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The End Run

by William Dean HintonSilicon Valley/Santa Cruz Metro
October 27th, 2004

THE 1980s, Ralph Snodgrass' interest in developmental immunology led him to Switzerland, where his research allowed him to work with a profound biological discovery: embryonic stem cells-often called miracle cells or miniature fountains of youth-which, as Snodgrass would later write in scientific journals, had the ability to produce every type of cell in the body, opening the way for experiments on blood and genetic diseases.

Because this was the 1980s, science was still in the stem cell dark ages. The human embryonic stem cell was isolated only six years ago by University of Wisconsin biologist James Thomson. Snodgrass was limited to working on mouse embryonic cells.


Snodgrass is not someone you would automatically associate with lab coats and microscopes. He is athletic, a mountain climber, prideful enough that he doesn't like his age printed in the newspaper. When I ask him about Thomson's breakthrough, which has led to the most contentious politico-science conflict in 30 years, Snodgrass turns competitive. "From the mouse stem cells, we knew all this stuff long before Jimmy Thomson ID'd the human embryonic stem cell," he says.


It was Thomson's breakthrough, however, that led Snodgrass to where he is today, president, CEO and director of VistaGen Inc., which employs human embryonic stem cells to analyze drugs that will aid pancreatic cells to produce insulin. With only nine employees, the company shares office space in an ugly, stucco building with another biotech company in a light-industrial area of Burlington, within sight of Highway 101. Almost all of the lab work is farmed out to scientists as far away as Japan.


When I suggest to Snodgrass that companies such as his are sometimes referred to as mom-and-pop shops, he laughs.


In August 2001, President Bush gave a speech dedicated solely to embryonic stem cell research, the first speech ever by an American president devoted solely to bioethics. The speech placed limits on federal spending for embryonic research, but many potential investors saw it as a first step toward federal restrictions on companies that work with embryonic cells. "Venture capitalists have abandoned this sector of the biotech industry," Snodgrass says.


California voters could change VistaGen's fortunes next week. Proposition 71 would result in the state's investing $3 billion toward human embryonic stem cell research over the next 10 years. The money would instantly make California the world's largest single funder of embryonic stem cell research, a responsibility many feel Bush abdicated in 2001.


Part of the money will fund research institutions like UC-Irvine, Stanford and UC-San Francisco, which have been among the forerunners of embryonic stem cell experiments. Part of the money will help corporations like VistaGen turn research into drug and transplant therapies.


Critics of Proposition 71 like to say that the money will be spent to make venture capitalists rich. But there's nothing glamorous about VistaGen. Its headquarters consists of a single, short hallway from which you can access four small, tidy labs or several equally small offices. "As I understand it, a quarter of the Prop. 71 money will go toward infrastructure like labs," Snodgrass says. "Another three-quarters will go toward basic research. We expect to apply for both of those categories. We expect it will have a substantial impact."


Many biotech companies exist mostly in cyberspace or in name only so it's difficult to say how many there are in the Bay Area. According to the industry directory BioScan, there are six stem cell companies in the region, including VistaGen and Menlo Park-based Geron Corp., which funded Thomson's research and at least two other major embryonic breakthroughs. Since BioScan reports about 80 stem cell companies worldwide, the region stands poised to funnel a large percentage of the Proposition 71 money into the area, adding to the state's $7.8 billion biotech industry.


Similarly, nobody is making bold predictions how much Proposition 71 money will be infused into the South Bay. Two city officials, Ru Weerakoon of the Redevelopment Agency and Kim Walesh of the Economic Development Office, said they'd heard several companies had discussed relocating if the initiative passed.


Snodgrass is hoping for small steps-like finding qualified researchers as a result of the ballot measure. "The lack of federal support kept young scientists out of the field," Snodgrass says. "Nobody wants to go into a field where it's difficult to get funding. It's kept a whole generation of scientists out of the field for that reason. We can't hire anyone with embryonic stem cell experience. We have to train them in-house."


Potentially Dead


Scientists have studied stem cells since E.B. Wilson first located them in roundworms in 1896. Researchers learned more about the cells through bone marrow transplants in the 1950s and through in vitro fertilization beginning in the 1960s.


In biology class, most of us learned that the human body is composed of 50 trillion cells, all capable of dividing into more cells to replenish the body's needs. To a certain extent that's true. But the body is more complex than this simple explanation. There's actually a kind of cell hierarchy within each organism. At the top of the pyramid is the fertilized egg, which has been called the ultimate stem cell because every cell in an organism owes its existence to it.


Next in line are adult stem cells, master cells capable of doing two things: making another stem cell or generating a specialized cell. For example, an adult blood stem cell will produce other blood stem cells as well as varying types of specialized blood cells, such as white blood cells, red blood cells, lymphocytes, monocytes and so on.


Stanford's Irv Weissman was the first researcher to isolate adult stem cells. He is now head of the Institute for Cancer and Stem Cell Biology and Medicine, a virtual institute at the moment since it was founded with an anonymous $12 million grant but has yet to construct a building. Though his research is limited to adult stem cells, and he owns two adult stem cell biotechs, Weissman is among the scientists pushing Proposition 71 and further research on embryonic cells, appearing on congressional panels and appearing in the same kinds of Proposition 71 commercials that Michael J. Fox appears in. Last month, he hosted a seminar for journalists on the Stanford campus to provide an overview of embryonic research.


One of the myths he debunked was that adult stem cells have the same therapeutic and research potential as embryonic cells. Until recently, scientists thought these adult stem cells, under the right conditions, could morph into other types of cells-blood cells into muscle cells or bone cells, for example.


Scientists now believe that hypothesis was inaccurate Though adult stem cells are still valuable for research and therapeutic purposes, embryonic stem cells, we now know, have shown the ability to change into blood, heart or neural cells. Thus they have unlimited potential for therapeutic purposes, not to mention providing a fascinating look at life's origins. "They are like my son," Stanford's Seung Kim told journalists during Weissman's seminar. "They have unlimited wild potential but no direction."


This week Hans Keirstead of UC-Irvine is expected to unveil results of lab mice whose spinal cords were severed that were able to walk and run again after his team of researchers transplanted embryonic stem cells. Similar results are expected one day with heart stem cells in cardiac patients and neural stem cells in Parkinson's patients. Instead of waiting for a transplanted cadaver pancreas, diabetics might one day produce insulin from embryonic stem cells programmed to become pancreatic cells.


The point of contention, one that has made its way to the highest levels of government, is where embryonic cells come from. The short explanation is that in vitro clinics sell leftover fertilized eggs that would normally be incinerated.


On about the fifth day of fertilization, which would normally be the time the egg attaches to a woman's uterus, the egg has divided into about 300 cells inside a hard outer shell called a blastocyst, measuring about two-tenths of a millimeter in diameter, barely able to be seen with the naked eye. Scientists are able to crack open the blastocyst and remove the cells for research purposes, enticing them to multiply in a petri dish, producing millions of identical copies called cell lines.


But because embryonic stem cells are of human life, and because the blastocyst must be destroyed to recover embryonic stem cells, their scientific use has created a political furor with pro-life/pro-choice overtones even though at such an early stage there is no heartbeat, no consciousness, no ability to feel sensations. "There's no resemblance to anything that looks human," says biologist Michael Goldman of San Francisco State University.


Indeed, as even some conservative lawmakers have pointed out, like Sen. Orrin Hatch of Utah, there is a huge moral difference between a collection of cells inside a human body, incapable of sustaining life on their own, and those outside.


Yet some pundits claim harvesting stem cells is worse than abortion. Richard Doerflinger of the U.S. Conference of Catholic Bishops told Congress last month, "You have the prospect of creating lives just to destroy them. ...Every living member of the human species, including the human embryo, must be treated with the respect due to a human person."


Former Stanford Medical Center chaplain Ernle Young presents an alternative view, one that differentiates between potential personhood and actual personhood.


"Is potentiality the same as actuality?" he writes in this fall's Stanford Medical Magazine. "I think not. You and I are potentially dead. But we are not yet actually dead, and until we actually die it would be a mistake to treat us as if we were dead. Potential is not equivalent to actuality."


Human Experiments


In his August 2001 speech, the president essentially split the difference between the pro- and anti-stem cell sides. He permitted private funding and research on embryonic cells. But he limited federal funding, through the National Institutes of Health, to stem cell lines already in existence. The idea was to prevent federal dollars from funding the destruction of additional blastocysts.


At first, scientists were relieved Bush hadn't quashed embryonic stem cell research altogether, especially since he said he opposed such research during the 2000 campaign. But then it became obvious that Bush's speech had what amounted to a chilling effect across the scientific community. For one thing, Bush said there were plenty of stem cell lines already available. But it soon became obvious there were far fewer than he suggested. Instead of 60 lines, there were only 22 worldwide eligible for federal funds. (One of them is available through UC-San Francisco.) But all of the 22 lines were tainted because they were grown in mouse cultures, possibly contaminating each line with viruses.


About the same time as Bush's speech, two Republican congressmen, David Weldon of Florida and Sam Brownback of Kansas, introduced bills to criminalize a procedure instrumental to embryonic stem cell research. The procedure, known as somatic cell nuclear transfer or therapeutic cloning, removes the nucleus of an egg and replaces it with the nucleus of a regular cell. The donor cell can be taken from anywhere in the body-the cheek, the skin, muscle.


If the fertilized egg were placed in a uterus, it could possibly grow into a typical human fetus, complete with the genetic material of the cell donor. If such an implantation were to occur, it would likely result in a successful reproductive clone-the same kind of procedure that produced Dolly the sheep and two kittens, parented by a Sausalito company called Genetic Savings and Clone, that appeared in this year's annual Cat Fancier's show in New York City.


Therapeutic cloning, on the other hand, takes different steps after the nucleus transfer. Instead of harvesting stem cells from in vitro rejects, scientists, for example, can put a stem cell nucleus in a denucleated egg to create a stem cell line uncontaminated with mouse viruses. Or if researchers want to study how a certain cancer develops over time, they can put the nucleus of a cancer cell into a denucleated egg, creating a cancer stem cell line. Or if you were faced with the need for a transplanted heart, pancreas or bone marrow, doctors might remove stem cells from your body, put the nucleus in a denucleated egg and transplant heart, pancreas or blood cells derived from your stem cells. Containing your DNA, the cells will be less likely to be rejected by your immune system than a donor heart, pancreas or bone marrow. "Therapeutic cloning is nothing more than cells from you for you," Weissman explains.


Weissman chaired a panel of the prestigious Academy of Sciences that concluded that reproductive cloning should be outlawed. The panel also recommended that therapeutic cloning should be permitted to continue with sufficient government and peer oversight. When planted in the uterus, reproductive clones died 99.5 percent of the time, sometimes taking the mother with them. Those that lived often suffered from birth defects. "It was easy for my panel to decide this is not a permissible human experiment," Weissman says.


Weldon and Brownback sought to criminalize not only reproductive cloning but also therapeutic cloning, punishable by 10 years in prison and a $1 million fine. Patients who underwent therapeutic cloning overseas faced the same penalties.


The congressmen's bills failed, but their attempt rallied opponents like state Sen. Deborah Ortiz, who was motivated to turn California into a embryonic stem cell safe haven for researchers. First, she authored legislation, signed by Gov. Gray Davis in September 2002, outlawing reproductive cloning but permitting therapeutic cloning in California. She then turned her attention to funding. Ortiz tried to obtain $1 billion through the Assembly legislative process but her bill was blocked in committee.


So Ortiz turned to the initiative process and enlisted members of Cures Now, a Hollywood-based group formed in opposition to Brownback and Weldon's bills. The four founding members of Cures Now have children with juvenile diabetes. Their network of associates eventually led them to Robert Klein, a 59-year-old Palo Alto real estate developer who is on the national board of the Juvenile Diabetes Research Foundation.


Klein likens the current reluctance of the Bush administration to fund embryonic research to Ronald Reagan's myopia on AIDS funding in the 1980s. California then, as California now, must fill the scientific void, he says. "If we had been hesitant to step in at the time, the AIDS epidemic would have run wild," Klein says. "The federal government is paralyzed. California has to take responsibility."


A number of newspaper columnists have said funding for Proposition 71 is a good idea, but not something a state government should undertake, especially not through the ballot initiative process. Klein takes the exact opposite view. He says no other government besides California is able to fund research. Countries like South Korea and Singapore, which have established modest stem cell infrastructure, don't have the means for complete stem cell funding.


"Only California can do this," Klein says. "We have 50 percent of all the biomedical companies in the United States We have more medical research gathered here than any country in the world. We're the only state that can be a substitute for a national program."


Remaking Eden


Robert Klein himself contributed more than $2 million to the Yes on Proposition 71 campaign and has been instrumental in collecting major sums from Bill Gates, eBay founder Pierre Omidyar and the Junior Diabetes Research Foundation toward a $20 million television campaign blitz. Contrary to opponents' complaints, Klein says only about 10 percent of the campaign's funds was collected from venture capitalists.


Proposition 71 proposes to build a California Institute for Regenerative Medicine, which would easily surpass the National Institutes for Health in embryonic stem cell funding and research. Last year, the NIH, the world's leading research institution, allocated more than $190.7 million in grants toward adult stem cell research but only $24.8 million toward embryonic studies.


The California Institute would hand out approximately $50 million per year to build research facilities and another $250 million in grants to pay salaries and other necessities of research. The total $6 billion tab-$3 billion in bonds plus $3 billion in interest-would be paid from the state's general fund. But the first payment wouldn't be due for five years, which Klein hopes will be enough time to spark the economy and begin to slow the cost to the state's overwhelmed health-care system.


"You would expect several thousand new jobs in the Bay Area alone," Klein says. "Three out of 12 of the leading research institutions are here."


Not all of the Proposition 71 critics are religious fundamentalists. In fact, in a secular state like California, hardly any ideological opponents mention morality or abortion as reasons to vote against the measure.


Jesse Reynolds is program director Center for Genetics and Society, a progressive, pro-choice group based in Oakland opposing Proposition 71. One of the drawbacks Reynolds sees with spending state money to conduct an end run around Bush's stem cell policy is the inflexibility. Embryonic cells are the hot topic today. That doesn't mean they'll lead to the miracle recoveries envisioned by supporters. "Our fear is that in 10 years we'll look back at Proposition 71 as a big mistake that produced none of the benefits while putting the state in graver financial straights than it is in now," Reynolds says. "This is not the way we should be legislating this amount of money. The NIH can adapt year to year. The new institute would not be able to adapt. It's too narrow a funding agenda."


The Center for Genetics and Society was founded in 1999 as a response to Princeton University molecular biologist Lee Silver, who predicted a new, superhuman race of people in his book Remaking Eden. The Center for Genetics' seven bioethicists were repulsed at Silver's idea of a biological caste system, where the rich and powerful are able to afford genetic surgery to make them stronger and faster than the unfortunate plebs too unsophisticated and poor to afford such enhancements.


Supporters of Proposition 71 say nothing could be further from their minds. Their intentions are not to create designer babies but to aid over half the California population suffering from cancer, spinal cord injuries, Parkinson's disease, Alzheimer's and other diseases stem cell therapy might cure or ameliorate. "Technology developed in the modern age must take cost effectiveness into consideration," says Tom Okarma, CEO of Geron Corp. "We are all aware that any therapy people can't afford or Medicare can't afford, we can't generate it. I've been in cell therapy for 20 years, and if there's a point of concern, it's this very point of cost."


The Menlo Park company has been at the forefront of nearly every embryonic breakthrough in recent memory, including funding for James Thomson's discovery, Dr. Susan Fisher of UCSF's development of a new embryonic stem cell line and Dr. Keirstead's work with spine-damaged mice at UC-Irvine. Geron has developed eight stem cell lines, two of which (cells to repair damaged hearts and cells for diabetics) are two years away from human trials. (I asked a Geron spokeswoman for a tour of its facility, located near Bayshore Park, but she politely declined.)


Okarma says much of the hand-wringing over Proposition 71 reminds him of the moralists in the 1850s who opposed anesthesia. He says as soon as embryonic cells help spinal-cord patients walk again or help rid the world of cancer, most critics will disappear. "Game's over," he says. "That's what the world is waiting for. And that's what is going to be required to stop this baloney."


What hardly is mentioned by most stem cell scientist is that in the next few decades, they hope to move medicine in a profound direction, from pharmaceutical-based therapies to cell-based therapies. "Living cells will be tomorrow's pills," Okarma says. "We are convinced this is the medicine of the future."


The battle over Proposition 71 probably ended last week when Gov. Arnold Schwarzenegger broke ranks with the national Republican Party and endorsed the measure. The thinking was that if Schwarzenegger at least remained neutral, that would mean a victory for the referendum. His backing gives Proposition 71 the endorsements of the state's top three officeholders, including Steve Westly and Phil Angelides, making it difficult for ideological opponents to claim the measure will bankrupt the state.


The next step, obviously, is for scientists to put the money where their mouths have been. The public will be clamoring for more breakthroughs: for people to walk, for heart disease to vanish. Scientists have already begun saying we have to be patient. "It takes several years to get drugs on the market," says Dr. Snodgrass, who expects Proposition 71 money to modestly improve VistaGen's labs and to add staff. "That's a fact of drug development. It takes years to identify a drug and to show it's safe. This could take a long time."



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