Revolution road

  • Derived from human embryonic stem cells, precursor neural cells grow in a lab dish and generate mature neurons (red) and glial cells (green). Image credit: Su-Chun Zhang
  • Gabriela Cezar, an assistant professor of animal sciences at the University of Wisconsin-Madison, removes trays containing vials of frozen human embryonic stem cells from long-term storage in liquid nitrogen.
  • Transplant surgeon Jon Odorico.
  • Professor James Thomson.
  • Microscopic 10x view of a colony of undifferentiated human embryonic stems cells being studied in developmental biologist James Thomson"â„¢s research lab. The embryonic stem cell colonies are the rounded, dense masses of cells.
  • Researcher Jessica Antosiewicz removes human embryonic stem cells from liquid-nitrogen storage in the James Thomson lab at the University of Wisconsin-Madison.
  • Revolution road
  • A red blood cell colony derived from human embryonic stem cells.
  • Research associate Jamie Sperger works under a fume hood dispersing a feeder solution necessary to maintain growing stem cell cultures in researcher James Thomson"â„¢s lab at the University of Wisconsin-Madison.
  • People with spinal cord injuries hope embryonic stem cells can be the basis for treatment or a cure, but Bob Coomber is not waiting around. He was the first person to ascend California"â„¢s 4 344 m White Mountain by wheelchair.
Date:31 May 2009 Tags:, , , ,

It’s an encouraging headline, say researchers, but there’s a long way to go

On March 9, President Barack Obama revoked the limits on funding research with embryonic stem cells, telling a White House audience that US scientists could apply for funding to investigate many types of embryonic stem (ES) cells, and not just the few varieties permitted under the 2001 policy imposed by former President Bush.

Although ES cells have not produced any cures to date, in January, the US Food and Drug Administration approved the first human trial of embryonic stem cells for treating spinal cord injury.

As expected, Obama’s edict evoked enthusiasm. “It’s magic,” responded Alan Trounson, president of the California Institute for Regenerative Medicine, a state body that is spending R30 billion on ES cells and other stem cells. “It’s been difficult to explain to people in this country, and all over the world, why the US was not really part of the whole stem-cell revolution. Patient treatments have been set back as a result of this delay.”

“I would say we have now left the dark ages in stem cell research and entered the Renaissance,” says transplant surgeon Jon Odorico of the University of Wisconsin-Madison, who uses stem cells to explore treatments for diabetes. “Think about the analogy – when scientists struggled with church control. There are many parallels with the recent experience on stem cells.

“We were thrilled to see the great potential for progress that this decision represents,” says Stephen Byer, an advocate for people with the fatal nerve disorder Lou Gehrig’s disease. Talking with others whose lives have been affected by diseases that may be treated with ES-cell research, Byer says: “I have personally seen a number of people literally in tears of joy now that the president has done what so many of us have been awaiting for eight-plus years.”

James Thomson, a University of Wisconsin-Madison professor of anatomy who first grew human embryonic stem cells in the lab almost 11 years ago, called the action “a welcome milestone for our field. The decision will help restore America as a leader in this field and is a clear path out of a policy thicket that has slowed the pace of discovery for eight years. It also removes a stigma that has discouraged many bright young people from embarking on careers in stem cell research”.

Stem cells, by definition, are able to divide into other cell types, and some stem cells, including those derived from embryos, can form all cell types. Thomson’s 1998 discovery of human embryonic stem cells sparked hope for the emergence of cell therapy – a replacement-parts strategy for curing paralysis and diseases such as Parkinson’s, Alzheimer’s and diabetes.

The biggest single barrier to cell therapy was identifying the subtle chemical cues that cause a stem cell to differentiate into, say, a heart muscle cell as opposed to a nerve cell. Meanwhile, researchers learned to create stem cells carrying the genes for specific human diseases, and these cells quickly became critical lab tools for exploring the causes and mechanisms of disease and testing drug treatments.

Not quite unanimous joy
Because removing ES cells kills the embryo, people who believe that life begins at conception essentially equate ES cell research to murder, and this reasoning lay behind George W Bush’s 2001 decision to ban federal funding for any research on any embryonic stem cells not already in existence. The decision did allow federally funded scientists to study 21 genetically distinct “lines” of stem cells, but if you wanted to work on a newer line – one that could not, say, carry an unknown virus – you had to build and maintain a separate lab and payroll. You could not use even an extension cord if it was bought with federal dollars.

Obama’s decision was unpopular in right-to-life circles. Cardinal Justin Rigali of the US Conference of Catholic Bishops called Obama’s order “a sad victory of politics over science and ethics”. (Ironically, that is the identical charge that ES cell advocates levelled against the Bush ban.)

In any event, Bush’s ES cell decision stigmatised medical researchers who were used to playing hero, not villain. Suddenly, people working to cure diseases such as diabetes and Parkinson’s were tarred as collaborators in a “culture of death”.

In fact, the embryonic stem cells being studied had come from “surplus” embryos that fertility clinics no longer wanted because the parents had as many children as they wanted. Researchers wanted to know if it better to discard these embryos than to use them to try to heal grave diseases.

“Rather than see an embryo discarded as medical waste, it can serve a higher purpose,” says Bernard Siegel, director of the Genetics Policy Institute. “It has no feeling; it’s a microscopic ball of cells that, if left alone, would die in a matter of days. If scientific research can take advantage of the embryo, I think there is a moral imperative to move forward with the research.”

Polls say many Americans agree. In February, Gallup found that 38 per cent of Americans support easing the Bush restrictions, while another 14 per cent oppose any restrictions on ES cell research. Interestingly, in a June 2008 poll specifying that the source embryos would otherwise have been discarded, 73 per cent of Americans supported ES cell research. So what did eight years of restrictions cost the field of stem cell research? We could not get a numerical answer, as we could not find a planet that was identical except for the absence of the ban, so we asked some people who should know.

“It slowed down the field,” says bioethicist Alta Charo, a professor of law at University of Wisconsin-Madison and adviser to the Obama Administration. “Younger scientists entered in smaller numbers due to the relative dearth of funding. Research was made more expensive due to the requirements for strict separation of federally purchased laboratory equipment from the equipment used for this research. The US is still a leader, but only due to the depth of its pool of scientific talent, not because it has in fact led the world in supporting the work.”

Following the Bush rules has been very inefficient in many respects, says Alan Trounson, of the California Institute for Regenerative Medicine, which funds an extensive portfolio of stem-cell research in California. “Trying to run research with two different rules, where the facilities and the grants had to be completely separate, has been very complicated, very tiresome. It cost a lot in administration and auditing, trying to keep to the rules.”

The Obama decision, Trounson says, “has taken away a lot of the excess bureaucracy, and now the research will go forward in a more unrestrained way”.

“I think we are tremendously behind where this should be,” says Bernard Siegel, director of the Genetics Policy Institute, a group that tries to meld the needs of patients with those of researchers. He maintains that spending by the National Institutes of Health on human embryonic stem cells over the last eight years has been a pittance compared with what it should have been, given the potential of the field. “We have been on an eight-year hold.”

Siegel mentions a key objection to the 21 stem cell lines for which Bush did allow funding: these products of the first efforts to grow embryonic stem cells had been exposed to animal proteins, which could carry animal viruses and therefore were not safe for human use. In addition, Siegel says, “there are many new lines, some disease-specific lines, available to researchers, but the NIH money was not there for them. NIH has been the great engine for basic medical research in the world, so we have been going too slow on something that holds a great deal of promise”.

Two, three, many stem cells
Assessing the cost of the ban is also complicated by the elusive nature of stem cells. These flexible cells originate in the embryo and gradually spawn populations of mature cells that form the skin, gut, blood vessels and everything else. A group of intermediate stem cells, called adult stem cells, include those in the bone marrow that produce blood cells, persist for a lifetime. The use of adult stem cells in bone marrow transplants for treating cancer helped opponents of ES cell research argue against the need to fund embryoderived cells.

Then, more than a year ago, scientists learned to make induced pluripotent stem (iPS) cells, which closely resemble embryonic stem cells but have some advantages, such as dispensing with the need for embryos. Although both iPS and adult stem cells helped shift funding away from ES cell research, scientists almost unanimously insist that ES cells remain a primary driver of research.

James Thomson, the discoverer of ES cells and co-discoverer of iPS cells, wrote recently: “Human-induced pluripotent stem cells – the transformed adult cells that seem to mimic the qualities of embryonic stem cells – would not have been possible without research on human embryonic stem cells.” Embryonic stem cells, he says, remain the “gold standard” for stem cell research.

When the University of Wisconsin- Madison’s The Why Files scrounged around for an objective comparison of stem-cell progress between the United States and other nations where the ban had no effect, the only study they found ended in 2004. The report showed a quick uptick of international publications compared with a flatter rise for US publications in 2004, so they phoned co-author Jennifer McCormick of the Mayo Clinic in Minnesota. She told them: “We really can’t draw a strong conclusion about current trends based on the earlier study.” However, she added: “I think that the Bush policy didn’t help the field. When the policy took effect, human embryonic stem cell research as a new emerging area was stymied.”

Another way to assess the cost of the eight-year restriction is to focus on a laboratory that uses stem cells. Jon Odorico, associate professor of surgery at the University of Wisconsin-Madison, uses stem cells to study diabetes, looking in particular at the formation of beta cells, which produce the hormone insulin in the pancreas.

“We are using embryonic stem cells as an in vitro (in the dish) model for studying pancreas development and the formation of beta cells,” he says. “What genes and what growth factors are involved in this process? Can we construct a protocol in the culture dish, to turn embryonic stem cells into beta cells?”

These studies could shed light on how to make replacement beta cells for cell transplants that might restore the body’s normal insulin production. They could also show how beta cells grow during normal human development; most studies on their development have been performed in mice, chickens, fish and frogs, Odorico says.

Odorico’s lab has studied several federally approved embryonic stem cell lines, but ideally he would have studied other lines as well. Comparisons are critical, he explains. “If we compare stem cells from an embryo of a young couple that had no genetic history of type 2 diabetes to a stem cell line with that tendency, we can find differences in the genetic code or in other factors that control how insulin is produced and how well beta cells survive.” Stem-cell lines from people with genetic diabetes may show abnormal beta-cell development, he adds. “They might become progenitor cells, but not beta cells, or not even become progenitor cells. Or they could become beta cells but die off readily.” But because federal funding regulations have prevented Odorico’s lab from establishing new ES cell lines and from acquiring non-approved lines from other labs, those critical comparisons have not been done. Doing these types of in-thedish lab studies can advance diabetes research, he adds, and ultimately lead to either stem cell therapies or drug treatments for diabetes.

So how much did the ban hurt researchers who want to use embryonic stem cells? “It’s hard to quantify,” says Odorico. “Would there be more scientists doing stem cell research in the absence of the Bush ban? Certainly. The field would have grown even faster, and more broadly, and perhaps there would have been more incentive for commercialisation. The Bush ruling definitely delayed and inhibited progress.”

So where do we go from here? In his announcement about liberalising rules on stem cell research, President Obama placed the changes in the context of a sweeping need to cleave politics from science policy: promoting science isn’t just about providing resources – it’s also about protecting free and open inquiry. It’s about letting scientists like those who are here today do their jobs, free from manipulation or coercion, and listening to what they tell us, even when it’s inconvenient – especially when it’s inconvenient. It is about ensuring that scientific data is never distorted or concealed to serve a political agenda, and that we make scientific decisions based on facts, not ideology.

During the George W Bush Administration, there were “a number of situations in which politics appeared to interfere either with doing scientific research or with reporting the results of scientific research”, says Alta Charo, a medical ethicist at the University of Wisconsin- Madison. She notes that a National Cancer Institute Web site exaggerated the risk of breast cancer after an abortion; the Department of Health and Human Services rejected studies showing the failure of abstinence-only sex education; and the administration depreciated the reality of climate change. Unjustifiable editing? As Obama calls for the removal of politics from science, we recall the Bush era, when Senate testimony by Centres for Disease Control Director Julie Gerberding on climate change and public health shrank from 12 pages to six after some delicate editing by the Office of Management and Budget.

Issues remaining
Although Obama’s decision was widely welcomed in the scientific community, questions remain to be answered: what will the fine print say? Opponents have trumpeted the scary notion of “unrestricted” research with stem cells and embryos, but Obama himself ruled out using cloning for reproduction, and gave the National Institutes of Health 120 days to issue rules on federal grants for ES cell research.

Currently, the Dickey-Wicker amendment to budget bills prohibits using tax money to make embryos or support research that injures embryos, so the federal government cannot fund creation of embryos to provide embryonic stem cells. Although Obama did not announce a position on the amendment, eliminating it would be, in equal measure, helpful to researchers who want to control the genetics of their stem cells, and loathsome to opponents of ES cell research.

Another question: will the NIH rules prohibit international transfers from nations with different rules on medical research? What about state funding? In the face of the Bush ban, Maryland, Illinois, Connecticut, New Jersey, New York and especially California established mechanisms to fund ES cell research.

Will that funding dry up now that the federal tap is beginning to open? It’s hard to say, but Alan Trounson expects the head-start conferred by California’s R30 billion in funding to continue helping researchers in his state. “California has been well funding stem cells, the research is very strong, and we are in a more competitive position for federal funding, which is allocated on a competitive basis. I think (California researchers) will do proportionately better than colleagues in other places, who have had a tough time being involved (due to the funding limit).”

What about safety? Even those who think stem cells have great promise worry about hazards. In February, scientists reported that a boy in Israel had developed brain tumours as a result of a foetal stem cell transplant (performed in Moscow in 2001 to treat a rare brain disorder). “We need to develop methods to clean up the transplant preparation to assure a degree of safety, to deliver the cells you want to deliver, and not anything else,” says transplant surgeon Odorico. “That’s important from an experimental point of view, and a clinical trial and safety point of view, from a public trust point of view.”

Otherwise, he warns, “the enthusiasm and promise of the procedure can push us so hard to move forward that initial trials may have tragic consequences, and that will have a recoil effect on the entire field”.

When will we see some cures? As mentioned, in January, the Food and Drug Administration okayed the first test of embryonic stem cells as a treatment for new spinal cord injury. Other trials, however, are percolating through the medical system, and may get a boost from the Obama decision.

Movement toward the clinic is becoming evident in California, which approved proposition 71 in 2004, creating by far the biggest pile of state cash for stem cell research, says Trounson. “We have been strongly funding the basic research, but now is the time to really get into translational, preclinical research. We have a R2 billion disease programme for projects that can move toward investigational new drug applications within four years that we believe will bring in excess of 100 applications.” (Investigational new drug applications, or INDs, are an early milestone for clinical trials of a candidate drug.)

To those awaiting real medical benefits from the remarkable discovery of human embryonic stem cells, March 9 was a good day. But Obama’s decision brought hope rather than tangible relief: despite their promise, ES cells have not yet produced any proven cures. The Why Files asked Steve Levick, a Philadelphia psychiatrist, about the response from Noah, his 14-yearold son, who has a type 1 diabetes, and Steve responded: “He glanced at the headline on the Obama announcement, said ‘That’s good,’ and went off to a basketball game.”

Although Noah understood the ramifications of Obama’s decision, he was more interested in his game. His father, however, stresses that the calendar pages are still turning for those who need the benefits that stem cell research could provide. Due to the ban, he says, “I imagine a couple of years of progress have been lost because scientists in the United States, which has been the leading light in biomedical science, have really been hampered. Life being a time-limited affair, two years is not an insignificant part.”

Type 1 diabetes, while serious, is not the worst of the conditions that stem cells might heal. People dying of Parkinson’s disease or heart disease could also benefit.

Levick recalls talking with the father of a man paralysed below the neck from a spinal-cord injury. “I asked, ‘How is your son doing?’ and he said, ‘He’s still paralysed’. My son Noah is getting on with his life, but for some people each day of delay is a day they can’t spare. They are suffering.” – © 2009, University of
Wisconsin, Board of Regents

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