Longaker, Michael Stem Cells June 28 2007
<p class="default">11:23 PM, June 28, 2007 
Longasker, Michael Stem Celss June 28. REGENERATIVE MEDICINE 
Reparative, replacement and tissue engineering. TE (tissue engineering). 
 
Today at 7 PM. He was introduced by his dean:  <b>Dean David Stevenson </b>(Med School). 
 <b><u>Outdoor Science Talk 1</u></b>  <b> - Regenerative Medicine: What is it? Where Do We Stand? Where are We Going?</b>  
Regenerative, reparative, replacement, and tissue engineering medicine represent an emerging field that holds great promise for core problems in medicine worldwide. Our strategy is to understand the capability of multipotent cells from an abundant source, such as fat, to repair or replace deficient or missing organs. Tissue engineering (TE) is a new interdisciplinary field that combines the principles of engineering and life sciences toward the development of biological substitutes. In this talk we will analyze the emerging TE field and examine the ethical and social issues related to new tissue technologies. 
 <b>MICHAEL T. LONGAKER, </b> <b><i>Deane P. and Louise Mitchell Professor Director, Children's Surgical Research, Department of Surgery</i></b>  
Michael Longaker's extensive research experience includes the cellular and molecular biology of extracellular matrix with specific applications to the differences between fetal and post-natal wound healing, the biology of keloids and hypertrophic scars and, most recently, the cellular and molecular events that surround distraction osteogenesis with respect to craniofacial development. He brings to Stanford his unique understanding of wound healing, fetal wound healing research, developmental biology and tissue engineering. He is a member of the Society of University Surgeons, American Surgical Association and American Society for Clinical Investigation; currently, he serves as Treasurer for the Society of University Surgeons. To date, he has published over 750 publications and has 5 federal grants to support his research. 
He played college basketball. 
He was recruited from NYU. He is from the mid West. (Lots of fat people there). 
After he heard the intro from Dean Stevenson he said 
"I wish my mother was here to listen to that intro. She never believes any of it." 
- Health Care System as constituted now is CORRECTIVE. Can only correct disorder that have happened. 
HC is a 2 trillion dollar per year industry. 
People send him cartoons. He got one showing Frankenstein and Igor with a patient on the table. 
Frankenst says to Igor .. "Now, bring me the stem cells." 
SEED and SOIL to make a plant grow. 
Not enough just to have ESC's (embryonic stem cells); they depend on their environment (chemicals or whatever, sho knows) to develop. 
So, eg. a 90% destroyed lived can regenerate from ? adult SC's ... the liver is the soil. 
The Med. School has been partially reorganized into Institutes that cross tradition departmental lines. 
eg. There is now an Institute of Stem Cell Biology and Regenerative Medicine (Irv Weissman is the head). 
There is an Institute of Neurobiology. etc. 
BUSH came along and in Aug 2001 said "there will be no more generation of new stem cell lines other than what exists (with Fed money)." 
Of those cell lines, prob only about 6 cell lines are viable.. All are grown on mouse feeder layers, so can never be used clinically. 
Prop 71 was passed in Calif. in 2004. It created the CIRM: Calif Instit of Regenerative Medicine. 
Dole out 300M dollars per year for ten years. It was a 60:40 victory. 
Raise money by selling Calif bonds. Held up in courts by multiple suits; they were all rolled into one; then defeated; 
now in appeal. Will be done in 1 month. Meanwhile research has proceeded with foundation money and private money. 
Will prob. take 2-3 decades to grow a whole kidney. 
Many different goals of SC stem cell research. 1. cell models of disease by getting SC's from patients with partic. disease. 
- dx of disease 3. high thru put screening of drugs for dis. rx. 
Paper just appeared in ? Nature Biotech: 1 month ago; studied the potential ROI (return on investment) of Prop 71. 
They took just one disease: JODM juven. onset diabetes mellitus; there are ? 13,000 new cases per year (? in California) 
They said, suppose you could improve the disease in just 50% of those people by extending their life by 5 years ... that is 
add 5 QALY's per patient quality-adjusted life years. Average person lives in age 78; say diabetics live (say) to age 55 and 
instead make it 60 (5 extra years). 
Say 1 year of perfect health = 1.0. And say, 90% health would be .9 . 
The value of 1 additional QALY per person is 50k. Then they also added costs of caring for DM. 
Found that the SAVINGS for DM alone was 42 billion. 
This was just by reducing the burden of DM by 50%. 
If instead the money was invested in bonds that yielded 10%, as of 2020 it would only be worth 26B. 
So, we are ahead even with just lessening burden due to DM. 
90 scientists work on SC's at Stanford. Stfd has gotten the most awards from CIRM. Many grants are for training. 
SC's do two things 1) they renew themselves (immortal) and 2) they develop into other cells. 
There are 210 different cell types in the body. ESC's are taken from a blastula after 5-6 days post conception. 
Adults have stem cells: bone marrow, intestine, hair. 
NUCLEAR TRANSFER. (there are proteins that are folded over onto dna that limit which regions get expressedd) 
Put a Q tip into your mouth and swizzle it around; you pull out about 500 epithelial cells. 
Now remove the DNA from one and put it into an ESC from which you have removed the nucleus. . It gets REPROGRAMMED to be an ESC.. 
That is, the limits imposed by the proteins folded over the dna are removed. 
A group in BOSTON found that there are 4 master genes which, when inserted into a mature cell can reprogram it and turn it into an ESC. 
For example, you can do that with a fibroblast. 
Stanford researchers found that there are cancer stem cells that cause cancer to reoccur (after it has been removed surgically, eg). 
?now (or ? goal) is to put human cells into a mouse without an immune system and grow that totipotent cell into just one layer, eg 
just ectoderm, or mesoderm, or endoderm. 
Irv Weissman in ? 1998 showed there were hematopoietic SC's that could regrow blood. 
In Surgery the problem is that frequently there is just not enough tissue to close a wound or whatder. 
We want to grow tissue to use it. We've seen picture of human ear cartilage or nose growing from the scalp of a mouse. 
Not that easy. 
Longaker does craniofacial surgery in kids. eg GSW (gun shot wound) of face: a lot of reconst4ruction needed and 
do not have any tissue .... must move it from other parts of the body. may take 10-12 operation. get bone from fibula. 
but still do not have any nerves, poor blood supply, sense organs, not great. 
Seeds and soils: 
Consider liposuction which 50k Americans have. remove 3 liters of fat: a lot of SC's in there mixed in with the removed fat. 
Coach them to become a muscle cell. 
Dept of Geology knows about calcificaiton, eg in star fish. 
Take a sponge and seed it with fat-derived SC's and it can form a tissue that you can use to fill a gap in a mouse. 
In future would like to put cells in a biodegradable scaffold. 
May not even need to place the cells correctly ... just put them in the organism. 
cells may just migrate to the site of the injury and implant. was shown to work with 
fat-derived multipotent cells which only become muscle or cartilage (mesoderm). 
label with luciferase. They GO to the site of injury. 
Gene chips were developed at Stanford originaly by Pat Brown. 
with those you can simultan. look at 30k genes. 
after spinal cord inury, a scar forms that prevents the neurons from rehooking up; 
if you coud suppress scarring you might prevent problem. 
These are some of the best known applications of SC's (below) but there are several other classes of applications. 
DIABETES: there are less than 1 million islet cells in the body. need to replace those. 
Parkinsons: want to be able to take an oral epithelial cell (eg) and turn it into a dopaminergic neuron. 
?? Take a self-assembling polymer and put it in a small electric current: it will then release 
? some factors that will cause the scar tissue that has occurred following a myocardial infarction into cardiomyocytes. 
Osteoporosis: balance btwn osteoblasts and osteoclasts in which the clasts win and the bone dissolves. 
would be nice to be able to jack up the osteoblasts. 
Dean Dave Stevenson (who introduced Michael Longaker) runs a huge Neonatal ICU. 
There are huge numbers of cleft lips and palates. Its the second most common birth defect: 1 in 600 to 1 in 1000 births. 
(2nd most common after club foot) 
He describes Karen Lew's work (she was an architect and then went to work on wall street then went into bio research). 
Wanted to develop a drug to cross the placenta ... mother takes it to correct the gene defect in the fetus in utero. 
Some success. 
Stanford: 7 schools; 2 hospitals and SLAC ... all involved with SC's. 
I ask 2nd Q to him: how soon for islet cells and is it low-hanging fruit? 
gets his interest. He says ... very difficult; a lot of interest; Shu Kim (or Kim Shu) working on it at Stfd with Irv Weissman. 
Its a major target of SC research. Not easy. btw adult SC's cannot transform into neurons or into islet cells. 
Proscription of Fed funds is a major stumbling block: every item of furniture, etc. must be separate. pain in the ass. 
Fed funds are the life blood of research groups. doing work on SC's now with private funds / philanthropy. 
NIH money used to incr. by 7-8% per year; has been flat for a while. 
Would like to be able to get fibroblasts from skin; add 4 genes and turn them into totipotent cells. 
Stanford med students do an xtra year of research in lab. 
Knee cartilage is tough problem cuz of poor blood supply; right now you can scrap off a few cells at 
arthroscopy and send them to a company that iwll clone them up over a long time (and a lot of $) and send 
you back a gluey pellet to reinset into knee ... bad blood supplytho. 
Stfd med center ? 1000 post docs. 
One THIRD of Venture Capital Money in the WORLD is managed on Sand Hill Road!!!! 
Hank Greeley: effect of intel. property on SC's (does it help or hinder). 
Bayh-Dole Act of ? 20 yrs ago or so: you could commercialize your research findings even tho supported by 
fed. $ and not pay back govt. Freedom to Operate (FTO). 
Does IP inhibit FTO. 
Example : Univ of Wisconcin has a very broad patent on SC's; and $ got to WARF. 
Their patents are now being re-examined cuz they are a strangle hold on the field. 
Cosmetic surgery in foreign countries paid for out of pocket might drive the technolgoy. 
VCs look at IP risk; tech risk; regulatory risk (FDA); market risk. 
Mkt risk might be overcome by very high margins or large unmet need. 
Having a payor code for reimbursement is good. 
High margins draw a crowd. 
There is no primate center at Stfd; others have done successful somatic nuclear xfer using primates. 
 
 
 
 
 
 
 
 
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