Politics Mondays: Stem Cell Veto A Tempest In A Test Tube by Michael Smith

In many respects, President Bush's veto this week of a bill to relax federal-financing restrictions on embryonic stem cell research is a tempest in a Petri dish.

If the bill had passed, cell biologists would have heaved a sigh of relief: The rules mean they can only do embryonic stem cell research using a small number of cell lines that existed before 2001 - if they want federal grant money to do so. The rules also forbid the creation of new cell lines.

The veto is "unfortunate - I don't know what else to say," said Gordon Keller, Ph.D., of Mount Sinai School of Medicine in New York.

But there's nothing that says scientists can't create new cell lines and use them for research as long as they find other ways of paying for the work. And researchers have managed to find an estimated $4 billion in embryonic stem cell research support from private sources and from other public sources, such as state governments.

By contrast, the National Institutes of Health is budgeting $39 million in 2007 for embryonic stem cell research using the approved cell lines held in the National Stem Cell Bank (NTSB) at the University of Wisconsin at Madison.

So science is marching on. What's the problem?

The veto "doesn't change the near-term difficulties that scientists have in getting this work done," says Stanford University cell biologist Christopher Scott, Ph.D., executive director of the university's Program on Stem Cells and Society.

One example of those difficulties is seen at the University of California San Francisco, where researchers are rebuilding a laboratory originally financed with U.S. government grants so they can use it for privately-funded embryonic stem cell research.

In the same building, other scientists will use government money to conduct nearly identical experiments using the so-called "presidential" cell lines from the NTSB. The two labs will not be able to share equipment, supplies - or even graduate students, who are forbidden from working together.

Rebuilding the lab to comply with the federal rules is not only cumbersome, it's costly. "It's a burden, a huge financial burden," Arnold Kriegstein, M.D., Ph.D., director of UCSF's stem cell institute, said.

But it's the long term that bothers Dr. Scott. "What I worry about," he said in an interview, "is that young scientists (faced with limited government research money and possible sanctions) would, it seems to me, choose another career."

"The American research system could lose a generation or perhaps two who could be making sure that America remains at the top of the heap in terms of biomedical research," he said.

"Nobody does biological and biomedical research better than we do," he said. "We're the gorilla - but is the gorilla getting sick?"

There's at least some evidence that the administration policy is having a deleterious effect. In a report in Nature Biotechnology in April, Jennifer McCormack, Ph.D., and Owen Smith, Ph.D., of the University of Michigan said that the pace of embryonic stem cell research is slowing in the U.S., compared with the rest of the world.

For example, in 2002, about a third of the 10 published articles involving human embryonic stem cells were from U.S. research groups. Two years later, U.S. groups accounted for only one-quarter of the 77 publications.

"It's preliminary," Dr. Scott said, but it may be a straw to show which way the wind blows. "I worry about that a lot, and I don't think it's reported enough."

Another fear, Dr. Scott said, is that some scientists may be voting with their feet - moving to jurisdictions where there are fewer limits on research.

Mount Sinai's Dr. Keller is one of those. Born in Canada, he's moving to Toronto in the new year to become director of a new center for regenerative medicine there.

But although he admits the attraction of Canada's looser rules - he'll be able to get government grants to work on any embryonic stem cell line in the world - he doesn't think of his move as part of a brain drain.

The Bush policy has been in place since 2001, he said in an interview, and "I haven't seen a brain drain."

Meanwhile, just hours after. Bush vetoed the bill, his Republican colleague, California Governor Arnold Schwarzenegger, allocated $150 million to kick-start the science in California.

The two actions illustrate two key aspects of the often confusing debate over embryonic stem cells.

First, Bush is in a minority. Recent polls show that about 70% of Americans support embryonic stem cell research; the bill that President Bush vetoed made it through the House and Senate with bipartisan support; and even Bush's own party is fractured on the issue.

His veto illustrates the "stark contrast" between his position and his electorate. Dr. Scott said. "Americans want this to happen and a minority of Americans and our President feel that it shouldn't happen."

Second, the federal restrictions are not doing what Bush wants them to -- preventing the creation of new embryonic stem cell lines, which can only come from human blastocysts.

Harvard, to take one example, has created a privately funded institute to perform research using new embryonic stem cell lines created there. At the same time, it is sharing those cell lines with other researchers - at a rate three times that of the National Stem Cell Bank.

Also, states such as California and Connecticut have set up their own stem cell research initiatives, offering state money to researchers, although litigation has slowed the rate at which the money has flowed.

It's clear that the Bush policy - whatever its effect on the climate of science - has not stopped the creation of new embryonic stem cell lines.

One reason for that, scientists say, is that the approved cell lines are scientifically past the sell-by date. They are genetically unrepresentative, they die easily, and they were created using techniques that may make them unsafe for any therapeutic use.

They are, Dr. Scott said, a "vanishingly small resource" on which to base a large research enterprise.

"We're still going to be needing new cell lines under new conditions all the time in order to better understand what the properties of these cells are," said Kevin Eggan, Ph.D., of Harvard, speaking at the International Society for Stem Cell Research meeting in Toronto earlier this month.

Dr. Keller added another drawback: the more the few presidential cell lines are used - grown in culture, divided, re-grown, divided again, and so on --the greater is the likelihood of genetic changes.

New cell lines avoid that danger, he said.

The interplay between embryonic stem cell lines and so-called adult stem cells is another factor in the debate. Adult stem cells have been known for about two decades and they don't carry the emotional freight that embryonic stem cells do.

But adults stem cells arise from embryonic stem cells, Dr. Scott notes, and it's impossible to understand one type of cell completely without understanding the other. "These two types of cells and two types of research are so tightly linked that it's inconceivable to any cell biologist that you could bury one without hurting the other," he said.

Opponents of embryonic stem cell research argue that adult stem cells are already useful in therapy - such as in bone marrow transplants -- while embryonic stem cells have no track record, so that research should concentrate on adult cells.

Hematopoietic stem cells are currently the only type of stem cells commonly used for therapy; they've been used in bone marrow transplants for more than 40 years. Clinical potential has also been demonstrated in other diseases, such as diabetes and kidney cancer, but those therapies are not yet in wide use.

Meanwhile, new uses for adult stem cells are under investigation, including the treatment of liver diseases, coronary diseases, autoimmune and metabolic disorders such as amyloidosis, chronic inflammatory diseases such as lupus, and other cancers.

Proponents of the research note that embryonic stem cells give rise to all 200-odd tissue types in the human body, unlike adult cells, which are more restricted in their potential. And, they note, it's less than a decade since James Thompson, Ph.D., DVM, of the University of Wisconsin at Madison, first isolated embryonic stem cells.

"What we know about them is only 10 years old," Dr. Scott said, but in principle, embryonic stem cells could be used to replace or repair any tissue in the body, adding to the repertoire of the adult stem cells. The difficulty, of course, is finding out how and, in a world where clinical studies of relatively straightforward new drugs can take a decade, it's not surprising that ES cells have had no clinical successes so far.

Nonetheless, there is promise. Geron Corp., of Menlo Park, Calif., is expected to announce soon that it will begin clinical trials in humans with spinal cord injuries of embryonic stem cell-derived oligodendrocytes. In rats with spinal cord injuries, the company reported just hours before Bush's veto, the process was safe and restored myelin to the damaged nerves.

Perhaps paradoxically, the neurons used in the experiments were derived from embryonic stem cells originally isolated by Dr. Thompson - cells that now form part of the National Stem Cell Bank.

This article was published by Medpage Today.

Michael Smith

Monday, July 24, 2006

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