Research ReformResearch Reform

The author of Tomorrow's Cures Today? Donald Forsdyke, is professor of biochemistry at Queen's University, Ontario, Canada, having doctorates in medicine and biochemistry. His basic research record includes work in DNA sequencing, genetics, evolution, leukemia, and AIDS. This volume updates and expands on a number of previously published essays. Chapters have catchy but not always informative titles.

This review is about Forsdyke's observations and recommendations relative to how granting agencies fund research. To present and critique the author's thoughts, I adopt the imaginary interview format he effectively uses in two of the book's 14 chapters. My title is: "Author Debates Thesis with Reviewer."

Reviewer: You propose to do away with conventional peer review for research funding decisions. How come?

Author: Its current purpose is to evaluate the "promise" that important advances might result and to improve the quality of proposals through feedback. It is not concerned with an investigator's past performance. It is inaccurate and fickle for the first purpose and redundant for the second. A "promise rating" cutoff is set on the basis of funds available; investigators above it are fully funded; those below it get nothing. Agencies are saying, "It's better to fund a less able researcher for an approved idea than an able one for an unapproved idea." This often is more related to political expediency than potential benefits to humankind. The agencies are not getting the biggest bang for their buck.

Reviewer: I agree the all-or-nothing approach is often disruptive. However, I don't agree that current peer review is largely concerned with assessing the vague "promise" of important advances. Peer reviewers ask the following questions: Is it an important problem? Have research objectives been clearly defined? Are proposed methods and analyses appropriate? Is the budget realistic? Does the investigator have background and facilities portending success? Past performance is key.

Author: I rest my case. Your comments and questions merely define "promise."

Reviewer: What other problems result from current peer review?

Author: Investigators are pressed to work on what is currently popular, rather than areas that might show more promise. There is the rat race of writing, rewriting, and defending proposals to keep research afloat. Countless hours detract from real research time. On missing a cutoff, many turn away from research. Collaboration among researchers should increase the rate of progress, but, although lip service is given to collaboration, current peer review engenders secrecy and competition.

Reviewer: While proposals are written to obtain funding, they serve other purposes. They force the investigator to review the literature and clearly plan what should be done. They introduce new team members to the investigation and are a road map for evaluating progress. Serving as a reviewer is a real learning process.

Author: I grant these points, but the negatives remain.

Reviewer: What do you propose in place of the current peer review approach?

Author: Each proposal would receive two reviews, a "bicameral" approach: (1) "retrospective review" of the investigator's past research achievements as related to past funding; all applicants would be rated by research peers, then ranked; (2)"prospective review" of the realism of the proposed budget by fiscal specialists of the funding agency; a "100% budget" amount is set for each proposal. The agency would decide on a cutoff of the "retrospective rating" above which at least minimal funding would always be granted. It would also set cutoffs related to what fractions of "100% budget" proposals would be allocated. Higher ratings would get 100%; the lowest might be 10%.

Reviewer: OK, you've got a plan. But I see problems and missing details. How does a newcomer get started?

Author: We wouldn't completely do away with conventional peer review; it would be used for those without a prior track record.

Reviewer: Your approach otherwise rejects any consideration of "promise." Does that mean any crackpot idea will be funded provided the investigator has an adequate track record?

Author: The granting agency would retain veto power.

Reviewer: You have more faith in the skill of your proposed budgetary gatekeepers than I have.

Author: So be it.

Reviewer: If an investigator needs "100% budget," how do you expect survival on 10%?

Author: The scope and rate would be compromised, but 10% is better than 0%. Many projects could still limp along. Budgets are often part fiction. They are inflated so the researcher can investigate promising byways.

Reviewer: How will decisions be made about the no-funding cutoff, the percentage-grouping cutoffs, and the crack-pot veto?

Author: Each granting agency will decide.

Reviewer: Some agencies already do some of what you advocate but haven't widely advertised it. Here's how I would pick from and modify your ideas. I believe peer review should be expanded to include a rating of past performance. A sliding scale based on a combination of proposal merit and past performance should determine what percentage of "needed" funds are allocated. I hesitate to go as low as 10%, perhaps down to 30%.

Author: I prefer my original algorithm. However, I've tooted this horn for about 20 years with only limited success. I would welcome any real progress in my direction.

For additional information and other articles by the author, access: http://post.queensu.ca/~forsdyke/peerrev.htm.

This book by ethicist Glenn McGee, PhD, merits a more encompassing title. Dr McGee goes far beyond the effect of genetic and assisted reproduction technologies, present and future, on the individual parent and child to explore how these innovations affect entire cultures. The need for a second edition of The Perfect Baby a scant three years after the first demonstrates the explosive rate of new information acquisition. The cloning of the sheep Dolly became public a week after the first edition appeared and is addressed in the new edition.

Three anecdotes quickly draw the reader into the human dimensions of technology. A couple who have a child with cystic fibrosis await the results of an amniocentesis in their new pregnancy. Another couple, unable to achieve a pregnancy because of low sperm motility, reluctantly reject the alternative that would create a zygote to which both might contribute: intracytoplasmic sperm injection (ICSI). Because of the prohibitive expense of ICSI, they instead choose to use a sperm donor. A third couple hope a vector will be found to carry genetic material into the lungs to thin the secretions of their child who is choking on the viscid mucus of cystic fibrosis.

A concise but complete survey of the elements of heredity follows, beginning with Mendel and ending with the Human Genome Project, including brief stops in eugenics, cloning, and assisted reproductive technology. The potential of the Human Genome Project elicits citations ranging from Leroy Hood's hope that congenital diseases can be purged from the gene pool to Jeremy Rivkin's concern that we are "trading away our humanity" by a new eugenics based on "the engineering of life to improve its performance." The caveats of Hans Jonas concerning our impositions on future generations are noted: "Who is to judge the excellence of the specimens . . . and by what standards? . . . [D]iabetes, epilepsy, schizophrenia, hemophilia, are [indisputably] undesirable. . . . But what is ‘better'—a cool head or a warm heart, high sensitivity or robustness, a placid or rebellious temperament, and in what proportion or distribution."

McGee expands on this survey, noting that most academicians fail to descend into the world of everyday experience. "We need to filter out some of the noise," he writes; by "noise" he means the myths and misconceptions about genetics, which find their way into the popular media, eg, one gene yields one trait or one disease. He then goes on to argue convincingly:

Technology is unavoidable and no more artificial and any other kind of human activity. . . . Our attempts—and our technologies—are suffused with values. The hammer is raw materials fashioned into a tool. As a tool, it expresses our values and goals. Thus the choice of a new technology is not instrumentalist, nor are particular technologies value-free. . . . [W]e must move away from debates about technology that oppose it to nature . . . intelligent debate must focus on which technologies are best suited to competing needs in a complex society and environment.

A wonderful exploration follows of what it means to be a parent and the opportunities and responsibilities entailed in use of genetics testing and assisted reproduction. The author explains somatic and germ-line interventions are explained and makes the important point that genes function independent of environment only in the laboratory. To his own thoughts he adds those of Richard Lewontin, who emphasizes that genes alone do not determine an organism. Both point out that the critical roles of environment and the intrinsic nature of the organism itself are seriously underestimated in discussions about gene therapy and enhancement. Choosing a mate is also engineering our posterity. "Blind" reproduction is also a threat. Genetic decisions, he holds, are not qualitatively different from other "enhancements" that parents employ on behalf of their children, such as private schools, music lessons, and athletic training. "Genetic determination of social traits pales by comparison to the social power of parental activities." McGee lists and explains current parental "sins" in raising children that may be more deleterious than future genetic manipulation.

In his epilogue McGee addresses the problem of human cloning. He discusses the biology, with its uncertainty of what may be truly called a clone, and the cultural influences in a world in which new types of families are springing up. In an earlier chapter, he expounds on the value of genetic diversity, which allows many approaches for maximizing an individual's potential. He asks, "If dozens of children were created from the genes of an Einstein, would the world be a better place? Albert Einstein was the product of a particular set of parents, experiences, and inspirations. Growing up in suburban Dallas as the child of an oil baron, a cloned Einstein might as easily end up driving a truck or selling horizontal drilling rigs."

The great merit of this book is the amount of information both biological and philosophical that is packed into its 177 pages. It is profusely referenced and annotated and offers much practical wisdom. The numerous pithy quotations reflect the extraordinary breadth of McGee's scholarship. For those faced with the practical decisions involved in reproductive technology, for those counseling such people, or for those who want a readable quick-study on the multifarious, often conflicting outlooks on genetic and reproductive technology and the ethical issues raised, this book is a "must read."

The story of Luc Montagnier is an intriguing one. He and his coworkers in Paris discovered HIV-1, the single most important cause of AIDS, and HIV-2, the less virulent and less transmissible variant of this group of human viruses. After the initial virus discovery Montagnier always distanced himself somewhat from those who claim that HIV was not only necessary but also sufficient to cause AIDS. Montagnier and the Pasteur team had discovered HIV in the blood of people with AIDS and people at risk for AIDS, but most researchers would agree that it was Gallo and his coworkers who first showed the strong correlation between AIDS and HIV by demonstrating the significant difference in number of virus isolations and seroprevalence between people at high vs low risk for AIDS.

I always wanted to know how Montagnier had perceived these early years of HIV research and if his early experiences could explain his relentless search for cofactors in addition to HIV that he thought were crucial for progression to AIDS. The answers can only partially be found in his memoir Virus. But one thing is clear: Montagnier looks back at this early period with "a feeling of bitterness," evoked perhaps most by the refusal of the French scientific community to back him and the fact that the premier European science journal Nature failed him on several occasions.

I vividly remember my visit to the Pasteur Institute in the fall of 1983, when I first met Françoise Barré-Sinoussi, Françoise Brun-Vézinet, and Jean-Claude Chermann. My colleagues and I had studied the seminal paper of Montagnier's group appearing in the May 20, 1983, issue of Science and tended to believe that this newly described virus was the cause of AIDS. We immunologists, epidemiologists, and virologists of the Amsterdam Cohort Studies suspected a viral origin, but the fact that we collected urine, faeces, and blood in those early days revealed that we ourselves had no clue as to what kind of virus caused AIDS. I received from the Pasteur group a vial of HIV—then known as LAV (lymphadenopathy-associated virus)—cultured in B cells. Unfortunately, I was unable to grow virus from this vial at the time or use it as antigen for antibody assays. Gallo helped us out about half a year later.

Montagnier acknowledges that the discovery of the AIDS virus was technically made possible by the fact that Chermann and Barré-Sinoussi, both retrovirus experts, joined his team from the Pasteur Institute in the Paris suburb Garches. It was Chermann who told me in September 1983 how terrified he and Barré-Sinoussi were when they found out that the reverse transcriptase activity present in short-term cultures was rapidly lost, even in the presence of anti-interferon serum to neutralize endogenous interferon in the culture and IL-2 (called T-cell growth factor or, even earlier, conditioned medium), discovered by Gallo and coworkers. The solution was found in feeding the cultures with fresh and uninfected T lymphocytes at regular intervals, as can be read in Montagnier's book, but their struggle to get permanent cell lines to produce virus at a constant high rate, as is necessary to obtain enough virus for antibody tests, is unfortunately only superficially discussed.

Another element handled somewhat unsatisfactorily in Montagnier's book is the biological versus the sociopolitical explanation for the mix-up of the different virus strains in different labs all over the world, including the Pasteur lab,¹ which ignited the controversy about the origin of the first HIV strains. The same applies to the antigenic relationship of the LAV gag gene product to the gag gene products of human T-lymphotropic virus 1(HTLV-I) on the one hand and equine infectious anemia virus (EIAV) and caprine arthritis-encephalitis virus(CAEV)/visna/maedi virus on the other, in particular at which moment in time the Pasteur team did become convinced that LAV belonged to the lentivirus family.

Montagnier portrays himself in the subtitle of his book as "the co-discoverer of HIV." He truly is the discoverer of HIV jointly with the key members of the Pasteur team Chermann and Barré-Sinoussi, but he may not be generally considered the person who showed for the first time that HIV was the cause of AIDS. While early independent isolations were made by Montagnier, Gallo, and Levy in the years 1983 and 1984, Montagnier, Chermann, and Barré-Sinoussi were without any doubt the first to identify the virus that was later shown by epidemiological research to be the cause of AIDS. This is relevant because even in this 2000 edition of his book, Montagnier devotes many pages to the issue of causation in a section with the telling title "The Future of AIDS." Genetic factors appear to modulate the rate at which HIV causes immunodeficiency, in particular marked by heterozygosity in the CCR5 coreceptor and particular HLA types; Montagnier downplays these effects in favor of an infectious cofactor modulating the virulence of HIV: Mycoplasma penetrans. While Montagnier acknowledges that most researchers in the AIDS field argue against the necessity of cofactors, he writes about researching mycoplasma as a virulence factor of HIV that "[i]t is a deplorable fact that to this day, the number of researchers interested in this line of investigation worldwide barely exceeds the number of fingers on both hands." Having read this, it does not come as a surprise that the "Future of AIDS" section has a chapter on researcher Peter Duesberg, PhD, who disputes the HIV-AIDS causal connection.

In his book Dancing Naked in the Mind Field,² Nobel laureate Kary Mullis claims that Luc Montagnier could not give him a single reference supporting that HIV is the cause of AIDS. For Mullis this was the defining moment in his joining the Duesberg camp. In his book Montagnier blames confusion on the part of the dissenters about the difference between the primary cause of AIDS—which Montagnier agrees is HIV—and cofactors necessary for HIV to become as aggressive as it is. As a coorganizer of the Durban Declaration (see http://www.durbandeclaration.org), Montagnier, however, cannot escape the conclusion that the virus he discovered is proven to be the one and only cause of AIDS, although, as seeps through between the lines of his book, he himself is still not completely convinced.

In summary, Virus provides important insight into the way Montagnier's mind works: a somewhat elusive process that has led to the discovery of the first human lentiviruses, one of the most important discoveries in infectious diseases of the last century.

It is not difficult to concur with David K. C. Cooper, MD, and Robert P. Lanza, MD, that we are on the verge of the next great medical revolution— xenotransplantation: "transplanting animal organs into humans." Their comprehensive book Xeno amply defines the evolution of this extraordinary field.

In his introduction novelist Robin Cook, MD, praises the authors for addressing important and significant questions on the immunological hurdles of xenotransplantation. He believes with most world experts that innovative molecular biology and genetic laboratory techniques will be the keys to rapid progression of this fascinating scientific endeavor.

The present and future of organ transplantation are contrasted, specifically as to the differences in organ donor retrieval from the brain-dead human cadaver and from the pig. Time, efficiency, routine, and planning will be the positive attributes of xenotransplant procedures. Review of critical aspects of the technique is carefully presented and offers evidence of its sustainable real advantage.

An attraction of animal organ donation is that supply will approach demand. Data on the current disparity and the donor shortage in the United States are from reputable sources and well analyzed, but the discussion does not fully address the situation when potential non–heart-beating cadaver donors are included.

The history of transplantation is adequately covered, especially the advances of the 20th century and the prediction of surgeon and Nobel laureate Alexis Carrel, MD, of the potential importance of animal organ transplants in humans. Decades later, his assertions begin to make sense. Reemtsma, Starzl, Hardy, Barnard, and Bailey have furthered modern knowledge of clinical xenotransplantation. In this direction, how one selects the ideal animal organ donor for humans is a question that the authors completely define. Among apes, baboons, and pigs, the last seems to be superior.

Understanding the immunological barriers to xenotransplantation is essential. The chapter "Zero Tolerance" addresses the rejection of human and animals organs, including hyperacute rejection, amply studied by Najarian, Perper, and others. The prevention of rejection, whether with antibodies, altered Gal sugars (galactose surface sugars), or other synthetic chemicals, is under special scrutiny. All currently available drugs are mentioned except for the anti-CD25 antibodies and mTOR (mammalian target of rapamycin) inhibitors, about which information may not have been readily available when the book went to press. Other immune phenomena in the areas of cloning and molecular chimerism are well considered in this book.

Cell xenotransplantation, xenoincompatibility, and the fear of AIDS and other viral diseases are all well covered. When should this technology be taken into the clinical setting? How does one select the first patients? What are the ethics of a clinical trial? What are the animal rights? How does one protect the public? What are the potential legal problems? What will be the impact on health care economics? These are only a few of the many critical questions appropriately addressed by Cooper and Lanza in their book. Interested professionals and institutions will benefit from their knowledge and experience.

Xeno is recommended to all students of general transplantation, particularly to those searching for answers to the questions frequently asked in this continuously expanding field. Experts will find this work to be a concise and thorough analysis. The authors quote an unknown writer: " ‘A vision without a task is a dream/A task without a vision is a drudgery/A vision with a task is the hope of the world.' Xenotransplantation researchers are indeed fortunate to have both a vision and a task."

Approaching genetics from the perspective of anthropology, Professor Kaja Finkler argues in Experiencing the New Genetics that the notion of genetic inheritance has achieved hegemonic proportions in the contemporary United States, as a result profoundly influencing people's lives and interactions with family and kin. Her book addresses two questions: "How do people experience the ideology of genetic inheritance, particularly within the context of their family and kin relations, and why has genetic inheritance become a major theme in contemporary life?" To answer these questions, Finkler draws upon a broad range of anthropological and biomedical literature as well as her own empirical research.

Part 1 includes three chapters that set the stage for the material following. Readers are introduced to the way family and kinship vary cross-culturally, to anthropological debates about the social construction of kinship, and to new reproductive technologies that highlight the deficiencies of conventional definitions of family and kinship. This overview, which emphasizes the necessity of thinking in terms of families rather than "the family," is followed by a historical review of the concept of genetic inheritance in Western thought. Ranging from the 19th century to the present, the review shows how ideas about the concept have metamorphosed from the notion that behavioral change could change inheritance to the contemporary belief that the essence of people is predetermined.

Part 2, based on Finkler's empirical research, explores the way people use the ideology of genetic inheritance to explain the etiology of disease in terms of family and kinship. First, seven healthy women with a family history of breast, ovarian, or colon cancer explain how the imperatives of risk and prevention propelled them into "patienthood" and brought into being close ties with family members. Next, 15 breast cancer survivors who believe that their disease was inherited, albeit in varying degree, tell how this understanding resulted in close ties with kin. Finally, 13 adopted women and men narrate how the search for their birth families grew out of the ideology of genetic inheritance, thereby reinforcing their belief that kinship is "established by reproduction and genetics."

In part 3 the author discusses the implications of her findings. Arguing that family and kinship have been medicalized in the contemporary United States, Finkler first examines the concept of medicalization and its significance for contemporary understandings of kinship and family. In her view, because the medicalization process "changes people's perspective on reality, on their being, and on how they experience the world," the medicalization of kinship establishes a connection between people "irrespective of love and choice." The appraisal of critiques of the ideology of genetic inheritance that follows leads her to contend that "genes do not stand independent of and cannot be isolated from the internal and external environments in which they are embedded." Finally, addressing the prevalence of the concept of genetic inheritance in contemporary life, Finkler concludes that the hegemony of the gene and the medicalization of kinship are products of the construction of kinship and the current role of family and kinship in contemporary America as well as biomedical knowledge and practice themselves.

The preceding synopsis is, unfortunately, too brief to do justice to Professor Finkler's well-written and superbly argued book. Based on a broad range of primary and secondary data, she has produced a nuanced and sophisticated analysis that illuminates the way scientific knowledge affects both the individual and society. While the book will probably be of greatest interest to social scientists, it should be a "must read" for health professionals. After all, as she argues, "Every time doctors take a family history, they reinforce the notion that there is an association between kinship and health," an association that at best may comfort the individual but at worst "forebodes a return to the era of eugenics."