Charo says her panel did not consider the political ramifications of its findings. “We looked at these
questions without considering what happens in the political sphere. That is a moving target,” she says.
“That is beyond us.”
The Economist
Reproductive technologies
Gene editing, clones and the science of making babies
Ways of reproducing without sexual
intercourse are multiplying. History
suggests that they should be embraced
Feb 18th 2017



IT USED to be so simple. Girl met boy. Gametes were transferred through plumbing optimised by millions
of years of evolution. Then, nine months later, part of that plumbing presented the finished product to the
world. Now things are becoming a lot more complicated. A report published on February 14th by
America’s National Academy of Sciences gives qualified support to research into gene-editing techniques
so precise that genetic diseases like haemophilia and sickle-cell anaemia can be fixed before an embryo
even starts to develop. The idea of human cloning triggered a furore when, 20 years ago this week, Dolly
the sheep was revealed to the world (see article); much fuss about nothing, some would say, looking back.
But other technological advances are making cloning humans steadily more feasible.
Some are horrified at the prospect of people “playing God” with reproduction. Others, whose lives are
blighted by childlessness or genetic disease, argue passionately for the right to alleviate suffering. Either
way, the science is coming and society will have to work out what it thinks.
Where have you been, my blue-eyed son?
The range of reproductive options has steadily widened. AID (artificial insemination by donor, which dates
back to the 19th century) and IVF (in vitro fertilisation, first used in the 1970s) have become everyday
techniques. So has ICSI, intracytoplasmic sperm injection, in which a sperm cell is physically inserted into
an egg, bringing fatherhood to otherwise infertile men. Last year another practice was added—
mitochondrial transplantation or, as the headlines would have it, three-parent children. The world may soon
face the possibility of eggs and sperm made from putative parents’ body cells (probably their skin) rather
than in their ovaries and testes.
Such methods separate sexual intercourse from reproduction. Most of them bring the possibility of
choosing which embryo will live, and which will die. At first they can seem bewildering—disgusting, even.
But one thing experience has shown is that, in this area, disgust is not a good guide to policy. AID was
treated by at least one American court as a species of adultery and its progeny deemed illegitimate in the
eyes of the law. IVF led to anguish among some theologians about whether “test-tube” babies would have
souls.
Disgust often goes along with dystopian alarm. Science-fiction versions of gene editing imagine, say, the
creation of supermen and superwomen of great intelligence or physical prowess. When Dolly was
announced the press was full of headlines about clone armies. In truth no one has the slightest clue how to
create Übermenschen even if they wanted to. Yet the record shows how fast reproductive science can
progress. So it makes sense to think about the ethics of reproductive science even for outcomes that are not
yet available.
It helps to start with IVF and AID, which have made the journey from freakishness to familiarity. Both give
healthy children to happy parents, who would otherwise have been alone. The same will no doubt prove
true for mitochondrial transplants, which are intended to avoid rare but dangerous diseases that affect
cellular energy production.
Happy parents and healthy children make a pretty good rule for thinking about any reproductive
technology. A procedure’s safety is the central concern. Proving this is a high hurdle. Researchers are,
wrongly in the eyes of some, allowed to experiment on human embryos when they consist of just a few
cells. They cannot, though, experiment on human fetuses. Nor can they experiment easily on fetuses from
humanity’s closest relatives, the great apes, since these animals are rare and often legally protected, too. So
far, therefore, there has had to be a “leap of faith” when a technique that has been tested as far as is possible
within the law’s bounds is used for real. That should continue, in order to avoid “freelance” operations
outside reliable jurisdictions. This is not a theoretical concern. Although Britain developed mitochondrial
transplants and was the first country to license them, the first couple known to have had such a transplant
travelled from Jordan to Mexico to do so.
Defining the limits of what should be allowed is more slippery. But again, the test of happy parents and
healthy children is the right one. Growing sperm and eggs from body cells is surely the least problematic
new technique soon to be on offer. One advantage of this approach is that gay couples could have children
related to both parents. But the law should insist that two people be involved. If one person tried to be both
father and mother to a child, the resulting eggs and sperm would, without recourse to wholesale gene
editing, combine to concentrate harmful mutations in what would amount to the ultimate form of
inbreeding.
Gene editing and cloning involve more than parents’ happiness and children’s health. The first gene editing
will eliminate genetic diseases in a way that now requires embryo selection—an advance many would
applaud. Adults should be able to clone perfect copies of themselves, as an aspect of self-determination.
But breeding babies with new traits and cloning other people raises questions of equality and of whether it
is ever right to use other people’s tissues without their consent.
A sense of identity
The questions will be legion. Should bereaved parents be able to clone a lost child? Or a widow her
departed husband? Should the wealthy be able to pay for their children to be intelligent and diligent, if
nobody else can afford to do so?
Commissions of experts will need to search for answers; and courts will need to apply the rules—to protect
the interests of the unborn. They will be able to draw on precedents, such as identical twins, where society
copes with clones perfectly well, or “saviour siblings”, selected using IVF to provide stem cells that can
cure a critically ill older brother or sister. Any regime must be adaptable, because opinions change as
people get used to new techniques. Going by the past, though, the risk is not of people rushing headlong to
the reproductive extremes, but of holding back, and leaving people to suffer out of a misplaced sense of
what feels right.
The Economist
Biotechnology
All latest updates
Cell-free biotech will make for better products
A new type of biological engineering
should speed up innovation
May 3rd 2017 | Science and technology


THE stuff of life comes wrapped in tiny bags called cells. Inside are DNA molecules that carry the
instructions for how to run the cell, to make it grow, and to cause it, ultimately, to divide into two cells, if
that is to be its fate. Messages made of a slightly different molecule, RNA, carry these instructions to
molecular machines called ribosomes. A ribosome’s job is to read the RNA messages and translate them
into proteins, the workhorse molecules of cells. Those proteins then supervise and execute the running, the
growing and the dividing.
It is a system that has worked well over the 4bn years that life has existed on Earth. To some
biotechnologists, though, the cell is old hat. They approve of the machinery of DNA, RNA, ribosomes and
proteins, which can be engineered to make useful chemicals, ranging from drugs to the building-blocks of
plastics. But they want to get rid of the bags that contain it, retaining only the part of the protoplasmic
“gloop” inside a cell needed to do their bidding.
In this way they hope to control, far more precisely than is possible by conventional genetic engineering (or
even by improved methods of gene modification, such as CRISPR-Cas9, that are now being developed)
which genes are translated by the ribosomes—and thus what products are churned out. Equally important,
cell-free biotechnology of this sort means no biochemical effort is wasted on running, growing or dividing
any actual cells. The initial intention is to create a quicker way of finding the best genes for making a
particular product. In the end, those working in the field aspire to the idea that cell-free production will
equal mass production.
Processing power
A typical recipe for making cell-free protoplasmic gloop is this. Take four litres of culture containing E.
coli (a gut bacterium favoured by genetic engineers). Split the bacterial cells open by forcing them through
a tiny valve at pressure, thus shredding their membranes and DNA, and liberating the ribosomes. Incubate
the resulting mixture at 37°C for an hour, to activate enzymes called exonucleases that will eat up the
fragmented DNA. Centrifuge, to separate the scraps of cell membrane and other detritus from the gloop
that contains ribosomes. Dialyse to remove unwanted ions. Then stir in amino acids (the building blocks of
proteins), sugar and an energy-carrying molecule called adenosine triphosphate (ATP) to power the
process. Finally, add a pinch of new DNA to taste, to tell the gloop which proteins it is supposed to
produce.
This particular recipe is the one used by Synvitrobio of Berkeley, California, a firm founded by Zachary
Sun and Richard Murray of the California Institute of Technology and George Church of Harvard
University. Other recipes, with different starting organisms, are possible. Yeast works, as does
Streptomyces, another bacterium. Cells from tobacco plants or the ovaries of Chinese hamsters are also
good places to begin. But all such formulae are variations on the theme of isolating a cell’s protein-making
machinery in a free-floating suspension.
Synvitrobio’s engineers have built a robotic system to mix the final stage of their recipe. This robot parcels
the purified protoplasm into an array of 384 miniscule test tubes, each with a volume of a few millionths of
a litre. It then drops some DNA molecules into each tube and the gloop gets to work on the process of
turning the information in those molecules into proteins. Currently, the system can handle eight DNA
sequences per test tube, meaning 3,072 proteins can be processed in parallel. The sequences can be up to
10,000 genetic “letters” long—enough to encode almost any protein you care to mention.
At present, Synvitrobio is using its system to test DNA sequences (or, rather, the resulting proteins) to see
if they might be worth investigating as antibiotic drugs. Such drugs work by binding to a biologically
important molecule and changing that molecule’s characteristics in some way that is detrimental to the
organism of which it is part. To look for this binding, each mini test tube is also supplied with some of the
target molecules, each attached to a “reporter” molecule that emits a flash of light if binding takes place.
Tubes which flash brightly indicate that one or more of the DNA sequences therein are worth a second
glance. Synvitrobio’s technique is thus able to screen potential drugs at a rate limited only by the
availability of new DNA sequences. Since synthesising new sequences on demand is now a routine
technology, that means the world’s gene libraries can be plundered for likely candidates, and the best of
these then tweaked mercilessly until something good enough for the job turns up. Inserting such sequences
into the genomes of organisms is far more time-consuming than simply dropping them in some gloop.
At the moment, that is the point when Synvitrobio passes the newly discovered molecule on, for a suitable
cut of the proceeds, to someone who can turn it out in bulk by the conventional technique of pasting the
relevant gene into appropriate cells, and breeding these cells in fermentation tanks similar to those used for
brewing beer. This is because it is expensive to produce cell-free protoplasm in the volumes required to
manufacture antibiotics for sale. A few firms are, however, doing so for drugs that can command high
prices.
One such is Sutro Biopharma, based near San Francisco. It uses a cell-free system to create antibodies for
the treatment of cancer. In April, Sutro announced it had employed its system to make STRO-001, an
antibody that inhibits tumour growth. The firm plans to start trials of STRO-001 in 2018. Cell-free
production of the antibodies for that trial is about to begin.
Antibodies are specialised proteins, so once Sutro’s system has identified the best candidate for the job, all
that is required is to seed the gloop with the DNA which encodes that candidate. Other firms, though, hope
to go further than this, by devising manufacturing systems that put together entire metabolic pathways for
the production of chemicals other than proteins. These, as in a natural metabolic pathway, consist of a
series of enzymes (another type of specialised protein) that catalyse a sequence of chemical changes,
gradually converting one molecule into another.
Genomatica, an established biotechnology firm based in San Diego, is experimenting with a cell-free
system which produces 1,4-butanediol in this way from simple sugars. 1,4-butanediol is a small molecule
that is used to make polymers such as Lycra. Generally, it is cheaper to manufacture molecules of this size
using chemistry, rather than biology, but 1,4-butanediol is an exception. It is already made for industry with
the aid of genetically modified E. coli. Genomatica’s system churns out the enzymes involved in this
synthesis, creating an entire cell-free metabolic pathway—and one in which all the sugar is devoted to
making the target chemical, rather than a percentage of it being creamed off to run a cell’s other
biochemical processes. The firm has not yet put the system to commercial use, but has high hopes for it.
GreenLight Biosciences, a firm in Medford, Massachusetts, proposes to use its own cell-free system, also
based on E. coli, to produce industrial quantities of an undigestible analogue of ribose, a naturally occurring
sugar, for use in zero-calorie beverages. The company says it has already got its process to the point where
it can make thousands of litres of solution of this sugar at a time. GreenLight is also working on cell-free
systems that will generate industrial qualities of specially designed RNA molecules that interfere with the
development of insect larvae, and can thus be used as pesticides. Currently, such RNA costs $5,000 per
kilogram to produce. GreenLight thinks that by scaling the process up it can reduce this to between $50 and
$100.
Whether cell-free biotechnology will be able to displace fermentation by genetically modified organisms as
a routine way of making chemicals remains to be seen. Fermentation is a tried and trusted technique, used
by humans since the invention of beer around 12,000 years ago. But the idea of stripping molecular biology
down to its bare essentials has an efficiency about it which suggests that, for some applications at least, the
utility of the biological cell may have run its course.