Download Human Embryology and Natural Stem Cells iPS…..induced

Sam Rhine - Genetic Update Conferences - www.samrhine.com - Twitter: @samrhineguc
Human Embryology and Natural Stem Cells
iPS…..induced Pluripotent Stem Cells…..Lab-Made
CRISPR/Cas9 and Applications for Human Gene Editing
I. Miraculous Event #1…..it happens all the time, we have all been involved
it takes eight weeks - formation of a human fetus
A. How can this happen in just eight weeks - the Human Anatomy perspective
Human Embryology - the Biologic Levels of Complexity perspective
B. When does this all begin? Egg from the Ovary + Sperm from the Testis
Mitosis: Equational Cell Division v. Meiosis: Reductional Cell Division
Egg = Oocyte / Ovum from Primary Oocyte / Sperm from Primary Spermatocyte
Male: leads to formation of 4 Spermatids - each differentiates > flagellated sperm
begins at puberty and continues throughout life
Female: leads to formation of 1 oocyte nucleus and three (two) polar bodies
begins in fetal ovary before birth - then goes into meiotic arrest
one egg a month resumes meiosis at puberty - ends at menopause
Ovulation - release of oocyte from ovary - Meiosis I > first Polar Body forms
Fertilization - sperm enters the oocyte - Meiosis II > second Polar Body forms
Females rarely complete meiosis
Oocyte nucleus becomes Female Pronucleus, Sperm nucleus - Male Pronucleus
C. Zygote Nucleus - fusion of female and female pronuclei - contains the Fetal Genome
Genome = sum total of all the genetic information for any organism;
>3,000,000,000 nucleotides; over 6 meters of DNA; 46 chromosomes;
~23,000 coding genes
- code for proteins;
~13,500 non-coding genes - produce RNAs = ~36,500 total genes
~0.000055% of genome - not in nucleus…..16,569nts in mitochondrial DNA
Baby born with three genetic parents - put mother’s nucleus in donor egg cytoplasm
D. Zygote = fertilized egg, largest human cell, point of a straight pin, visible with naked eye
Zona Pelucida (ZP) = gelatin surrounding zygote; sperm penetrate ZP for fertilization
Two Cell Embryo at about 36 hours = two blastomeres; 6 cleavage divisions
Embryo Splitting > Twins: MZ Twins - monozygotic - identical - one zygote splits
DZ Twins - dizygotic
- fraternal - two zygotes
Cleavage Divisions: 1 >2 >4 >8 >16 >32 >64; 64 cell embryo = morula
Human Hatching: ZP turns into a hard case = shell, embryo emerges on day 4
E. Blastocyst - embryo turns into a hollow sphere by days 5 - 6
Where does this all take place? Uterus (womb), Fallopian Tubes, Ovaries
Fertilization occurs in the tube = day 1; first four days…..‘going down the tube’
Implantation on days 6-10; embryo implants in uterine wall . produces sprouts
Pregnancy: Sprouts hook into mother’s blood stream – source of food and oxygen
Sprouts = chorionic villi - Beta HCG hormone - pregnancy test hormone
Ectopic Pregnancy - embryo implants outside the uterus
F. Inside the blastocyst: fetus form…..produces 220 new cell types
* *Any newly formed human cell…..comes from a pre-existing Stem Cell* *
Stem Cells - 4 Categories:
1. Embryonic Stem Cells (ESC)…..10 day life span
- Natural
2. Adult Stem Cells (ACS)…………4 types
- Natural
3. Cancer Stem Cells (CSC)……….Mutate to cause cancer - Natural
4. induced Pluripotent Stem Cells (iPS)
- Man-Made
Somatic Cells - normal body cells, each with a specialized function…..~220 types
‘Stem’ - word borrowed from the plants - gives rise to branches
ESCs give rise to 220 branches…..220 somatic cells
G. Stem Cell Jargon: Pluripotent Stems - produce ANY / ALL of the 220 CELL TYPES
1.ESCs 4. iPSCs
Multipotent Stems - produce many, but not all, of the 220 cells
2. ASCs
Totipotent Stems - produce a fetus, cord, membranes and placenta
Zygote - up to eight cell blastomeres
H. DIFFERENTIATION:
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EMBRYONIC STEM CELLS…..day 9, 10, 11 - morph into four major branches:
ADULT STEM CELLS:
HSCs - Hematopoietic SCs > forms all blood cells - RBCs, WBCs etc.
MSCs - Mesenchymal SCs > forms muscle, bone, cartilage, heart etc.
ESCs - Endodermal SCs
> forms liver, stomach, lungs, pancreas etc.
NSCs - Neural SCs
> brain, spinal cord, epidermis
Human Embryo - up to 13 days in vitro Nature, Vol 533, pp.15-16, May 5, 2-16
DIFFERENTIATION:
Amazing process where 220 somatic cells become 'Specialized'…..220 Ways
220 One Way Streets = 220 Sets of Signals - bring into existence 220 new cell types
Terminal Differentiation - end point of 220 Streets - 220 Specialized Cells
All Embryology - ‘One Way Street’ - Basic Tenet of Human Embryology
Programming - another word for differentiation…..220 programs
I. Where does the fetus form?
in the Amniotic Cavity – forms within the embryonic stem cell mass
implantation day 6-10; embryo covered with sprouts = chorionic villi
Day 21 - Chorionic Vesicle; Day 21 to 28 spinal tube closes = neurulation
Day 28 - the size of a pea; 6 weeks - chorion covered with villi
Day 34, 35, 36 - face forms - upper lip fuses together
Day 49 - fontanel (soft spot) present; neural tube closed on top of head
Where does the water in the amnion come from? Fetal kidneys / Recycles
Where does the umbilical cord go? the placenta - develops from the villi
Placenta: first human organ, largest human organ, only external organ,
only temporary human organ, most important organ
End of pregnancy - two deliveries - 1. deliver baby, 2. deliver placenta
J. What are the signals: 1. Transcription Factors
2. Epigenetic Chromatin Regulators
Turn Genes ON and OFF
They can Activate or Repress dozens to hundreds of genes at one time
Example - Pathway (One Way Street) for Pancreatic Beta cells
HUMAN EMBRYOME PROJECT: find all 220 Sets of Signals
II. Miraculous Event #2…..the DREAM
A. Millions of people around the world are suffering and dying…..
because one cell out of 220 is slowly disappearing!
Millions of people around the world are suffering and dying…..
because one cell out of 220 has disappeared - they have 219!
B. DREAM…..‘Cell Replacement Therapy’
1. IF we could find all 220 sets of signals…..and
2. IF we had Pluripotent Stem Cells in the laboratory
We could possibly make any human cell in the laboratory!
Dilemma - Need Pluripotent Stems in the Laboratory
We only had Pluripotent Stems in an embryo
Very difficult to study in the laboratory
Rejection of new cells was a concern
Ethical concerns
Miraculous Event #2: Dr. Shimya Yamanaka Skin becomes Lab-Made Pluripotent Stem Cells in a laboratory
Miracle in Stem Cell Technology…..2006-2007!
Help from a very special female from Scotland…..who was dead!
Dolly - the famous cloned sheep
(Nature, Cover article, June 30, 2016)
To clone Dolly: Researchers had to take a mammary gland somatic cell
nucleus and reprogram it back to a pluripotent state.
Yamanaka found the signals in the oocyte of the sheep that reprogrammed
the somatic nucleus back to pluripotency. They converted the one-way street
into a two-way street! Out of 24 potential signals, he found the FOUR that
could make it happen - they are today referred to as the ‘Stemness Signals’.
CELL REPLACEMENT THERAPY came true thanks to Dolly!!
July 7, 2006: Yamanaka announces he has taken somatic cells from the skin
of a mouse, inserted four ‘Stemness Signals’ - Oct3/4, Sox2, c-Myc & Klf4,
also known as (OSMK), and reprogrammed the skin cells into pluripotent
stem cells = mouse iPS. The 4 signals also called the ‘Yamanaka Factors’.
November 20, 2007: Yamanaka announces he has done the same procedure
with human skin fibroblast cells and created Human induced Pluripotent
Stem cells - iPSCs or iPS. ‘Lab-Made’ human pluripotent stem cells.
That paved the way for the “Miraculous Swap”:
TRADE: Pluripotent Embryonic Stem Cells in a blastocyst
FOR:
Pluripotent iPSCs in a petri dish
December 10, 2012: Yamanaka received Nobel Prize in Stockholm
Stem Cell Technology is…..Applied Embryology
C. POTENTIAL APPLICATIONS of iPSCs:
1. CELL REPLACEMENT THERAPY:
Autologous = no rejection because you use your own skin.
Dopamine producing neurons - Parkinson Disease
Oligodendrocytes for Multiple Sclerosis
Red Blood Cells - Sickle Cell Anemia…..~216 other possibilities
Parkinson Disease: Skin > iPS > human NSCs > Dopamine Neurons
Multiple Sclerosis: Skin > iPS > human NSCs > Oligodendrocytes
Blood: Skin > iPS > human HSCs > platelets and erythrocytes
Macular Degeneration: Skin > iPS > Retinal Pigment Epithelium
Diabetes Type I:
Alginate Capsules protect the iPS Beta Cells from
human Immune System T-Cells destruction!
Viacyte - human trials underway http://viacyte.com/
VIDEO: https://www.youtube.com/watch?v=Q6U5kf5ByNE
‘Artificial Pancreas’ - Medtronic MiniMed 670G
2. HUMAN DISEASE MODELING: ‘Disease in a Dish’
Follow the cellular development of any genetic disease in vitro…..
Lou Gerhig's Disease (ALS) donor > loss of motor neurons
study the degeneration of motor neurons in a petri dish
Huntington Disease donor > loss of medium spiny neurons
Type I Diabetes donor
> loss of pancreatic beta cells
Organoids - rudimentary, simplistic, 3-D human organs
Skin > iPS > NSCs > ear organoids - hearing loss
Skin > iPS > NSCs > eye organoids - retinitis pigmentosa
Skin > iPS > ESCs > liver organoids > liver buds - hepatitis
Skin > iPS > ESCs > lung organoids - COPD / lung cancer
Skin > iPS > ESCs > kidney organoids - kidney failure
Skin > iPS > NSEs > brain organoids - microcephaly / autism
‘Lab-Made Brains’ - Scientific American, pp. 26-31,January 2017
‘Induction of Expansion and Folding in Human Brain Oganoids’
Cell Stem Cell, December 29, 2-16
Organ on a Chip - Skin > iPS > study organ cells on plastic chip
Lung on a Chip / Heart on a Chip / Nephron on a Chip
Artery on a Chi / Bone Marrow on a Chip / Spleen on a Chip
Person on a Chip - coming soon
3, DRUG THERAPY SCREENING:
Screen thousands of small molecules, all at one time, in a petri dish,
find one, out of 1000s, with desired beneficial therapeutic effect
Lou Gerhig's Disease (Amyotrophic Lateral Sclerosis)
screened over 5,000 molecules to find one: Kenpallone
4. REGENERATIVE MEDICINE:
1. Produce human tissues and organs in the laboratory
Cell Replacement Examples: Cell Stem Cell - July2, 2015
Scaffold = Framework
basic shape of the organ…..spherical, tubular etc.
What about making…..Heart, Lung, Liver or Kidney in a lab
in the past…..“cannot do it”….scaffolds are too complex
2. BIO-ARTIFICIAL ORGANS: bioengineering replacement organs
There is a normal, natural, heart scaffold…..inside every heart
DeCellularization - detergent pumped through the heart via
the aorta into all the arteries - dissolves away all the
cardiomyocyte heart cells leaving natural heart scaffold
made of non-cellular collagen and laminin matrix
Recellularization - introduce autologous replacement heart
pulsing cardiomyocyte cells and endothelial cells to
line the arteries and veins
Re-Start the bioengineered heart - pulsing flow of nutrients
pumped into the heart - forces heart to begin beating;
electrical stimulation helps the heart muscles begin to
contract on their own
Future Heart Transplant: Recipient skin > iPS > heart cells;
Donor does not have to be compatible - decellularize,
add new heart cells, re-start > transplant…..2020!
Same will be possible for Liver, Lung, Kidney, Limb etc.
3. CHIMERIC EMBRYOS: (Chimera = Mixture)
mixture of cells from two species in one blastocyst
add iPs of one species to the blastocyst of another
Mouse / Rat Chimeric embryo in modified mouse embryo
produce an organ of one species in the embryo of another
Human / Pig Chimeric embryo
Produce human kidney from a pig embryo genetically
modified to be unable to form a pig kidney. Kidney
= transplanted into person who donated skin > iPS
with no rejection!
III. Miraculous Event #3…..the DREAM
A. Millions of people around the world are suffering and dying…..
Because one of their two genes is not working - AD (Autosomal Dominant)
Because both of their two genes are not working - AR (Autosomal Recessive)
1. IF we could find a way to dissect the human genomic DNA
2. IF we could accurately control the precision of the cut
We may be able to correct any genetic disease in the laboratory
Remove a …..‘Bad Gene’.…..‘Knock Out’
Insert a……..‘Good Gene’…..‘Knock In’
B. DREAM…..’GENOME EDITING’ of the human genome
Cut and Paste our DNA
Cut out a bad gene and Paste in a good gene…..in our own DNA
DREAM: GENE REPLACEMENT THERAPY
Previous methods of Genome Editing:
1. ZFNs - Zinc Finger Nucleases
2. TALEN - Transcription Activator Like Effector Nucleases
very slow and tedious and lacked accuracy
Gene Replacement Therapy: precision genome editing
fast and easy - 99% faster than before
Precision: cut any one of over 3,000,000,000 human nucleotides
Initial discovery - 2005…..mechanism of bacterial ‘Adaptive’ immunity
primitive bacterial immune system
Review: Bacteriophage viruses attack and kill bacterial cells
Bacterial Immune System - ‘remembers previous virus infections’
If that virus enters bacterium again - it is destroyed by chopping virus DNA
Discovery came from ‘cup of yogurt’ - studying Streptococcus thermophiles
Bacterium carries repeated RNA sequences in bacterial genome - which
remembers previous virus infections > enter again > kills virus
Bacterial RNA sequence referred to as:
Clustered Regularly Interspersed Short Palindromic Repeats - ‘CRISPR’
C. CRISPR/Cas9 System for natural bacterial immunity
Recognized virus DNA when it enters the bacterial cell > destroys it
Destroys virus DNA with CRISPR associated proteins = Cas proteins
1. Helicase - unwinds the virus DNA - separates two DNA strands
2. Nuclease - destroys the virus DNA with a double strand cut
CRISPR/Cas9 - two components
1. Cas9: Enzyme component - Nuclease and Helicase
Nuclease - cuts virus DNA:double scissors/cut both strands
2. CRISPR Guide RNA = gRNA - evaluates the foreign (virus) DNA
then Guides it to the Nuclease for precise cutting
gRNA recognizes virus DNA in bacterial cell and destroys it…..
by guiding it to the Cas9 Nuclease enzyme for the DNA double cut
gRNA ‘Homing Mechanism’- Homes to specific viral DNA sequence
D. CRISPR/Cas9 System Controlled in the Lab for Human Gene Editing
WE PROVIDE the GUIDE…..lab-made gRNA combined with CRISPR
Guide sequence is usually ~20 nucleotide sequence made in a laboratory
gRNA recognizes any Target we Specify in any cell - precisely cuts DNA
NHEJ: Non-Homologous End Joining - ‘Knock Out’ inactivates DNA
HDR: Homology Directed Recombination…..’Knock In’ add normal gene
‘Cut Out a Bad Gene and Paste in a Good Gene’ - in your own DNA
Edit DNA to Correct: Sickle Cell, Cystic Fibrosis, Parkinson Dx, MS
E. The Miracle in Genome Editing Technology - 2012
Dr. Jennifer Doudna and Dr. Emmanuelle Carpentier
Science, vol. 337, pp.816-821, August 17, 2012
Dr. Feng Zhang and Dr. George Church - CRISPR/Cas9 in human cells
*Patent Battle: Cal Berkeley v. Broad Institute - MIT*
F. References and Videos on CRISPR/Cas9
1. ‘Applications of CRISPR technologies in research and beyond’
Nature Biotechnology, September 2016, pp. 933-940
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‘The Gene Machine’ - Time Magazine, Cover Article, July 4, 2016
‘Dawn of the Age of Genome Editing’ - Nature - March 10, 2016, pp.155-167
‘The DNA Revolution’ - National Geographic - Cover Article - August 2016
‘What is CRISPR?’ - https://www.youtube.com/watch?v=MnYppmstxIs
‘Genome Editing with CRISPR’ - https://www.youtube.com/watch?v=2pp17E4E-O8
TED Talk: ‘How CRISPR lets us edit out DNA’ - Jennifer Doudna
https://www.youtube.com/watch?v=TdBAHexVYzc
8. Genetic engineering will change everything forever - CRISPR
https://www.youtube.com/watch?v=jAhjPd4uNFY
9. ‘The CRISPR Pioneers’ - Time Magazine, pp. 116-122, December 19, 2016
G. CRISPR Applications…..
1. Yeast - reprogramming to convert sugars into Biofuels
2. Wheat - delete genes to gain resistance to Powdery Mildew
3. Mushrooms - delete gene to prevent browning and early decay
4. Tomato - delete PL gene for better fruit softening, shelf life and flavor
5. Cabbage - knock out Psbs gene for better flavor and shelf life
first GM fried cabbage and first cabbage pasta salad
6. Mosquitos - delete gene to cause sterilization…..Malaria, Zika, Dengue
Science - Zika vaccine, Sept 19, 2016, pp. 1073, 1094
7. Bacteria - enhance plastic degradation genes…..‘plastic eating bacteria’
8. Golden Rice - altered to produce Vitamin A…..prevention of blindness
* See notes on page 11 regarding safety of GMOs *
9. Ferret - help save endangered species by increasing their genetic diversity
10. Save elephant species by DeExtinction procedures…..insert genes from
extinct wooly mammoth - open tundra habitat for elephants
11. Prevent AIDS - delete CCR-5 Gene and CCR-5 T-cell receptor for HIV
12. Prevent AIDS - delete HIV proviruses hiding in infected T-cells
‘Cure HIV’ - Nature Medicine, August 2016, pp. 839-850
13. Delete myostatin gene to create Double Muscled dogs, rabbits, mice
14. Macaque - Delete three zygote genes show ease of procedures in primates
15. Pigs - deleted all 62 PREV virus genes and 20 pig antigen genes
transplant CRISPR Pig organs into humans…..~12 months away!
16. Duchene Muscular Dystrophy - delete exon 51 that harbors the mutation
17. Sickle Cell Anemia - delete gene that inactivates gamma gene of fetal Hg
…..patients can live well with fetal hemoglobin
18. Common Diseases - delete and study multiple polygenic effects
19. iPS + CRISPR - ‘corrected’ medium spiny neurons in Huntington Dx
20. CURE for Sickle Cell Anemia - edit and replace SCA mutation in HSCs
23. Cancer research - create / delete cancer mutations - Newsweek, July 29, 2016
24. Edit Human embryos in China: 1. Beta Thalassemia - April 18, 2015,
2. HIV receptor
- April 6, 2016
25. Edit Human embryos in London: study early embryologic cell divisions
*Most cases embryo editing - will not be necessary because of PGD*
H. CRISPR Summits:
1. National Academy of Science ‘Gene Editing Summit’ - December 2015
2. NIH Committee on Gene Editing - meets regularly
I. THERAPY v ENHAMCEMENT:
1. Therapy
- a procedure to help a person reach normality
Enhancement - a procedure to reach above and beyond normality
2. Book - Brave New World by Aldous Huxley - 1932
3. Movie - GATTACA - with Ethan Hawk and Uma Thurman - 1997
4. ‘Editing Humanity’ - The Economist, August 22-28, 2015
IV. Miraculous Event #4…..coming in the future
who will be next?
V. >100 Nobel Laureates sign letter blasting Greenpeace over GMOs
June 29th 2016
To the Leaders of Greenpeace, the United Nations and Governments around the world
The United Nations Food & Agriculture Program has noted that global production of food, feed and fiber will need
approximately to double by 2050 to meet the demands of a growing global population. Organizations opposed to modern plant
breeding, with Greenpeace at their lead, have repeatedly denied these facts and opposed biotechnological innovations in
agriculture. They have misrepresented their risks, benefits, and impacts, and supported the criminal destruction of approved
field trials and research projects.
We urge Greenpeace and its supporters to re-examine the experience of farmers and consumers worldwide with crops and
foods improved through biotechnology, recognize the findings of authoritative scientific bodies and regulatory agencies, and
abandon their campaign against "GMOs" in general and Golden Rice in particular.
Scientific and regulatory agencies around the world have repeatedly and consistently found crops and foods improved through
biotechnology to be as safe as, if not safer than those derived from any other method of production. There has never been a
single confirmed case of a negative health outcome for humans or animals from their consumption. Their environmental
impacts have been shown repeatedly to be less damaging to the environment, and a boon to global biodiversity.
Greenpeace has spearheaded opposition to Golden Rice, which has the potential to reduce or eliminate much of the death and
disease caused by a vitamin A deficiency (VAD), which has the greatest impact on the poorest people in Africa and Southeast
Asia.
The World Health Organization estimates that 250 million people, suffer from VAD, including 40 percent of the children under
five in the developing world. Based on UNICEF statistics, a total of one to two million preventable deaths occur annually as a
result of VAD, because it compromises the immune system, putting babies and children at great risk. VAD itself is the leading
cause of childhood blindness globally affecting 250,000 - 500,000 children each year. Half die within 12 months of losing their
eyesight.
WE CALL UPON GREENPEACE to cease and desist in its campaign against Golden Rice specifically, and crops and foods
improved through biotechnology in general;
WE CALL UPON GOVERNMENTS OF THE WORLD to reject Greenpeace's campaign against Golden Rice specifically, and
crops and foods improved through biotechnology in general; and to do everything in their power to oppose Greenpeace's
actions and accelerate the access of farmers to all the tools of modern biology, especially seeds improved through biotechnology.
Opposition based on emotion and dogma contradicted by data must be stopped.
How many poor people in the world must die before we consider this a "crime against humanity"?
Sincerely,
Nobel Prize winners
http://supportprecisionagriculture.org/view-signatures_rjr.html
Sam Rhine - College and Career suggestions:
Check Out: http://www.kumc.edu/gec/prof/career.html
1. Go to you favorite Undergraduate college and obtain your 4-year Bachelor's degree.
Major in biology, biochemistry, molecular biology, bio-engineering etc.
Make sure you satisfy the Pre-Med requirements so you can apply to
medical school if you decide that is the best route for you.
2. Medical School is four years and the curriculum is very similar at all
medical schools in the US. The reason for that is that everyone must pass
the same national exam after finishing medical school - therefore the
schools must cover the basic subject matter. If you pass that exam the summer
after finishing medical school, you can then put M.D. behind your name.
3. Residency is then 4 - 8 years of ‘Specialty Training’ to become a pediatrician,
obstetrician, orthopedic surgeon, oncologist, neurosurgeon or whichever
specialty you choose. If you want to pursue a career in Tissue Engineering
then you might want to get a residency with Dr. Anthony Atalla at Wake
Forest University. If you want to use CD-47 antibodies to functionally disable
cancer stem cells you might want to do your residency in oncology at
Stanford University with Dr. Irv Weissman or Dr. Michael Clarke.
Keep your ‘antennae out’ during your four years of medical school – to determine
who is doing the research you want to pursue for a career - and go do your residency
with that person - he or she.
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2. For those who are not interested in medical school - they might want to
pursue a career in research and they will go on after their undergrad work
and get their Masters and Ph.D. which may be 4 to 6 more years.
3. The Ph.D. is usually followed by Post Doctoral studies, Post Doc, for 2 - 4 years to
gain more special expertise for the research career you want to follow. Then
you will be ready to join the faculty at a university to do research and
teach. Others will opt to get a job doing research in industry for biotech companies.
Also, some of these people are getting their Ph.D. in biostatistics or computer
sciences where they will help with the planning and evaluation of research data.
4. M.D. / Ph.D. Most major Medical Schools offer a combined M.D. / Ph.D. for a person who
may one day be the chairperson of the Department of Molecular Medicine at
some medical college - check that out for each individual medical school.
5. Masters Degree in Genetic Counseling - is another option for some.
There are almost 30 places in the US where those programs are available.
For more information - check out this web site:
http://www.nsgc.org/iframepages/GeneticCounselingTrainingPrograms/tabid/336/Default.aspx
6. Teaching - Also Remember…..many people who will make a major contribution to all
These careers in the future will do so by majoring in Education in college and
will be preparing young people in the future…..as your Teachers have been
preparing you!!
"Teachers Make All Other Professions Happen!"
Also Consider: Physician Assistant (PA): http://www.aapa.org/
Student Academy: http://www.aapa.org/saaapa/
MD/MS Genomic Medicine:
http://admissions.med.miami.edu/md-programs/md-ms-in-genomic- medicine
UPDATED: January 10, 2017