Beyond the Double Helix: Highlights of the Conference Celebrating the Completion of the Human Genome Project

Robert C. Green, MD, MPH

Disclosures

May 22, 2003

Introduction

"Welcome to the Genome Era."

With these words, Francis Collins, Director of the National Human Genome Research Institute, opened one of the most remarkable conferences in the history of science. Standing before a roomful of Nobel Prize winners and genomic scientists, he declared: "I am pleased and honored -- even exhilarated -- to declare the goals of the Human Genome Project to be completed."

For some biological scientists around the world, these words rang out like Neil Armstrong's statement after first landing on the moon. As with the moon landing, the Human Genome Project began in controversy with seemingly overwhelming obstacles, demanded massive funding from the government, required dedicated work from thousands of persons, and reinvented technologies along the way. But unlike the moon landing (or any other project in modern history), the Human Genome Project was completed early and under budget and has the potential to change life for every human being on the planet.

Thus, for the 2 days of this conference, staid and sober scientists, normally given to understatement, could be forgiven for sounding a little giddy as they celebrated this achievement, in the manner of scientists, by talking to each other. Dozens of Nobel laureates, many of the world's greatest geneticists, and virtually all of the scientists responsible for sequencing the human genome gathered in an ordinary auditorium at the National Institutes of Health (NIH) to remember, to reflect, and to marvel at the leap of progress during the past 50 years. This conference was both an anniversary party and a victory celebration. Thousands of workers have labored intensively to complete the "final draft" of the human genome, just in time for the 50-year anniversary of the publication of the structure of DNA by Francis Crick and James Watson in April 1953.

What made the conference so startling and poignant was the presence of James Watson, Francis Crick (by video), Marshall Nirenberg, and others who had defined the structure of DNA and elucidated the mechanisms of genetic function. Those who discovered the alphabet of all life on earth were there to see the decoding and unveiling of the first edition of evolution's masterwork. Elias Zerhouni, Director of NIH, aptly called the day the "dawn of a new era."

After the opening comments by Drs. Zerhouni and Collins, the conference began with brief musings by James Watson and Francis Crick. The remarks by Watson, now Director of the Cold Spring Harbor Laboratory in New York, were particularly moving as he discussed his son's handicaps and shared his hopes that understanding the genetic basis of disease would diminish human suffering in the future.

Marshall Nirenberg of NIH gave the first formal scientific talk of the conference, "Deciphering the Genetic Code." Nirenberg described some of the earliest experiments in the race to synthesize triplet nucleotide sequences and to determine which amino acids were produced by each sequence.

Next, Stanley Cohen of Stanford University, Palo Alto, California, described how he, in collaboration with Herb Boyer and others, had discovered cloning. Cohen showed how DNA from one species could be expressed in another and described how he had initially broken apart bacterial plasmid DNA circles with mechanical shearing, allowing nucleotides on one strand to interact with complementary nucleotides on the other strand. He then described cleavage of DNA using EcoR-1, such that fragments could be rejoined by hydrogen bonding. The first cloning took place within bacterial species and was demonstrated by transferring resistance to antibiotics. Shortly after, DNA from a frog was recombined with bacterial DNA, and interspecies cloning became a reality. Later, when David Baltimore discovered reverse transcriptase, messenger RNA would be used to make DNA in any cell, including mammalian cells, and the biotechnology revolution was born.

Throughout the first day of the conference, a video of vignettes and commentary on the discovery of DNA was shown. The video included remarks by James Watson, Francis Crick, Mathew Meselson, Maxine Singer, Walter Gilbert, Sydney Brenner, David Baltimore, Stanley Cohen, Herb Boyer, Daniel Kevies, Robert Sinsheimer, David Botstein, Nancy Wexler, Lee Hood, Pete Domenici, Patricia King, Craig Venter, and Gerry Rubin. Among the most interesting segments of the video were interviews that described the moratorium on genetic recombination that arose in the early 1970s. By this time, the potential for life-altering consequences of manipulating DNA were becoming clear to scientists and the world at large. Genetic scientists wanted to avoid the moral taint of nuclear scientists, who had been widely perceived as insensitive to the social and ethical implications of their work. Thus, an unprecedented voluntary moratorium was established. In February 1975, the Asilomar Conference gathered genetic scientists, ethicists, and policy makers for an open debate that resulted in rules being issued for conducting DNA research in 1976. After this, recombinant DNA research was able to continue. Indeed, in 1976, Genentech (an amalgam of the words "genetic engineering technology") was formed by Swanson and Boyer, and in 1978, using recombinant techniques, human insulin was created.

As the genome celebration continued, Philip Sharp, of the Massachusetts Institute of Technology (MIT), described the development of RNA splicing. He also described the discovery that progression of DNA to RNA and then to protein goes through a process of RNA splicing and capping. This discovery led to the development of an in vitro splicing system and the notion of the spliceosome. Sharp explained the importance of alternative splicing by reminding the audience that only about 35,000 genes, or units of transcription, exist in the mammalian genome--hardly enough to account for the complexity of biological systems. However, the complexity of alternative splicing provides an extraordinary number of possibilities; for example, a single Drosophila gene could theoretically be expressed in over 38,000 ways to become protein. Sharp pointed out that this variability goes a long way toward explaining how only 35,000 genes can code for the complexity of the mammalian genome and, en passant, how far we have to go beyond simply sequencing the genome to understand the real details of genetic coding.

The historian Horace Freeland Judson, from George Washington University in Washington, DC, spoke about 2 revolutionary ideas that grew out of the discovery and decoding of DNA. These concepts, sequence hypothesis and central dogma, have fundamentally changed our sense of the world. The sequence hypothesis maintains that the specificity of a nucleic acid is expressed solely by its sequence, which creates a code. Central dogma is the phrase that describes the notion that DNA is translated into RNA that, in turn, is translated into protein. In light of discoveries that RNA could be translated back into DNA, Judson pointed out that a more accurate description would be that "once information has passed into protein, it cannot get out again." In other words, transfer of information from nucleic acid to nucleic acid or from nucleic acid to protein is possible, but information from protein cannot be transferred back to nucleic acid. This revelation, Judson said, explains why there cannot be inheritance of acquired information and makes each generation doomed (or blessed) to discover life's lessons over and over again, transmitting no facts or wisdom through the genome.

The personal scientific recollections of the gathered speakers complemented the broader historical perspective of the documentary filmmakers. A fascinating vignette entitled "Brainstorming the Genome" described the controversial genesis of the Human Genome Project in the 1980s and was enhanced by live remarks from Charles DeLisi, now a retired dean from Boston University, and Bruce Albert, from the National Academy of Sciences in Washington, DC. While multimillion dollar "big science" programs were common in the pursuit of nuclear technology and the space program, the traditions of scientific discovery in biology emphasized the initiative of the single investigator or the small investigative team. When the Human Genome Project was proposed, its critics charged that it would be produce only "tedious, unrewarding work," and there was real doubt about whether the benefits could possibly justify the $3 billion price tag.

To address this dispute, the National Academy of Sciences set up a committee, headed by Bruce Alberts, to study the proposed mapping and sequencing project. In February 1988, the committee released its 104-page report, which favored creation of the sequencing initiative as a special project to be funded by the government. The recommendations were to focus initially on high-resolution genetic linkage and mapping and emphasize comparative genetics. A budget of $200 million/year for 15 years was proposed. Immediately after the report was released, NIH convened a planning meeting that resulted in the appointment of James Watson as the first director of the Human Genome Project on October 1, 1988.

While enormous projects like this were new to biology and even to the NIH, they were regularly undertaken by other branches of the federal government. One of the curious aspects of the Human Genome Project was that it was championed and shepherded not only by the NIH but also by scientists within the Department of Energy, such as Charles DeLisi and Aristides Patrinos. DeLisi recalled how the greatest uncertainties about the project were economic and how the budget was ultimately presented as an "engineering project." Recorded comments from New Mexico Senator Pete Dominici recalled that the convergence of reproductive technology and genomics, Darwinian themes, prenatal screening, and embryo selection, was "almost guaranteed to polarize." Despite the political minefields, Dominici steadfastly supported the project in Congress.

At the Project's first press conference, which was held just as the Project was beginning, James Watson announced without warning that 3% of the budget would be set aside for ethical, legal, and social issues (ELSI). According to Eric Juengst, the first director of the ELSI program, the congressional appropriations committee was as surprised and skeptical about earmarking these funds as the rest of the scientific community. However, from the start Watson's vision was that mere scientific progress was not enough: Scientific discoveries had to be accompanied by inquiry into the impact on society. Remarkably, the NIH stood behind this philosophy, although there was no clear plan on how the ELSI program should be implemented and how NIH should go about "social impact assessment." To these ends, Nancy Wexler chaired a working group that developed a 5-year plan involving 2 major goals: to develop programs that defined major issues and to develop policy options. The existing NIH grant structure was chosen as the means to attain these goals, and the Genome Project became the only major NIH program to specifically study the impact of its science on society.

Juengst summarized the successes of the ELSI program to date in broad strokes: (1) most states have passed some form of legislation to protect genetic privacy, and federal legislation has been in development for several years; (2) new genome centers at top-level institutions typically are designed to include an ELSI component; and (3) in planning post-genome project initiatives, the planning committees for science have been integrated with administrators and scientists from the ELSI program.

In addition to celebrating the anniversary of the discovery of DNA and completion of the Human Genome Project, various speakers were also celebrating a new vision for biology as a science and for genomic science and health. Eric Lander of MIT summarized the history of modern biology to date as moving from "biology as organisms" to "biology as molecules." With the completion of the human genome sequencing, Lander envisions a new age of "biology as information."

Just as scientists have, in recent decades, been able to "purify" molecules outside the organism and even the cell, in the future information (in the form of genetic sequencing and its variants) will be purified outside the molecule. As for the genetic sequences in each discrete species of life on this planet , Lander compared them to a vast reference waiting to be read: "Life is an extraordinary library gathered over 3.5 billion years of experimentation. These [sequences] are the laboratory notebooks of evolution... and we will now have all the successful experiments of each species." Lander also pointed out that comparisons between species will deliver unprecedented results in the future. For example, why are some sections of the genome conserved through evolution better than they should be?

So what has been accomplished? The sequence announced in 2000 was a "draft" version of the human genome, but now the actual sequence, fully covering 99% of the genome, is complete and continuous across all chromosomes. For almost every gene, the sequence -- including the exons -- is fully decoded, and the error rate is less than 1 per 100,000 bases. In addition to NIH, 18 major organizations around the world took part, with Britain's Welcome Trust supporting the completion of one third of the finished sequence.

Today, the human genome is not only sequenced, the sequence is available to all via the Internet. It is updated daily as new discoveries are made. Tools for accessing the genome, including sophisticated Web browsers such as "Ensemble" are available to everyone and are currently registering up to 600,000 hits per week from scientists all over the globe. The sequencing of the human genome has proven its worth: It has already altered forever the way biological research is done.

By the end of the Genome Celebration Conference, several speakers pointed to recent discoveries that have allowed better understanding of such diseases as cardiovascular disease, diabetes, and asthma and discussed race as a biological and social construct. The full Web cast of the 2-day conference is available at http://www.videocast.nih.gov/ PastEvents.asp?c=998.

As this conference made clear, a remarkable chapter in human science has come to a close, and the future begins with high hopes. Such was the frenzied pace of this science that the original discoverers of the structure of DNA could participate a mere 50 years later in the celebration of the decoding and sequencing of that structure. Francis Crick immediately recognized the import of the discovery. On February 28, 1953, he announced over lunch at the Eagle Pub in Cambridge that he and Watson had discovered the "secret of life." And so they had.

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