The Burrill Report

Six years after President George W. Bush’s famous stem cell speech from his Crawford, Texas, ranch, it has become clear that the headlines can tell us little about the one thing people care about most: What is the future of embryonic stem cell research?

In those six years, the U.S. political landscape has shifted dramatically. At the national level, there has been a clear swing against the president’s policy. In June 2007, Congress passed legislation to ease restrictions on federal funding. But Bush vetoed the bill, saying that “the Congress has sent me legislation that would compel American taxpayers, for the first time in our history, to support the deliberate destruction of human embryos.” Since there are not enough votes to override a veto, there appears to be little prospect for liberalization until after the 2008 election.

The states, meanwhile, have been passing their own laws. California, of course, led the way when voters in the 2004 election approved $3 billion in bonds to support stem cell research. Other states, including New Jersey and Connecticut, have followed suit; some, such as North Dakota, have passed restrictions. More legislation is underway, although none that will significantly change the national picture. Stem cell policy is evolving; for now, the changes come in ever
smaller increments.

To see the real drama, look deeper. Stem cell research is part of a quest to uncover deep secrets of human biology that dates back to Galen, Hippocrates and Aristotle. Those who take part in that quest today understand that progress is rapidly accelerating. They can already see new scientific possibilities, new ethical questions—and new business opportunities.

This drama has been obscured by the way the research has been framed in medical terms. From the beginning, most public advocates have described stem cell research in terms of whom it might help. During some of their more overheated moments—like the battle to pass stem cell funding in California three years ago—we heard that 100 million Americans have diseases that might be cured by embryonic stem cell research. The promise of breakthroughs prompted a number of prominent conservatives to speak out in favor of the new science, including George Schultz and Nancy Reagan. Ron Reagan, Jr. came before the Democratic National Conference soon after his father’s death to declare that the use of embryonic stem cells “may be the greatest medical breakthrough in our or in any lifetime.” These cells, he went on, could “cure a wide range of fatal and debilitating illnesses: Parkinson’s disease, multiple sclerosis, diabetes, lymphoma, spinal-cord injuries, and much more.”

Critics of the research pointed out that embryonic stem cells have never healed anyone, which is true. But then they made claims that are equally speculative; for example, that cells from bone marrow might be able to treat a wide range of new diseases. The problem is that nobody on either side of the debate knows what medical applications will come from stem cell research. Curing a disease is not like building a bridge. Scientists don’t sit down and draw up a set of blueprints for a cure. Curing a disease is more like wandering an unexplored continent, following jungle trails that look like they might lead to somewhere interesting.

It is natural that the public wants to know what stem cell research might be able to do for medicine. When might there be a cure for Parkinson’s? For juvenile diabetes? These are questions that everyone would like to be able to answer. But they are unanswerable, even to the field’s most brilliant thinkers. They are also the wrong questions. To envision the contours of the future, ask not what stem cells will be able to do. Ask what new kinds of knowledge stem cell research will generate—and what possibilities, and problems, this will raise.

At the heart of modern stem cell research is an ancient mystery: What gives the body its form? Some two and half millennia ago, when Aristotle wrote On the Generation of Animals, he speculated that it was menstrual fluid that provided the raw material, and semen that provided the form and the shock of animation. In the seventeenth century, English doctor William Harvey, famous for describing the circulation of blood, suggested correctly that all animals come from eggs. And by the first part of the nineteenth century, new microscopes and other technology launched modern developmental biology.

Still, the mystery of biological development has lost none of its magic—from a microscopic dot comes the delicate perfection of a human hand—but scientists have come a long way in their understanding. The body emerges from a vast, ongoing conversation among cells. It is an iterative, self-referential process that Aristotle could not have imagined, though he seems to have anticipated the idea in another context when he observed that “the whole is greater than the sum of the parts.” 

Stem cells, of course, play a central role in this drama because they produce the more specialized cells of the body. In 1998, James Thomson announced that he had isolated human embryonic stem cells—cells called pluripotent owing to their potential to form any cell in the body. This was a major scientific milestone, but to the public, it seemed to border on the miraculous. They came to view embryonic stem cells as a kind of magic biological clay—material that can be molded into any kind of cell, and ultimately any organ, a patient needs.

There is, of course, an element of truth to this metaphor. Scientists are interested in stem cells precisely because they have the ability to generate replacement cells. This is what a bone marrow transplant is: an infusion of blood stem cells that mold themselves into the cells of the blood system, saving the patient. Researchers are now working on ways to generate the dopamine-producing cells lost in Parkinson’s disease, or the insulin-producing cells missing in juvenile diabetes, or the cells of the spinal column destroyed by injuries.

As alluring as this magic-clay vision is, it is not the best way to think about the immediate future of stem cell research. The next scientific steps, and the most immediate medical applications, will come from using stem cells as tools to unlock the secrets of development. At its core, stem cell research is not a quest for new hardware; it is a quest to understand life’s software. Cures most likely will come from applying information, not cells.

The modern pharmaceutical industry has built up a massive research and commercial infrastructure based on drug intervention, not cell replacement, so it is reasonable to expect that the industry will apply stem cell science to the complex process of drug discovery. One obvious approach is to use drugs to tap the body’s own healing potential. Nature has given us a tremendous capacity for rejuvenation. If scientists can uncover the biological secrets of the stem cells behind this, then perhaps they can find targets and molecules that would rally the right cells—in the heart, in the brain, in the liver—into action.

A modest variation of this approach is already being explored. Bone marrow transplants are one of modern medicine’s great triumphs, but thousands still die every year when transplants fail. Researchers are looking for drugs that can coax blood stem cells, the cells which make the transplant effective, to proliferate before they are given to a patient. This could improve the effectiveness of bone marrow transplants—particularly using cord blood, where the amount of material is limited—saving many more lives.

Another possibility is to use embryonic stem cells to help conquer two of drug development’s greatest enemies: heart and liver toxicity. Pharma can spend years on a therapy, only to discover that it will not work because it is too dangerous. Scientists are working on better ways to model toxicity in a Petri dish, so that drug developers can adjust their approach much earlier in the process. Embryonic stem cells, they hope, can be used to make human heart or liver cells that will accurately predict how a human heart or liver will respond to a drug. In the last few years, there has been dramatic progress in understanding how stem cells build the heart. Combined with ongoing progress in tissue engineering, this is an important new line
of attack.

But the most anticipated new technology is cloning, also called somatic cell nuclear transfer (SCNT). The ability to make lines of embryonic stem cells, with DNA taken from particular patients, would be a tremendous boon to research. It would give scientists a way to create human-cell models for diseases, such as Parkinson’s or juvenile diabetes, in which the underlying genetic causes are unknown. (Cloned embryonic stem cells would be created using the nucleus of a cell from a patient who suffers from the disease.)  

Consider the example of Parkinson’s disease, in which the brain’s dopamine-producing cells die off. It is not known why these cells die, and this ignorance is a major obstacle to the search for cures. For a Parkinson’s disease model, scientists would start with embryonic stem cells cloned from a Parkinson’s patient. Then they would push these cells down the developmental pathway to become dopamine-producing cells to see whether they can detect precisely where the process goes awry. This could provide insights into the molecular biology of the disease, and could also be used to look for drug targets—for chemicals that could arrest or reverse the disease process. And this same approach could be used to study juvenile diabetes, ALS and a long list of other genetic diseases.

A global race is now underway to master the technical challenges of SCNT. A handful of teams in the United States, the United Kingdom and other countries have been struggling to get the process to work. Though nobody can predict how important cloning will prove to be—scientists, like other explorers, don’t know until they get there—there is general agreement that the stakes in this race are high. New disease models have a history of opening up entirely new areas of research. The team (and the country) that crosses the line first will gain not only prestige, but new sources of intellectual property and new business opportunities. 

This pursuit, interestingly, also reflects the broader dynamics of the international stem cell picture today. The U.S. has been held back by federal regulation, but private money and a huge base of scientific talent have kept it competitive. Fears of a brain drain have proven unfounded. And researchers wonder whether China, whose astonishing intellectual and financial resources still sit on the other side of cultural barriers, will emerge as a new international powerhouse.

At the same time, cloning highlights the changing ethical terrain that lies ahead for stem cell researchers. After years of debate, Americans seem to be growing more comfortable with the idea of embryonic stem cell research, despite concerns over the moral status of embryos. But cloning raises new ethical issues. The procedure requires women to donate eggs. But is this too risky? Should the women be paid? The work also puts scientists in the position of creating embryos that they will then destroy, which is different from using the spare embryos from in vitro fertilization clinics that would have
been discarded.

The very word “cloning” touches a deep nerve. Opposition to embryonic stem cell research has been framed mainly in “when does life begin” terms, familiar from the abortion debate. But, as with that debate, there are deeper anxieties at work. Biological research generally is now moving so rapidly that it is dizzying even for the participants, never mind the baffled public. Stem cell research is producing discoveries that reveal the inner workings behind the creation of the human form. It is easy to understand why some feel that science is going places it was never meant to go.

Indeed, some scientists worry privately about the risk of a political backlash. State stem cell initiatives like the California bond were approved on a wave of public enthusiasm for the possibilities of stem cell research. Some fear that expectations of treatments and cures have gotten ahead of anything that science can reasonably be expected to deliver. It is hard to gauge public expectations, and whether advocates have done enough to
temper them.

There is also the danger that someone will rush into a clinical trial based on embryonic stem cells, yielding bad results and a chilling effect for the entire field. If embryonic stem cells are used therapeutically, there’s certainly a possibility that some patients could have bad outcomes. When one patient died in a gene therapy trial, it almost shut down the field. 

Even so, the long-term prospects appear bright. The research has not shown signs of slowing; it is accelerating. And, eventually, a clearer understanding of development will likely resolve some of the ethical issues that are so pressing today. Scientists could gain such a command of the process that they would not need to use the raw materials—human eggs and embryos—which are so controversial. Recently, in fact, three teams of scientists reported producing the equivalent of embryonic stem cells in mice using skin cells, avoiding the use of embryos. If the same procedure could be adapted to work with human skin cells, the whole controversy surrounding embryonic stem cell research could disappear.

Stem cell research is itself an iterative process, unfolding before us. The whole will be greater than the sum of its parts, and its final form remains a mystery. Clearly, though, it will be a stunning sight to behold. 

 

Gareth Cook was awarded a 2005 Pulitzer Prize for his coverage of stem cell research. He is now editor of the Boston Globe’s Ideas section.

September 01, 2007
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