Selected Case Studies

The Human Genome Project
The National Nanotechnology Initiative

The Human Genome Project

The human genome project (HGP) was a landmark in the field of biomedical research.   It was the first attempt biologists have made into "big science".   Biology research previously was typified by hypothesis driven studies in small labs.   The main source of biomedical research at the National Institutes of Health (NIH) was the R01 grant that are awarded to independent investigators.   In contrast, the HGP was a massive goal-driven effort, leading to a wealth of information, but not answering a specific question or challenging a specific hypothesis.

The search to understand the nature of DNA (deoxyribonucleic acid) can be traced back to early experiment of Mendel, but really if began in the 1950's when DNA was determined to be the source of genetic information.   In 1952, Alfred Hershey and Martha Chase, in an elegant experiment with bacterial phage (virus), showed it was DNA and not proteins that transferred genetic information.   This work along with other earlier experiments shocked the scientific community, which leaned towards the belief that proteins were most likely the source of genes since they had a pool of 20 amino acids to work with while DNA only had four variations (A, T, C, and G).   The second milestone was the publication in 1953, by James Watson and Frances Crick describing the three dimensional structure of DNA.   After this, biologist began the study of DNA and the field of molecular biology was created.   The idea of sequencing the human genome was an extension of this new field and the direction molecular biology was going.

Robert Sinsheimer, a biologist who was at the time the chancellor of the University of California, Santa Cruz, originated the idea of sequencing the human genome in 1985.   He was looking for a project biologists could work on to initiate their venture into "big science".   Although his attempt to push forward the project failed, it did result in the exciting Walter Gilbert.  

Walter Gilbert's claim to fame in the scientific community was the invention a technique for sequencing DNA in 1977 based on chemical degradation.   A method by Sanger was also devised, in 1975, based on the elongation of DNA with DNA polymerase.   Sanger improved this method by adding labeled ddNTP.   These molecules terminated the DNA because when they are incorporated they cannot form further bonds with the normal dNTPs.   This technique is the basis for much of the current sequence technology.   Automated sequencing protocols utilized fluorochromes to label DNA and developed techniques for making the process faster and more accurate, resulting in longer sequence reads of better quality.

Gilbert's interest and support of the HGP kept the idea alive and soon he recruited James Watson and Charles DeLisi to promote the idea.   Charles DeLisi, a cancer biologist at the Office of Health and Environmental Research at the Department of Energy (DoE), justified the funding of the genome project as an outgrowth of the DoE's mandate to study the effects of radiation on human health as well as give a new direction for the national labs.   Because of this interest, Los Alamos National Labs hosted a workshop in 1986 to determine if the idea was possible as well as excite scientists.

Although many scientists were excited about the idea, many more including David Baltimore didn't like the idea of "big science" competing with the traditional investigator-initiated studies.   The HGP was more of a fishing expedition for information, which could later be used for hypothesis-driven research, but was not hypothesis-driven itself.   It was repetitive work with the only innovation the development of technologies.   Also many argued that the price of the project would rob funds from the rest of biology research.   In order to pay for the sequencing, the NIH would have to spend an estimated $3 billion.   Although this was a small price tag for a "big science" project, it would have stretched the NIH budget, which was only $5 billion dollars in 1986.   The scientific value was also questioned.   Much of the human genome doesn't encode genes.   It was believed only 5% of the genome contained genes.   A lot of money would be spent sequencing areas scientist believed were "junk".   In spite of the debate between scientists, the DoE continued with the project by lobbying and starting the Human Genome Initiative in 1986.

The state of the HGP was in limbo until 1988, when the National Academy of Science released a report endorsing the national effort, and requesting the project be run by a single agency.   Many on the panel wanted the effort to be lead by the National Institutes of Health (NIH), but the agency had expressed little interest in running the project.   Although the DoE was one of the early advocates of the project and had the commitment and resources to complete it, many worried about whether the money would be spent in a competitive way, or given to the national laboratories.

The Academy's report also gave a guide on how it wanted the project run.   The first goal was to making physical and genetic maps of increasing resolution, while developing better automated sequencing technology.   Then other small genomes of interest and regions of interest would be sequenced.   Full-scale sequencing of the human genome wouldn't begin until technology made it faster and cheaper.   The cost of the project was estimated to be $3 billion that would be spread over 15 years.   However, the money was to be "new and distinctive" and therefore not reduce funding of other biomedical research.   By starting with mapping and smaller genomes, the HGP had quick and immediate results that researchers could use.

In response to the report, the NIH quickly announced the Office of Human Genome Research (which a year later became the National Center for Human Genome Research, then the National Human Genome Research Institute) and brought in Watson as the head.   From this point on, the NIH became the lead agency for the HGP.   Watson began with the first goal of developing technology and mapping chromosomes.   By 1990 the physical map of the worm was nearly completed and faster and easier ways of manipulating and mapping DNA were being worked out.   Meanwhile, Craig Venter, the head of a large sequencing lab at NIH, and Mark Adams developed a new technique, called expression sequence tags, that allowed for the faster discovery and sequencing of genes.

In 1992, Watson left NIH and Francis Collins took over the project, followed by the expansion of the consortium by the Sanger Center (Great Britian) a new sequencing lab funded by the Wellcome Trust.   Sequencing was slowly producing more data per reaction and cost were dropping, but the big push that helped the project finish under budget and ahead of schedule was a result of Venter.

There are many examples of big steps in science, specifically biology, resulting from fierce competition.   The quest for glory helped create the polio vaccine (Salk and Sabin), discover the virus causing AIDS (Institut Pasteur and Gallo), and now sequence of the human genome.   In 1995 Venter demonstrated the used of a the shot-gun approach to sequence the first entire free-living organism, Haemophilus influenzae, in just a year.   Instead of the slow methodical approach of NIH, the shot-gun method shredded the entire genome into smaller fragments, using computers to reassemble them.   In 1998, Venter and Perkin-Elmer unveiled a new advanced automated sequencing machine and announced the creation of Celera Genomics, claiming he would complete the sequence of the human genome in 3 years for only $300 million, four years before NIH.   In response NIH announced new goals to complete the project by 2003 and produce a "rough draft" (covering 90% of the genome) at the same time as Celera.

In the end, with the help of Ari Patrinos of DoE, the two declared a truce where both groups would publish their drafts together.   Unfortunately, the truce lasted only five months, but the two groups did published simultaneously just in separate journals.   Both acknowledged the competition speeded up the project to everyone's benefit.

The HGP was a truly collaborative and international project.   The work was done at 20 centers in six countries:   China, France, Germany, Great Britain, Japan, and the United States.   The interactions were set-up on a scientist-to-scientist level, removing politics and focusing instead on the project and the advancement of science.   This proved to be an extremely effective and productive model, which other projects can learn from.   The results were shared worldwide and opened up a glut of new data for scientist to work with.

The HGP was biologists first "big science" project and declared a success on all levels.   Not only was the project completed early and under budget, the work pushed forward the fields of genetics and molecular biology as well as comparative biology/genetics.   The data can be used to help deduce genes involved in a variety of diseases as well as determine the effects of small genetic differences between individuals on health and drug interactions.   The technology from the HGP, not only improved sequencing, but also led to high throughput oligonucleotide synthesis, DNA microarrays, normalized and subtracted cDNA libraries, eukaryotic whole-genome knockouts (yeast), and the scale-up of two-hybrid mapping.   Scientists sequenced close to 3 billion bases, and discovered approximately 30-40,000 genes.   Another outcome of the HGP was the ethical, legal, and social implications (ELSI) program started by Watson to look at ethical and societal issues of genetics and sequencing the human genome.   ELSI has helped produce genetic nondiscrimination bills in more than 40 states and trained over 3000 judges on genetics to help with its future uses in courtrooms.   The success of the project has led to other large-scale biology programs involving genomics, structural biology, microbial genomics and proteomics, and haplotype mapping.   Other "big science" projects proposed have included construction of small molecule libraries and large-scale application of microarray technologies.   To top it all off, not only was traditional biomedical research unaffected financially by the HGP, but in the last five years of the project the NIH budget doubled (1998-2003) ushering in a new growth in biomedical research.

The National Nanotechnology Initiative

The origins of the National Nanotechnology Initiative (NNI) was in the work of the science and engineering research community, where remarkable progress was being made in controlling and manipulating matter at the atomic and molecular level.   By the mid- 1990's, it was becoming apparent that researchers had been making substantial leaps forward in nano-scale science and engineering.   In 1996, an informal inter-agency group was formed, with NSF playing a leadership role to evaluate what different agencies were supporting in this area and to begin planning for a coordinated government-wide program (table 1).

Table 1- The National Nanotechnology Initiative Timeline

In the fall of 1998, this inter-agency group was elevated to the Presidential level by reorganizing it under the wing of the National Science and Technology Council as the Interagency Working Group on Nanotechnology (IWGN) .   A plan for a possible budget initiative in nano-scale research was developed, reviewed by a panel of the PCAST, and formally proposed as the "National Nanotechnology Initiative" (NNI) to President Clinton as a part of his FY2001 budget request.   There were many proposed budget initiatives on the table that year and the competition within the White House budget decision process was tough, but the President liked the NNI (he called it his "tiny little initiative") and requested $495 million, nearly doubling what the federal government was spending in this area.   President Clinton flew out to California Institute of Technology to deliver a major address on science and technology, in which he talked about the importance of closing the "physical sciences funding gap" and announced the NNI as well as his request for large increases for most of the science and engineering programs in the federal government.   His request for NSF was unprecedented; it nearly doubled (in dollars) the largest increase the agency had ever received in a single year.   The proposal drew substantial bipartisan support and Congress appropriated $422 million for FY 2001.   The Bush Administration continued to support the NNI, which received $653 million in FY 2002, $774 million in FY 2003, and the President has requested nearly $850 million in FY 2004.   In December 2003, the U.S. Congress, through a bipartisan effort, passed and the President signed into law, a bill for the NNI known as the "21st Century Nanotechnology Research and Development Act".   The authorization bill called for $3.7 billion for research and development in nanotechnology for FY2005-2008.   The money goes to five of the agencies in the NNI (NSF, NASA, DoE, NIST, and EPA).   The legislation also required the creation of research centers, education and training efforts, studies into the societal and ethical consequences of nanotechnology, and activities directed toward transferring technology into the marketplace.   Finally, the bill sets up advisory committees and regular program reviews, and delineates additional tasks for the National Nanotechnology Coordination Office.

Many agencies contribute to the NNI.   The three largest, in terms of dollars allocated to NNI, are the NSF and the Departments of Energy and Defense (table 2).   In order to decide what is, and what is not, nanotechnology, the agencies have agreed on a definition that emphasizes "working at the atomic, molecular and supramolecular levels, in length scale of approximately 1-100 nm range, in order to create materials, devices, and systems with fundamentally new properties and functions because of their small structure".   The NNI supports a broad range of activities, including:   fundamental research, the so-called "Grand Challenges", centers and networks of excellence, research infrastructure, and research focused on societal implications, workforce education, and training.   Following America's lead, several other countries have launched nanotechnology initiatives (table 3).

Table 2 - Agencies which fund the nanotechnology research and development.

Table 3 - Nanotechnology in the World: Comparison of Industrialized Countries from 2000-2002.

There are a few lessons to take away from this story about the origins and status of NNI.   There were a number of critical factors that made it possible for the idea of a major research budget initiative in nanoscale research to become a reality.   First, the research community had already shown, that nanoscale research was exciting and promising.   Second, several funding agencies were able to agree on a multi-agency program that had coherence and fit well within their respective agencies' programs.   Third, several of the President's closest advisors, including his external advisors on PCAST, embraced the initiative.   Fourth, the economy was booming and it was an election year, hence, the White House and Congress were willing to agree on a substantial increase in the discretionary budget.   Fifth, the NNI was easy to explain to the public and policy-makers, both from the perspective of basic science and the promise of revolutionary applications to materials, computing, medicine, and many other areas of national importance.   And, sixth, there were many champions of the NNI from industry.

Advice from the S&T community came from several directions.   The agencies' advisory committees (e.g. the Advisory Committee for the Directorate of Mathematical and Physical Sciences, at the NSF) had followed developments in nanoscale research for many years and provided guidance at the programmatic level.   The NSB, which approves annual budget requests for NSF and advises on allocations to different fields, including emerging areas, supported NSF's increased funding in nanoscale research.   The President's external S&T advisors on PCAST formed an expert panel, chaired by President Chuck Vest, Massachusetts Institute of Technology, to review the multi-agency plans for NNI and recommend action to the full PCAST, which forwarded a recommendation to the President.

Relevant Websites

The Human Genome Project

NIH
National Human Genome Research Institute

DoE - Office of Science

Celera

National Academies of Science

Additional Reading

Watson, J.D. and Crick, F.H.C. (1953) Molecular Structure of Nucleic Acids.   Nature. 171, p737-8.

Watson, J.D. et al. (1992) Recombinant DNA. Scientific American Books, New York.

Roberts L. (2001) Controversial From the Start. Science. 291, p1182-8.

Davies, K. Cracking the Genome, Inside the Race to Unlock Human DNA . The Free Press, New York.

Collins, F.S., Morgan, M., and Patrinos, A. (2003) The Human Genome Project:   Lessons from Large-Scale Biology. Science. 300, p286-90.

Human Genome "Rough Drafts

Venter, C, et. al., (2001) The Sequence of the Human Genome. Science. 291, p1304-51.

International Human Genome Consortium. (2001) Initial Sequencing and Analysis of the Human Genome. Nature. 409, p860-921.

National Nanotechnology Initiative

National Nanotechnology Inititative
NNI Grand Challenges
President Bush's 21st Century Nanotechnology Research and Development Act
National Nanotechnology Coordination Office

National S&T Council

President's Council of Advisors on S&T

President Clinton's speech at California Institute of Technology

National Science Foundation

National Aeronautic and Space Administration

Department of Energy

National Institute of Standards and Technology

Environmental Protection Agency

Department of Defense

 

 

Next Section: Gaps in Science and Technology Policy

Science Policy Page Homepage