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A skeptics views on the human genome project

There are very few scientific endeavors that can be recognized almost immediately as seminal moments in the progress of human knowledge. There is no question now that the information locked in the DNA of all of us is both wonderfully rich in content and critically important to understanding biology and medicine. The HGP, and the genomic revolution that it started, has become so much a part of biology that its history is often taken for granted.

We have been surprised that many biologists and medical researchers are unaware that the initial proposal to sequence the human genome was fraught with controversy, that there was no clear consensus in the scientific community about whether it was worth pursuing. Opponents argued that funding the HGP would severely restrict investigator-initiated research projects, that we lacked the technology to complete the project in a reasonable amount of time, that the biological sciences would become increasingly politicized, and that even if it could be completed, most of the information would be useless.

All these objections might have seemed reasonable, considering the unknown future of science and technology as well a skeptics views on the human genome project the tight research budgets, but in retrospect we can see that they were seriously misguided.

A careful review of the origins of the opposition and the nature of their objections reveals the complexity of the science policy process, particularly for novel, large-scale projects. When the project was first proposed in the mid-1980s, one prominent skeptic was Nobel laureate David Baltimore, who estimated that it would take 100 years to sequence the human genome, and many agreed.

The 100-year estimate would, in fact, have been about right if the technology had remained frozen at the level of 1985. But the technologies used in sequencing the genome improved rapidly, and the century of work was compressed into 15 years. To their credit, Baltimore and Botstein both quickly recognized the value of the project and were active in garnering support.

They are examples of how good interactions and scientific debate in the community informed and built the case for the HGP even in the face of broad opposition.

Others, however, remained irreversibly opposed. Even as late as 1990, after more than four years of debate, and after the project had been formally proposed and received seed funding, the controversy continued to fester.

Anxiety about the possible erosion of funding for individual research grants at NIH gave birth to a movement among university researchers opposed to the HGP. Davis argued that an organized project was unnecessary because the human genome would be mapped and sequenced by individual researchers working as they always had.

  1. Develop a process that could move quickly to evaluate and establish large, transformative inter-organizational projects.
  2. The assumption of the linear influence of individual genes has suffered a fatal, yet long overdue, blow. Early in 1987, Wyngaarden endorsed the HGP officially in congressional testimony.
  3. The HGP, and the genomic revolution that it started, has become so much a part of biology that its history is often taken for granted. The Russells made a number of advances in mouse genetics, but there was much more.

The hearing generated several letters and petitions from university departments opposed to the genome project that were included in the Congressional Record. Nor was there a shortage of fierce objections to the project on scientific grounds.

For example, Robert Weinberg, an eminent cancer researcher at the Massachusetts Institute of Technology, was one of a number of scientists who argued that the project made no sense since so little of the genome was used to code for proteins, and the data would likely reveal very little for the resources expended. Instead, we now have a rich resource whose scientific, medical, and economic impact has been transformative.

They outlined and briefly discussed six lessons, which emphasize the importance of partnerships, free data sharing, data analysis, technology development, and the ethical and moral issues that accompany all transformative technologies.

To these we can add two more: The success of the HGP a skeptics views on the human genome project in no small measure the result of cooperation among a number of agencies, and especially between the Department of Energy DOEthe birthplace of the project, and NIH, whose mission encompassed potential health benefits of the project. NIH provided an essential effort to address the medical implications, and DOE provided an equally essential piece that addressed the development of key technologies.

The multiagency, international project quickly gained the attention of a diverse set of organizations and individuals and as such provided a context that, in retrospect, was unusually complex and nuanced. Our focus here will not be on the scientific, medical, and economic importance of the HGP, since that is now widely accepted.

Nor can we offer fixed prescriptions about how to proceed successfully into an unknown future. Instead, we reflect on science policy lessons that can be learned from the way the project was initiated, unfolded, and ultimately reached a successful conclusion. This fact was in no small measure the source of considerable controversy and confusion.

More specifically, many of our suggestions underline the importance of openness to new ideas originating from unexpected sources and the development of guidelines for considering large, transformative ventures that cut across multiple scientific disciplines and organizations.

A skeptics views on the human genome project

We briefly discuss the development of effective processes for public-private partnering and ways to accelerate transformative, inter-organizational projects. Some of our observations and ideas are now more or less accepted and have helped the nation find pathways to better science policy, but others have not yet penetrated our collective consciousness or operational policies. The perspectives provided by the history of the HGP are brought into better focus when we recall some of the key cultural characteristics of biological research in the mid-1980s.

First, there was relatively little discussion and interaction among agencies, even when their mission boundaries were somewhat blurred. Second, the culture of biology valued, almost exclusively, the small science of individual investigators. The HGP was viewed by many as an embodiment of wanton, brute-force science, light on knowledge seeking, devoid of hypothesis, and with no assurance of the biological significance of the eventual results. Third, application of modern technology and interdisciplinary effort had not yet become part of the general culture in biology.

There were no large, complex, multiyear scientific projects in biomedical science that required contributions from multiple disciplines. Mathematics and computation, for example, were still largely foreign to the biomedical community, with the exception of statistical services for epidemiology, clinical trials, and some specialized areas, and much of technology development and engineering also stood well apart, though there were a few important exceptions.

Lessons learned The history of the HGP can usefully inform our approach to a wide swath of future science policy processes and help us avoid decisions that could lead to lost opportunities for the nation and the world, just as we nearly lost the opportunity to launch the HGP. The most important lessons include the following: Remain open to new ideas, particularly those that emerge from unexpected sources.

When a massive, decade-long, interdisciplinary project directly relevant to health sciences was proposed by DOE, the major funder of physics, chemistry, and engineering, the biomedical community was naturally surprised and somewhat skeptical. But whereas NIH valued and focused almost entirely on the small science of individual investigators, DOE had decades of experience managing large, complex, collaborative projects that often required capital-intensive resources, including some related to health and the environment.

As DOE capitalized on its expertise in advanced computation and instrumentation to move increasingly into modern biology, its culture became fertile ground for the growth of a project such as the HGP. Meanwhile, NIH was also beginning to accommodate proposals that were culturally aligned to what would become the substance of the HGP. These included new forms of mass spectrometry, the support of synchrotron X-ray stations at synchrotron particle accelerators for protein structural studies at several DOE national laboratories, and massively parallel supercomputing, all of which were starting to influence biological science and medicine.

These winds of change, sweeping across the scientific landscape, were mostly unnoticed in biomedical circles. Notwithstanding this neat and well-known division of responsibilities between the two agencies, DOE was no stranger to biology. In 1946, just before the birth of the Atomic Energy Commission from the Manhattan Project, Eugene Wigner, a physicist at Princeton University and a Nobel laureate, was persuaded to take over Oak Ridge National Laboratory as director and to create a new kind of focused haven for scientific research.

One of the first things he did was to hire Alexander Hollaender to build a biology division, in part to study the biological effects of radiation. Hollaender chose to build the research effort around genetics, and the study of the genetics of fruit flies, plants, and fungi became an Oak Ridge focus. By examining the genetic effects of radiation exposure, they soon discovered that the human exposure standards, which were based on fruit fly experiments, were far too high.

The mice were more than a skeptics views on the human genome project times more sensitive than flies to radiation mutations. For a while Oak Ridge was home to the largest biological research laboratory in the world, and it was richly productive. The Russells made a number of advances in mouse genetics, but there was much more.

Later on, in 1964, Richard Setlow discovered excision repair of DNA at Oak Ridge, and his student Philip Hanawalt subsequently worked out many of the implications of this seminal work. This sister division thrived as well, researching, for example, both the effects of radiation in inducing cancer and in treating it.

The irony that DOE was positioned to initiate a genome-like project, largely by historic accident, actually reveals a deep principle worth noting. Preexisting diversity, created for a skeptics views on the human genome project reason, can make transformations possible that might otherwise be unlikely. This echoes the themes of Darwinian evolution: At an organizational level, realization of this principle requires acute awareness, acceptance, and a philosophy fundamentally open to seizing unexpected opportunities for innovation.

Develop guidelines for vetting and responding to transformative ideas that cut across multiple scientific organizations and disciplines. Interagency partnering on large projects and strong lines of communication are now common.

This progress notwithstanding, the transformation is incomplete. The clear articulation of an inclusive vetting process for new and transformative ideas, and more focus on how to foster innovation, is a skeptics views on the human genome project needed.

And although interagency coordination on the HGP was established within only a few years of its inception, it happened in response to congressional influence and was contentious and far from optimal. NIH was initially opposed to getting involved in the project, and its director, James Wyngaarden, was hesitant to move too far ahead of a divided community.

Some of the key NIH advisers and several eminent scientists strongly advised Wyngaarden that NIH needed to support this effort on its merits and to assume its ownership, which had fallen to DOE by default because Senator Domenici had introduced a bill to start a national project under the aegis of DOE.

Early in 1987, Wyngaarden endorsed the HGP officially in congressional testimony.

  • The perspectives provided by the history of the HGP are brought into better focus when we recall some of the key cultural characteristics of biological research in the mid-1980s;
  • The HGP, and the genomic revolution that it started, has become so much a part of biology that its history is often taken for granted;
  • Perhaps the National Academies of Sciences, Engineering, and Medicine could play a significant role in this important process.

The interagency Human Genome Project was born. Develop effective processes for public-private partnering. Although interagency coordination is now much stronger than it was four decades ago, meaningful partnering and collaborative mechanisms need more development beyond the government. In the early genome era, there was one example of public-private interaction that stood out. HHMI also funded a number of meetings involving university scientists and people from several government agencies to discuss the issues surrounding the initiation of a genome project, and it provided initial funding for genetics databases, including OMIM, a continuously updated catalog of human genes and genetic disorders and traits.

In this brief essay we cannot begin to analyze the complexities and potential problems in partnerships between the government and for-profit organizations, but there is much potential to be gained in forming such partnerships. In the past few decades limited partnerships at the level of individual scientists from all sectors have become possible and are flourishing, whereas 30 years ago collaboration between a government scientist and an industrial researcher was routinely disallowed.

Solutions to this problem evolved naturally as the benefits were recognized. A problem that has yet to be solved is routine and timely access to data, but its importance has been recognized. Many scientists, us included, believe that data generated at public expense should be released without significant delay, after quality assurance. This is relevant to for-profit organizations, universities, and nonprofits as well.

Forty years ago, universities were not in the habit of patenting their intellectual property or spinning off new ventures, as they are now under the influence of the Bayh-Dole Act.

As this trend continues, the pressure to sustain periods in which data are proprietary may also increase.

  1. We have learned that organic biochemistry is not as simple as dialing a telephone number. Posted on September 30, 2008 at 09.
  2. Without this technology, it would have taken many more years to generate the data.
  3. Develop effective processes for public-private partnering.

We raise these issues to emphasize that considerable thought and attention is required in order to enable and encourage socially beneficial practices among all research institutions. Without this technology, it would have taken many more years to generate the data. Whereas collaborations among scientists in different sectors should certainly be encouraged, as should collaborations among groups that provide complementary expertise, there are occasions in which parallel competitive efforts are useful and perhaps inevitable.

The history of the HGP provides an example of the importance of such a parallel effort, although the way it played out was far from optimal. Although there were ultimately two genome projects—one public NIH and DOEincluding international efforts, and one private Celera —there was substantial mutual benefit.

  • First, there was relatively little discussion and interaction among agencies, even when their mission boundaries were somewhat blurred;
  • What is remarkable in retrospect is the boldness of the project, and even more, the rapid adaptation and cooperation by a biomedical research community that was traditionally conservative, by very different government agencies, and by a Congress with tight budget constraints;
  • The history of the HGP provides an example of the importance of such a parallel effort, although the way it played out was far from optimal;
  • We briefly discuss the development of effective processes for public-private partnering and ways to accelerate transformative, inter-organizational projects.

In retrospect, the HGP is not likely to have been completed as early as it was without the massive effort by Celera using some newly devised methods. The stimulus to the federal effort provided by an independent private effort was, in our view, substantial.

Ultimately, the initial reference genome, to which both contributed, was released sooner and with more data than would have been the case with either working alone. Although there were specific criticisms made of each team by the other, it is now clear that both strategies worked.

The overall goal of providing a huge amount of useful genome data to the community in a short time was greatly served by the parallel efforts.

Notes from a Revolution: Lessons from the Human Genome Project

Finally, we must note that one of the general hallmarks of good science is an effective balance between competition and collaboration. The HGP demonstrated that this is possible, if difficult to achieve, even when it involves multiple complex organizations. Develop a process that could move quickly to evaluate and establish large, transformative inter-organizational projects. It is worth considering where large, transformative projects come from. In all cases, ingredients include advances in science and technology as well as advocacy by a critical number of scientific leaders.

Beyond those, the flame might be lit by an agency as with the HGP or fueled by conflict the Manhattan Projector by a combination of both the space program or perhaps by an unanticipated global crisis.