In an interview at a DNA sequencing conference in Hilton Head, South Carolina,* David Smith, a founder and former Director of the DOE Human Genome Program, recalled the establishment of this country's first human genome project. The impressive early achievements and spinoff benefits, he noted, offer more than mere vindication for project founders. They also provide a tantalizing glimpse into the future where, he observed, "scientists will be empowered to study biology and make connections in ways undreamt of before."  

*The Seventh International Genome Sequencing and Analysis Conference, September 1995. 

The DOE Human Genome Program began as a natural outgrowth of the agency's longterm mission to develop better technologies for measuring health effects, particularly induced mutations. As Smith explained it, "DOE had been supporting mutation studies in Japan, where no heritable mutations could be detected in the offspring of populations exposed to the atomic blasts at Hiroshima and Nagasaki. The program really grew out of a need to characterize DNA differences between parents and children more efficiently. DOE led the development of many mutation tests, and we were interested in developing even more sensitive detection methods. Mortimer Mendelsohn of Lawrence Livermore National Laboratory, a member of the International Commission for Protection Against Environmental Mutagens and Carcinogens, and I decided to hold a workshop to discuss DNA-based methods (see Human Genome Project chronology). 

"Ray White (University of Utah) organized the meeting, which took place in Alta, Utah, in December 1984. It was a small meeting but very stimulating intellectually. We concluded the obviousthat if you really wanted to use DNA-based technologies, you had to come up with more efficient ways to characterize the DNA of much larger regions of the genome. And the ultimate sensitivity would be the capability to compare the complete DNA sequences of parents and their offspring." 

Project Begins  
Smith recalled reaction to the first public statement that DOE was starting a program with the aim of sequencing the human genome. "I announced it at the Cold Spring Harbor meeting in May 1986, and there was a big hullabaloo." After a year-long review, a National Academy of Sciences National Research Council panel endorsed the project and the basic strategy proposed. Smith pointed out that NIH and others were also having discussions on the feasibility of sequencing the human genome. "Once NIH got interested, many more people became involved. DOE and NIH signed a Memorandum of Understanding in October 1988 to coordinate our activities aimed at characterizing the human genome." But, he observed, it wasn't all smooth sailing. The nascent project had many detractors. 

Responding to Critics 
Many scientists, prominent biologists among them, thought having the sequence would be a misuse of scarce resources. Smith, laughing now, recalls one scientist complaining, "Even if I had the sequence, I wouldn't know what to do with it." Other critics worried that the genome project would siphon shrinking research funds away from individual investigator-initiated research projects. Smith takes the opposite view. "In fact, individual investigators can do things they would never be able to do otherwise. We're beginning to see that demonstrated at this meeting. For the first time, we're finding people exploring systematic ways of looking at gene function in organisms. The genome project opens up enormous new research fields to be mined. Cottage-industry biologists won't need a lot of robots, but they will have to be computer literate to put the information all together."  

The genome project also is providing enabling technologies essential to the future of the emerging biotechnology industry, catalyzing its tremendous growth. According to Smith, the technologies are apable of more than elucidating the human genome. "We're developing an infrastructure for future research. These technologies will allow us to efficiently characterize any of the organisms out there that pertain to various DOE missions, with such applications as better fuels from biomass, bioremediation, and waste control. They also will lead to a greater understanding of global cycles, such as the carbon cycle, and the identification of potential biological interventions. Look at the ocean; an amazing number of microbes are in there, but we don't know how to use them to influence cycles to control some of the harmful things that might be happening. Up to now, biotechnology has been nearly all health oriented, but applications of genome research to modern biology really go beyond health. That's one of the things motivating our program to try to develop some of these other biotechnological applications." 

Responding to criticism about not researching gene function early in the project, Smith reasserted that the purpose of the Human Genome Project is to build technologies and resources that will enable researchers to learn about biology in a much more efficient way. "The genome budget is devoted to very specific goals, and we make sure that projects contribute toward reaching them." 

International Scope  
Smith credited the international community with contributing to many project successes. "The initial planning was for a U.S. project, but the outcome, of course, is that it is truly international, and we would not be nearly as far as we are today without those contributions. Also, there's been a fair amount of money from private companies, and support from the Muscular Dystrophy Association in France and The Wellcome Trust in the United Kingdom has been extremely important."  

Technology Advances  
While noting enormous advances across the board, Smith cited automation progress and observed that tremendously powerful robots and automated processes are changing the way molecular biology is done. "A lot of novel technologies probably won't be useful for initial sequencing but will be very valuable for comparing sequences of different people and for polymorphism studies. One of the most gratifying recent successes is the DNA polymerase engineering project. Researchers made a fairly simple change, but it resulted in a thermosequenase that may answer a lot of problems, reduce the cost of sequencing, and give us better data." 

Progress in genome research requires the use of maturing technologies in other fields. "The combination of technologies that are coming together has been fortuitous; for example, advances in informatics and datahandling technologies have had a tremendous impact on the genome project. We would be in deep trouble if they were at a lessmature stage of development. They have been an important DOE focus." 

ELSI  
Smith described tangible progress toward goals associated with programs on the ethical, legal, and social issues (ELSI) related to data produced by the genome project. "ELSI programs have done a lot to educate the thinkers, and this has produced a higher level of discourse in the country about these issues. DOE is spending a large fraction of its ELSI money on informing special populations who can reach others. Educating judges has been especially well received because they realize the potential impact of DNA technology on the courts." 

According to Smith, more people and groups need to be involved in ELSI matters. "We have some ELSI products: the DOE-NIH Joint ELSI Working Group has an insurance task force report, and a DOE ELSI grantee has produced draft privacy legislation. Now it's time for others to come and translate ELSI efforts into policy. Perhaps the new National Bioethics Advisory Commission can do some of this." 

New Model for Biological Research  
Smith spoke of a changing paradigm guiding DOE-supported biology. "Some years ago, the central idea or dogma in molecular biology research was that information in DNA directs RNA, and RNA directs proteins. Today, I think there is a new paradigm to guide us: Sequence implies structure, and structure implies function. The word 'implies' in our new paradigm means there are rules," continued Smith, "but these are rules we don't understand today. With the aid of structural information, algorithms, and computers, we will be able to relate sequence to structure and eventually relate structure to function. Our effort focuses on developing the technologies and tools that will allow us to do this efficiently." 

"That's how I think about what we do at DOE," he said. "We're working a lot on technology and projects aimed at human and microbial genome sequencing. For understanding sequence implications, we are making major, increasing investments in synchrotrons, synchrotron user facilities, neutron user facilities, and big nuclear magnetic resonance machines. These are all aimed at rapid structure determination." Smith explained that now we are seeing the beginnings of the biotechnology revolution implied by the sequencetostructure tofunction paradigm. "If you really understand the relationship between sequence and function, you can begin to design sequences for particular purposes. We don't yet know that much about the world around us, but there are capabilities out there in the biological world, and if we can understand them, we can put those capabilities to use." 

"Comparative genomics," he continued, "will teach us a tremendous amount about human evolution. The current phylogenetic tree is based on ribosomal RNA sequences, but when we have determined whole genomic sequences of different microbes, they will probably give us different ideas about relationships among archaebacteria, eukaryotes, and prokaryotes." 

Feeling good about progress over the previous five years, Smith summed it up succinctly: "Genomics has come of age, and it is opening the door to entirely new approaches to biology." 


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David Smith retired at the end of January 1996. Taking responsibility for the DOE Human Genome Program is Aristides Patrinos, who is also Associate Director of the DOE Office of Biological and Environmental Research. Marvin Frazier is Director of the Health Effects and Life Sciences Research Division, which manages the Human Genome Program. 

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