Molecular genetics has transformed clinical neurology. We have learned that mutations in the same gene can cause different clinical syndromes (allelic heterogeneity) and that the same clinical syndrome can be caused by mutations in different genes (locus heterogeneity).
Inserting mutated human genes into the germline of mice or fruit flies has provided vital information about the pathogenesis of hereditary and sporadic versions of Alzheimer disease, Parkinson disease, and others.
Now the entire human genome has been sequenced; we have entered the genomic age. Formerly, it took many months or years to clone a disease gene; now it can be done in weeks. Now we expect to find heritable susceptibility factors that will lead to the identification of environmental causes of sporadic diseases.
How the genome was sequenced is a story that involves so many brilliant investigators that the Nobel Committee will have a hard time deciding whom to reward. The Gene Masters: How a New Breed of Scientific Entrepreneurs Raced for the Biggest Prize in Biology, a first book by talented science journalist Ingrid Wickelgren, is a stunning telling of that tale.
MOTIVES FOR MODERN RESEARCH
According to Wickelgren, the genome competition was not merely a race for the glory of being first. Rather, it was a fundamental debate about the support and motives for modern biomedical research. Should entrepreneurs raise money to support genetic research? Should private companies patent genes and proteins to bring profit to shareholders? This is a worldly problem: How much research should be funded by the federal government and how much by private companies? How much control should private companies have over academic research and how can universities and drug companies cooperate?
Wickelgren is fair in describing the contestants. On the public side were Francis Collins, Head of the Human Genome Project in the US, and John Sulston, the 2002 Nobel laureate for his work on the genome of the worm, Caenorhabditis, and head of the British team at Cambridge.
Collins, mapper of the gene for cystic fibrosis and Huntington disease, was now responsible for a biological research project unlike anything in history. He became a master of conflict resolution for the several laboratories on the public team; he also mastered press conferences, and had to be a master in dealing with the competition from J. Craig Venter.
Also prominent was Robert Waterston, formerly at Washington University in St. Louis, and now at the University of Washington in Seattle; he was the long time partner of Sulston in the trans-Atlantic effort to map the worm genome and therefore was among the first to tackle the human genome.
Maynard Olson was an early mapper of the yeast genome. Eric Lander, at MIT, was a major contributor to the acceleration of the public project and was the primary author of the 40,000-word document reporting their results in 2001. James Kent was the graduate student who had to defer the final push because he was preparing for his oral examinations and only afterwards could he apply his considerable computer skills to ordering the pieces of the genome.
Collins had to decide whether to fund a few of the more accomplished centers or whether to follow the National Institutes of Health (NIH) tradition of spreading grant support across the country; he opted for the top few.
On the private side, J. Craig Venter was the thorn-in-the-side of the public team. He started his work as a protein chemist, seeking to isolate receptors for neurotransmitters at the National Institute for Neurological Disorders and Stroke. It took him ten years to isolate his first receptor gene by traditional methods and he then devised a new approach that could shorten the time to months, but he was turned down when he requested supplemental funds for his NIH budget. That slight and others made him receptive to an offer from a private company.
Venter did not go alone. He picked a Nobel laureate, Hamilton Smith, to lead his science team. Mark Adams, who started as a post-doc with Venter, demonstrated the validity of Venter's “expressed sequence tag” as an effective marker, and emerged as a leader of the team. Eugene Myers and Granger Sutton led the shotgun approach, breaking up the chromosomes into thousands of pieces, sequencing them, and putting them in order by computer. Venter convinced Gerald Rubin, a distinguished academic, to join him in sequencing the Drosophila genome.
COMPETITIONS AND BATTLES
There were other competitions, too – between the several US centers, between Venter's company and one led by his erstwhile partner William Haseltine, between the Department of Energy and the NIH, between drug companies who wanted to lead the action, between investigators who promoted the search and those who feared it would divert funds from other essential biomedical research.
A battle about patents cost James Watson his job as the first NIH Director of the project. In the end, the entrepreneurs faced their biggest challenge, how to make a profit from the information gleaned from the genome. Celera, the company founded for Venter and led by him, saw its stock reach the heights, sink to the depths, and switch from information business to drug discovery – all in a few years.
Sometimes, the battles were intensely personal. Venter became a media star – in the newspapers, on magazine covers, and on television. He claimed his team could do the job faster, better and cheaper than the public project. Wickelgren reports that when Celera's stock tanked, Venter asked the Chief Executive Officer, Anthony White, what was wrong. The reply was brief: “Craig, I think it's you. I think you need to … shut up!”
A side issue embroiled neurologist Kári Stefánsson, who had been doing multiple sclerosis research at Harvard and was led to genetics. Knowing the need for large families, he returned to his native Iceland, set up a private company, and ultimately had access to the medical records of people on the entire island, including earlier generations. Then, with informed consent, he took blood from volunteers and gained access to the genome of an isolated people.
DEBATE ABOUT PRIVACY
A furious debate about privacy involved the parliament, but ultimately the company found genes for schizophrenia and entered the debate about the role of inheritance in Parkinson disease. Are genes important only for those with the young-onset form? Instead, they found evidence of genetic susceptibility in late-onset syndromes as well. And they mapped a gene for essential tremor.
Industry played a vital role for both the public and private enterprises when Michael Hunkapiller, of Celera, developed souped-up robotic sequencers that were used by both teams. The question of patents, however, was not resolved, and it was not merely a matter of profits. If a company had rights to a gene, academics would have to wait, pay a fee, or both. That would be inconsistent with the historically full and free access of scientists to accelerating information. When companies raised the huge sums to power the project, Michael Morgan, of the Wellcome Trust in England, spoke firmly: “To leave this to a private company, which has to make money, seems to me completely and utterly stupid.”
Ultimately, after the book was published, Venter had to resign from his position at Celera. Patents or not, profitability was not evident.
Wickelgren's book complements the one by Sulston and Georgina Ferry, The Common Thread, but it is less partisan. Both cover the same ground, and there are few conflicts in rendering the facts.
The two books make a fit combination, describing a monumental scientific achievement and proving that, even in technology-driven research, scientists are, after all, human.
Now comes the good part, the really hard part – how to convert activity from gene cloning to the treatment or prevention of diseases, too many of which are neurological.