Download `It`s alive!` How tiny `organs` on microchips could replace mice and

‘It’s alive!’ How tiny ‘organs’ on
microchips could replace mice and rats
in medical research labs.
Wyss Institute, Harvard UniversityThe lung-on-a-chip, developed by Harvard University scientists, is among the first examples
of a new technology that creates miniature versions of human organs to study disease and test drugs.
In hospital basements and laboratory back rooms around the world, they scurry about their cages, the workhorses of the
medical science world. But the mice and rats used to research disease and discover new ways to treat it turn out to be rather
poor stand-ins for homo sapiens.
More than 60% of the experimental drugs that seem promising when tested on lab animals are found to be either ineffective or
dangerous when tried on people.
Scientists, though, are working on a fascinating alternative to the erstwhile mouse “model” that they hope will transform
pharmaceutical development, making it speedier, less hit-and-miss and not so exorbitantly expensive.
Borrowing from electronics-industry technology, they are creating tiny “organs” on microchips, part-artificial, part-living versions
of lungs, hearts, kidneys and more that have already shown promise for testing drugs. Using the same kind of photolithography employed to create the miniature circuits that drive smart phones and computers, scientists craft chips about the
size of a memory stick, crisscrossed with tiny, fluid-carrying channels. The channels are in turn lined with living, human cells
from a particular organ, acting much like the real thing. What is more, the synthetic-polymer devices are transparent, giving
researchers an unprecedented view of what is happening inside.
“We literally have a window on human, organ-level function, with molecular-scale resolution — in real time,” said Don Ingber,
head of Harvard University’s Wyss Institute and one of the pioneers of the technology. “And it’s alive.”
Underlining the field’s unusual intersection between bio-engineering and electronics, Wyss recently forged a partnership with
Sony, which is switching some of its capacity for making an increasingly anachronistic product – CDs — into fabricating
cutting-edge bio-chips.
One of Wyss’s projects involves developing a way to automatically assess the impact of new medication on the chips.
“The pharmaceutical industry wants a big black box that you can put organs in like a DVD player and get out results that tell
you drug efficacy, toxicity,” said Prof. Ingber. “So that’s what we’re doing. We’re building an automated instrument that would
literally have 10 DVD-like cassettes and each one holds a chip, a different organ. “
His and other groups are also working on linking organs via fluid channels into a single, integrated “body on a chip.”
Canada is in the thick of the research, too. Labs headed by University of Toronto professors Axel Guenther and Dr. SteffenSebastian Bolz have developed an artery on a chip, where an actual piece of a blood vessel is integrated into the device.
A video posted online by the researchers shows an artery constricting, as a drug that increases blood pressure is applied to it
through the micro-channels.
The U.S. government, including a defence research agency anxious to find new, faster ways to develop antidotes to chemical
and biological weapons, decided a year ago to invest $150-million into the technology.
Cells used in organ chips now are usually removed directly from a person by biopsy or autopsy. One of the thrusts of the
burgeoning new field, though, is to develop an efficient way of turning stem cells extracted from human skin into the cells from
different human organs.
Ideally, scientists could then create lines of stem cells from thousands of people of various genetic makeups, so drugs in early
testing could be exposed to a vast array of DNA, said Dan Tagle, who is overseeing the organ-chip program for the National
Center for Advancing Translational Sciences (NCATS).
“You can have 10,000 bodies on chips, then it’s almost unlimited what you can do,” he said from his office in Bethesda, Md.
“You could even think of running clinical trials on these chips, because now you have a standard set of individuals that
represents, say, the world’s demographics,” he said. “You can [determine] which population will be responders to particular
drugs, and which will most likely have adverse events.”
Behind all the work lies medical science’s age-old reliance on animals: expendable, genetically modifiable fellow mammals.
Development of drugs typically begins with experiments using cell cultures in a petri dish, followed by studies on animals and,
ultimately, human trials.
Mice are widely used, not only because they are small and relatively inexpensive but because their anatomy, physiology and
genetics are surprisingly similar to those of humans. Yet a growing body of evidence suggests they make for less than perfect
predictors of what works in people.
A study published this year, for instance, found that mice were lousy models for sepsis and other forms of inflammation
caused by infection, trauma and burns. That is likely why not one of 150 different drugs deemed effective on mice for such
problems has worked in humans, the authors said.
Still, mice do work some of the time, and one of their key attributes is that they can be manipulated to develop diseases that
people get, a necessity for studying those conditions and devising treatments. Can the same be said for a microchip?
Early results suggest it is possible. Dr. Ingber’s lab applied the cancer drug interleukin 2 to his lung-on-a-chip and triggered
pulmonary edema — fluid on the lung — a known and potentially fatal side-effect of the medication in human patients. The
researchers also found drugs that could counter the problem, according to a journal paper published last year.
Some of the labs funded by NCATS are working to introduce long QT syndrome — a heart defect that can cause sudden
death in otherwise healthy people — onto cardiac chips, said Mr. Tagle.
The organs can also simply be made from the cells of patients with particular diseases.
Profs. Guenther and Bolz in Toronto have developed a somewhat different chip, using pieces of intact arteries, instead of
tissue grown from individual cells. They are using animal arteries now, but plan to eventually work with human blood vessels.
The devices could be used to observe the effects, positive and otherwise, of different drugs for hypertension and other
vascular problems.
“There is lots to be learned from these chip-based systems,” said Prof. Guenther.
The pharmaceutical industry, which says it spends hundreds of millions of dollars to bring a new drug to market, is showing
interest in the chip technology and its potential to weed out products that fail during pricey human trials.
Astra Zeneca has already partnered with the Wyss Institute.
It is even possible that organs on a chip will one day be used in the burgeoning field of personalized medicine, said Mr. Tagle.
Cells derived from individual patients’ stem cells could be turned into organs to determine which treatment would be most
effective on them.
For now, though, much of the technology’s potential has yet to be realized, and animals will continue to be an essential part of
the medical-research process.
The short-term plan is to have integrated organs on a chip ready for practical use within five years, said Mr. Tagle. That is a
prospect that Prof. Ingber clearly relishes.
“You could have an aerosol-based drug go into the lung on a chip, watch it be metabolized by the liver and broken down and
then see … whether it’s peed out by the kidney, and then see if it has heart toxicity on the heart chip,” he said.
“You’re looking … at what the net sum effect is on your target.”