Tuesday, October 01, 2002

A Classic Disorder Meets the Future

Healing the Brain: A Doctor’s Controversial Quest for a Cure for Parkinson’s Disease

By: Michele S. GarfinkelPh.D.

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Healing the Brain: A Doctor’s Controversial Quest for a Cure for Parkinson’s Disease tells the story of some of the earliest fetal cell transplantation trials for a human brain disease. In this well-known clinical experiment that started in 1988, one of the authors, Dr. Curt Freed, set out to inject brain cells taken from a human embryo or fetus into the brains of patients with Parkinson’s disease. The goal was to regenerate the cells in a patient’s brain that are responsible for producing the crucial chemical messenger dopamine—a neurotransmitter absent in Parkinson’s disease patients because a part of the brain, the substantia nigra, has been destroyed.

In many ways, the narrative is a timeless story of clinical research in its many dimensions: scientific, political, and personal. It manages at the same time, though, to be timely. Although Freed’s experiments were done with relatively crude preparations, his results have implications for today’s field of stem cell therapies. Both the medical history and the policy controversies surrounding his clinical experiments will be relevant in crafting guidelines for any trials that will take place using isolated human stem cells.

Freed and his co-author, Simon LeVay, frame their narrative with two complementary images. One is from James Parkinson’s famous 1817 essay, The Shaking Palsy, which suggests treatment by drawing blood from the patient’s neck veins, then applying blistering agents: Draw bad out. The other is Freed’s own procedure of introducing fetal cells into the damaged brain: Put good in. In these images, we see the powerful transforming nature of surgery and transplantation: the breaching of the body’s armor to effect a change in the patient’s physiology. Even in our resolutely scientific age, transplants still invoke awe; neurotransplantation, in particular, can be imagined as bringing the dead back to life.

Public education initiatives like the 1990s Decade of the Brain, and increased federal funding for basic research, have yielded a more detailed picture of brain topography and chemistry; but, in a very real sense, this knowledge has only deepened the mystery of brain function. Because brain function is critically dependent on the interconnectedness of different types of cells, even the smallest research advance often depends upon an experimental model, usually a mammal. Freed, now director of the neurotransplant program at the University of Colorado, established a monkey model for fetal cell experimentation for Parkinson’s. With a substance known to cause a Parkinson’s-like state in some users of illegal designer drugs, an adult monkey’s substantia nigra could be experimentally destroyed, and brain cells from a monkey fetus introduced. The solution containing the fetal cells was injected into only the right side only of the adult monkey’s brain, so each monkey served as its own control. (No anti-rejection drugs were used.) This protocol was followed virtually to the letter when it came to the human trials.

As Freed had hypothesized, the monkey’s left side showed improvement in movement, but the right side did not. One monkey died following a second transplant to the left side of the brain, and dissection revealed a large number of dopamine-producing cells in the right side but not the left.

REJUVENATING THE BRAIN

L-dopa, a precursor of dopamine, has been the treatment of choice for people with Parkinson’s. Unfortunately, its therapeutic activity, for reasons not understood, eventually becomes muted. The assumption, then, was that replacing the neurons that produce dopamine would be a treatment for patients no longer well served by taking L-dopa. Don Nelson, the recipient of the first transplant—his case a thread tying together many episodes in the book—had an early onset of the disease, diagnosed at age 35 but with symptoms first occurring at age 32. He had used L-dopa successfully for years, but as its effectiveness decreased and he lost more and more muscle control (dyskinesia, which is a serious side effect of high concentrations of L-dopa), a more radical therapy was called for. Fortunately for Nelson—and Freed—the first human trial was ready to move forward at about this time, and one of the requirements was that a patient had once been responsive to L-dopa, even if it caused dyskinesia.

Nelson’s surgery and that of several other patients was supported entirely by private funds, since federal regulations at that time prohibited the use of public money for most research involving human fetal or embryonic tissue. When money from the charitable organization that supported the early procedures ran out, the patients themselves had to pay. Public funding did become a reality on January 22, 1993, Bill Clinton’s second full day as President, with the lifting of the ban on using fetal tissue from elective abortions. In anticipation of the end of the ban, Freed and his colleagues had prepared a grant application to the National Institutes of Health. 

Many researchers find themselves at one time or another confronting an ethical quandary. Freed had to deal simultaneously with several: use of fetal tissue; use of placebos (in this case, sham surgery); and the necessity for clinicians and researchers to be involved in political processes.

POLITICS: CHORE OR PRIVILEGE?

Many researchers find themselves at one time or another confronting an ethical quandary. Freed had to deal simultaneously with several: use of fetal tissue; use of placebos (in this case, sham surgery); and the necessity for clinicians and researchers to be involved in political processes. The credibility of Healing the Brain hinges on whether the authors can convince the reader that Freed’s team adequately pondered these issues, and that the surgical procedures reflected such consideration. The authors industriously and successfully describe Freed’s reasoning from the viewpoint of a surgeon treating desperately ill patients. In communicating an understanding of the importance of fully integrating public policy concerns, and of researchers being intimately involved in the process of governance, they are less persuasive.

Freed and LeVay portray the relationship between the work of the biomedical community and its overseers (Congress, as a proxy for citizens) somewhat naively. Perhaps this is done for effect. But the politics of abortion intersect so powerfully with the work of doctors that I find it hard to believe Freed failed to anticipate not only that anti-abortion groups would have strong reactions to his research but that he would have to become personally involved in those politics. Instead, the tone of Healing the Brain echoes that of the scientific community as a whole: a wish to remain aloof from politics.

Yet, nearly universally and throughout the history of recent science, researchers —including the authors of this book—have called for more money and, less universally but still commonly, less oversight. While funding for the NIH has been increasing steadily, that increase has been more or less guaranteed through earlier congressional promises to double the NIH budget. Now that the doubling has been reached, increases will be more dependent on the NIH (and its grantees) making a good case.

That process itself is a key to the very democracy that is critical to the outstanding American scientific research enterprise. A call for more participation does not imply an expectation that every federally funded researcher will participate at a grass-roots level in every funding cycle, nor should they be expected to. Society is best served by researchers doing what they do best: research. But this is true in many other public spheres (art, social service, education), and we rightfully expect those actors to make their respective cases. Curt Freed has testified before Congress and in many public forums; he deserves credit for participating in the democratic process.

No doubt, though, he would welcome a little company on that circuit. In a society generally supportive of unfettered research, it should not be too much to ask that those appearances be considered by scientists and physicians as more than simply hoops to jump through in order to receive funding.

Healing the Brain addresses a general audience, but lack of attention to detail actually makes reading it difficult—in some cases, downright puzzling.

TOO MUCH, TOO LITTLE

Healing the Brain addresses a general audience (LeVay is a professional science writer, after an almost 30-year-long career as a brain researcher), but lack of attention to detail actually makes reading it difficult— in some cases, downright puzzling. One problem is the book’s broad, unsubstantiated statements: “In general, men are more willing to try new and risky activities than women are.” (p. 102). Those women who underwent bone marrow transplants for breast cancer might well describe themselves as willing to try something new and risky.

Another problem is the lack of citations or other bibliographic information (“they sent a written report of their discovery to a scientific journal….It was accepted immediately” [p. 17]; one wonders where). Understandably, the authors wanted to streamline the text to emphasize the human aspects of the story, but the absence of documentation is irritating.

More generally, the authors fail to sustain a consistent tone or level of detail. Sections range from three pages that read as a recycled lecture on creating and detecting 18-F-L fluorodopa for PET scans (pp. 199– 201) to passing mentions of topics that beg for more detailed clinical description—for example, episodes of frozen motion that some Parkinson’s patients suffer when passing through doorways.

The narrative also suffers from typographical and factual errors. The reference on p. 25 to “the 1921 influenza epidemic” is disturbing, but perhaps not critical (except to virologists, historians, epidemiologists, and the occasional policy wonk); more critical is the discussion on pp. 249–50 on genes causing Parkinson’s. Although somewhat qualified, the message here is that more knowledge of the genomic makeup of human beings (but perhaps not too much more) will allow an identification of genes  (presumably a small number) causing the disease. Only at one’s peril should the phrase “a gene causing…” ever be used in reference to complex diseases, even with qualification.

Although the issue is not mentioned until near the end of Healing the Brain, stem cell science and its potential for therapy were unfolding in parallel with Freed’s research, if only as a sketchy concept. Today, with several laboratories showing promising results in animal models that could apply to various diseases, including Parkinson’s, the questions about using stem cells are not so much “if” or even “when,” but rather, how far can the treatments be pushed? At a minimum, the availability of stem cells should make transplant procedures both more standard and more individualized.

Parkinson’s disease is likely to be amenable to stem cell therapies, particularly using embryonic stem cells. A chief reason is that, although the mechanism by which the substantia nigra is destroyed remains a mystery, the research described in this book, and other clinical insights, indicate that replacing only one kind of cell would be sufficient to restore significant function. Therefore, although the absolute number of cells introduced into the brain might be of concern, the problems inherent in introducing several types of new cells at once would be avoided. For example, using either isolated embryonic or adult stem cells will allow relatively straightforward genetic manipulations. The phrase “promise of stem cell research” has been used far too often to retain any real meaning (and should have been “potential of stem cell research” from the beginning), but, in the context of clinical research, the possibility of significant improvements for individual patients is real.

This situation largely parallels that of type I diabetes. Although the mechanism of destruction of insulin-producing cells is poorly understood, introducing just one type of cell appears to restore a large degree of function. It is not unimportant, either, that Parkinson’s disease research has a well-organized advocacy structure, several high-profile people living with the disease, and substantial data based on the transplants described here and from other groups, and in animal models. Whether or not significant federal funding becomes available for stem cell research, it would surprise no one to hear that the first embryonic stem cell trials will be for Parkinson’s disease. 

If a single case could demonstrate that “clinical research” is a euphemism for “human experimentation,” the protocol described in Healing the Brain is that case.

HUMAN RESEARCH: COMPELLING, IMPORTANT, TOO OFTEN UNDERVALUED

If a single case could demonstrate that “clinical research” is a euphemism for “human experimentation,” the protocol described in Healing the Brain is that case. The consensus among Americans is that the risks incurred in such trials are worth the potential payoffs. Curiously, however, mass media coverage of the first peer-reviewed reports of Freed’s transplant trials seemed to ignore this. Instead, coverage emphasized either the “disastrous” appearance of dyskinesia in some of the participants or the seeming “miracle” of previously paralyzed or dyskinetic patients functioning again. The bioethics community was well represented in the coverage, commenting on the nature of sham surgeries and the use of fetal tissue. Various groups representing patients and families were heard from on both sides. Seemingly lost was an opportunity for a public dialogue (a favorite of the bioethics, policy, legislative, and other communities concerned with governance) on a larger issue: What constitutes a successful clinical trial from a societal perspective?

Why is this germane? If a clinical trial is deemed a success, society as a whole will absorb the cost of delivering its new product or procedure. On the other hand, a failed clinical trial can be disastrous both for the subjects and the research organization. As many commentators have pointed out, virtually all early transplant recipients of bone marrow died. If anything, Freed underplays the full significance of the research physician’s role and how outcomes fuel the advance of innovation in the realm of medicine. Although strenuous lip service is given by some policymakers and science administrators to the inseparability of basic biomedical research and applied clinical research, the latter continues to be undervalued and underutilized precisely because it is difficult to do a bona fide controlled experiment that is both robust and ethical. Freed’s research is presented apologetically, even defensively, because it was neither strictly placebo-controlled (although holes were drilled in the skulls of the placebo patients, no injections were made and the dura mater was not punctured) nor double-blind. While placebo-controlled/doubleblind may be the gold standard, it is certainly not the only way. Although other clinical trials using sham surgeries (particularly some types of knee surgeries) have been analyzed at length by ethicists, the keenness of the criticisms of Freed’s surgeries stands out. Whether this is because of the more dangerous nature of brain surgery or because its controversial nature was further sharpened by pairing it to other ethical issues is unclear.

Recognizing that the force of Freed’s particular experimental approach lies in the results for individuals, Freed and LeVay relate the stories of several patients, moving and fascinating examples of the power of clinical research. George Doeschner received a transplant in January 1999 and suspended the use of L-dopa a year later. The full import of his transplant would become apparent in 2001 when, working at the World Trade Center as an electrician, he would walk down 33 flights of stairs to safety on September 11, 2001. Although we cannot know if he would have done just as well without a transplant and with L-dopa (and it is possible that individuals with Parkinson’s disease on L-dopa were among the evacuees), this is exactly the kind of outcome hoped for when the transplant protocols were first considered. As of the publication of the book, the other compelling figure, Don Nelson, the first recipient of Freed’s transplants, remained, in Freed and LeVay’s words, “a man of action.”

Given the spectrum of topics that Healing the Brain presents, many readers will find it interesting despite its shortcomings. Even those who believe the procedures should not have been allowed will learn from it. It is not an easy read—the narrative is too ponderous and fragmented for that— but readers interested in stem cell research may absorb the lesson that they must be prepared to be intimately, and if possible enthusiastically, involved in the policy process. Those interested in governance may reach greater understanding of what it means to be a medical doctor in an increasingly technologically driven health care system. Citizens seeking to understand the stakes in research (particularly federally funded research) will better appreciate the complex, high-powered U.S. biomedical community. And those embattled with Parkinson’s disease may recognize themselves and find in Freed’s story a ray of hope.  

EXCERPT

From Healing the Brain: A Doctor’s Controversial Quest for a Cure for Parkinson’sDisease, by Curt Freed, M.D., and Simon LeVay. ©2002 Henry Holt and Company.  Reprinted with permission.

The plan was simple in outline, but the details were devilish. Through the early winter of 1992-1993, an ever-accelerating torrent of phone calls, e-mails, FedExed documents, and in-person visits began to flow between Baltimore, Denver, and New York. We wanted to have a grant proposal to present to the NIH the moment that the fetal-tissue ban was lifted, and we expected that to be shortly after Bill Clinton’s inauguration in January. Grant proposals have to be very detailed and persuasive. Particularly because we would be asking for millions of dollars—far more than I had ever requested from the NIH. Every question, little or big, that a reviewer might think of, had to be anticipated and answered.

The biggest question was: What were the objectives of the study? As we saw it, the most important objective was to find out whether fetal-cell transplants did in fact alleviate Parkinson’s disease. That may sound like a foregone conclusion, given that I’ve described how several of our patients were markedly improved after receiving transplants. Bear in mind, however, that I am backtracking in time at this point. We wrote the grant application in late 1992, at a time when we had performed transplants on only twelve people, and only seven of these had reached their one-year anniversaries. Some of our most successful transplants, such as those on Bruce TenBroek and Dan Stewart, had not yet been done. Thus, we had much less convincing evidence for the value of the transplant procedure than we did later.

More important, we knew that a string of case histories, even ones with positive outcomes, did not constitute scientific proof of the value of a procedure. For a reminder of this within our own field of Parkinson’s disease research, we needed to look no further than the debacle over adrenal transplants. In 1987, Ignazio Madrazo published a glowing account of how patients had been helped by this procedure...but later it turned out to be worthless. The apparent successes were presumably due to a combination of factors: a possibly real but short-lived benefit of the surgery, plus a large measure of wishful thinking on the part of the patients and their doctors.

The time to do a properly controlled trial is early in the development of a procedure, before large numbers of patients are exposed to the procedure and it develops a life of its own. The history of medicine is full of useless procedures—from bloodletting to bone marrow transplants for breast cancer—that were allowed to become established without proper study and then became hard to dislodge.

Beyond the question of whether fetal-cell transplants were beneficial, however, was the question: Who did they help? The variability in our results was already obvious after our first two procedures: Don Nelson improved after his transplant, but Anthony Marsh did not. This variability in outcome continued to bedevil our program, as well as similar programs at other centers. Was the variability due to differences in the patients themselves, or was it due to differences in the way the fetal cell survived and developed in each patient?



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Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Robert Malenka, M.D., Ph.D., Stanford University School of Medicine
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine

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