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An insider’s account of the Human Genome Project

The Human Genome Project (HGP) – to put it simply – has changed science. It has contributed to making biology the science of the 21st century, as physics was the science of the 20th century. It has driven…

Close-up of a sculptural representation of deoxyribonucleic acid (DNA), the basic building block of nearly all organisms. ἀλέξ/Flickr

The Human Genome Project (HGP) – to put it simply – has changed science.

It has contributed to making biology the science of the 21st century, as physics was the science of the 20th century. It has driven advances in our understanding of biology at the cellular and molecular levels and provided new tools for medicine. It has led to routine genetic testing for many diseases including breast cancer and cystic fibrosis.

I see this as clearly now from the outside as I did during my 25 years of close association with the project.

As attested to on the HGP website, the projects goals were to:

  • identify all the approximately 20,000-25,000 genes in human DNA;
  • determine the sequences of the three billion chemical base pairs that make up human DNA;
  • store this information in databases;
  • improve tools for data analysis;
  • transfer related technologies to the private sector; and
  • address the ethical, legal and social issues that may arise from the project.

So how did it get from an idea stage to where it is today?

The project was stimulated, in part, by large-scale initiatives to win the second world war. Its initial proponents felt themselves to be the scientific descendants of the Manhattan Project – a research and development project that produced the first atomic bombs.

As with the Manhattan Project, Los Alamos Laboratory in New Mexico – constructed for the development of the atomic bomb – played a strong role in development of the Human Genome Project.

Having been recruited to Los Alamos in 1984, and ultimately leading its bioscience division from 1999 to 2004, I was witness to this exciting time in the history of biological research.

Early days

The HGP was officially founded in 1990 by the US Department of Energy’s Office of Health and Environmental Research – led for a period in the 1980s by the Boston University scientist Charles DeLisi – and was the culmination of many years of work and debate.

DeLisi had come to the Department of Energy from the National Institutes of Health (NIH) and had the view that understanding human susceptibility to environmental energy emissions could benefit from knowledge of the genome and genetic mutations linked to such susceptibility.

DeLisi asked the then-head of life science at Los Alamos, Mark Bitensky (who gave me my job at the laboratory), to convene one of the landmark early workshops, in 1986, leading up to the project.

Following the workshop, the Office of Health and Environmental Research’s advisory committee recommended a major project to map the entire genome and identify all gene sequences.

While welcomed by some in the science community, there was considerable debate following this recommendation about whether the available technology for sequencing was either fast enough, or cheap enough for the ambitious goals of sequencing the three billion base pairs that make up the human genome.

And not just that: many scientists felt biology was the realm of the individual researcher and that such a large project would consume all the available research funding.

In this climate of controversy and grand vision came the first funding (US$13 million in the 1987 presidential budget) for the effort from the Department of Energy. Then, in 1990, the Human Genome Project was established formally as a joint project to be funded by the National Institutes of Health and the department.

Initial estimates put the project cost at US$3 billion and expected it to take 15 years.

The first printout of the human genome to be presented as a series of books. The 3.4 billion units of DNA code are transcribed into more than a hundred volumes, each a thousand pages long, in type so small as to be barely legible. Russ London/Wikimedia Commons

Private concerns

The American biologist and entrepreneur Craig Venter and his company Celera Genomics entered the frame in 1998 and with private funding set up a competing human genome sequencing project in direct competition with the public project.

Venter’s innovation (that he hoped would allow the Celera project to go faster and cost an order of magnitude less that the public project) was to use “whole genome shot-gun sequencing”, previously used in sequencing smaller bacterial genome sequences but never applied to something as large as a human genome.

Venter’s team - then based in Rockville Maryland – broke the sequence into smaller parts. They then sequenced the ends of chromosomes and reassembled the sequence computationally by lining up the overlapping segments.

Competition was fierce and there was scepticism that Venter’s approach would lead to an accurate result. I also recall the intense public controversy over Venter’s proposal to seek patents on between 200 and 300 human genes, which the research community feared would “thwart promising genetic research by academics, as well as competitors”.

These fears were laid to rest on March 2000 when then-president Bill Clinton announced that the genome sequence should be made freely available to all researchers and could not be patented.

The statement resulted in a US$50 million loss in the biotechnology industry as Celera’s stock price plummeted.

A couple of months later – and five years ahead of schedule – the public and private projects jointly published the draft human genome sequence, a moment marked with a joint announcement by Bill Clinton and the then-UK prime minister Tony Blair.

This result was only possible thanks to the commitment and dedication of staff numerous universities and research centres throughout the United States and in the UK (with funds from the Wellcome Trust), as well as sites in France, Germany, Japan and China.

Into the noughties

In April 2003, the anniversary of James Watson and Francis Crick’s publication of the structure of DNA and their prediction of the chemical basis for DNA replication, the essentially finished version of the human genome sequence was celebrated.

As I wrote at the outset, the HGP has changed science. The extraordinary advances in sequencing technology that emerged from the project have led to databases of whole genome sequences of bacteria, viruses and fungi that are critically important for public health and biosecurity, including the HIV, influenza, and pathogen sequence databases.

The sequencing team in my division at Los Alamos was responsible for producing the draft and finished sequences of chromosome 16. This chromosome is made up of 90 million base pairs coding for more than 800 genes including genes linked to Batten’s disease, polycystic kidney disease, and inherited heart disease, which affects one in 500 young adults and can be fatal. We also contributed to finishing the sequencing of other chromosomes.

We felt the terror of knowing that the draft sequence had to be completed by a specific date because a prime minister and a president planned to make an announcement about it.

And we were subsequently held ransom to a later date reflecting the publication of the iconic scientific discovery 50 years earlier.

Were those pressures detrimental to our efforts? On the contrary, it’s a time I remember well and cherish greatly.

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4 Comments sorted by

  1. Emma Beckett

    Doctoral scholar, Human Molecular Nutrition Laboratory & Casual Academic at University of Newcastle

    Thank you for the insightful and concise recount Professor Trewhella, as I young scientist, I find it so inspiring to imagine that such a giant step in the body of knowledge was made during my own lifetime. It makes me excited to think what else amazing may happen in the next few decades and I might even be lucky enough to be a part of it!

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  2. Matthew Todd

    Associate Professor, School of Chemistry at University of Sydney

    The HGP was a wonderful achievement. For those interested in a comparison of the public vs. private projects, an interesting paper has just been published which suggests that patents on genes harmed research productivity:

    http://www.jstor.org/stable/10.1086/669706

    For those interested in the quantification of how the open data behind the HGP spurred economic activity, see this study from 2011:

    http://www.genome.gov/27544383

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  3. Devanshi Seth

    Senior Scientist

    great comprehensive article. as genome researcher, it is good to see this area progressing in leaps and bounds. the level of knowledge developed in the recent years will be the foundation of great research and medical breakthroughs....one hopes

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  4. rory robertson

    logged in via email @gmail.com

    Professor Trewhella,

    Congratulations on your extraordinary career at the highest levels of global science. I wonder if I could ask you - now Deputy Vice-Chancellor (Research) - about the University of Sydney's policy on research misconduct. First, does the University have and enforce such a policy? If not, why not? www.australianparadox.com

    Professor, should a faulty self-published "peer reviewed" paper with a false conclusion based on falsified data be corrected/retracted or is it just…

    Read more