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It was a momentous occasion when British scientist John Sulston embarked on the greatest scientific endeavor of our times: the sequencing of the Human Genome. In The Common Thread, Sulston takes us behind the scenes for an in-depth look at the controversial story behind the headlines. The accomplishments and the setbacks—along with the politics, personalities, and ethics—that shaped the research are frankly explored by a central figure key to the project.
From the beginning, Sulston fervently proclaimed his belief in the free and open exchange of the scientific information that would emerge from the project. Guided by these principles, The Human Genome Project was structured so that all the findings were public, encouraging an unparalleled international collaboration among scientists and researchers.
Then, in May 1998, Craig Venter announced that he was quitting the Human Genome Project—with plans to head up a commercial venture launched to bring out the complete sequence three years hence, but marketed in a proprietary database. Venter’s intentions, clearly anathema to Sulston and the global network of scientists working on the Project, marked the beginning of a dramatic struggle to keep the human genome in the public domain.
More than the story of human health versus corporate wealth, this is an exploration of the very nature of a scientific quest for discovery. Infused with Sulston’s own enthusiasm and excitement, the tale unfolds to reveal the scientists who painstakingly turn the key that will unlock the riddle of the human genome. We are privy to the joy and exuberance of success as well as the stark disappointments posed by inevitable failures. It is truly a wild and wonderful ride.
The Common Thread is at once a compelling history and an impassioned call for ethical responsibility in scientific research. As the boundaries between science and big business increasingly blur, and researchers race to patent medical discoveries, the international community needs to find a common protocol for the protection of the wider human interest. This extraordinary enterprise is a glimpse of our shared human heritage, offering hope for future research and a fresh outlook on our understanding of ourselves.
IF THERE IS A SINGLE ICON ABOVE ALL OTHERS THAT ART ACQUIRED from science in the twentieth century, it is DNA. And with good reason: this molecule, as Francis Crick famously shouted to the bemused customers of the Eagle pub in March 1953, contains the secret of life. In most representations we see it as a rather stubby double helix, for they seldom show its other striking feature: it is immensely long and thin. In every cell of your body you have two meters of the stuff; if we were to draw a scaled-up picture of it with the DNA as thick as sewing thread, that cell's worth would be about 200 kilometers long.
Like the fibers of cotton, DNA molecules can stick together side by side to make a visible thread, and this makes possible a rather lovely experiment. So when the contemporary artist Marc Quinn asked me about a DNA exhibit for his show at London's White Cube gallery in 2000, I was delighted to help. He gave me a sample of his semen (Marc is renowned for using his own body fluids in work that explores the concept of the self; in 1991 he made a cast of his head using eight pints of frozen blood), and I broke open thesperm with detergent and a special chemical that softens their tough coats. Sperm are basically just packaged DNA, and the solution became very viscous as their contents were released. We transferred a little puddle of it to a tall glass tube, and gently overlaid it with pure alcohol. Then we lowered a glass rod through the alcohol to the puddle, stirred slightly, and slowly drew the rod upwards. Tiny fibers appeared and coalesced into a thread attached to the rod. We pulled it up until it reached the top of the tube, then stuck it to the rim. Marc put the tube in front of a jet black surface, and we stood back and hugged each other at the beauty of it: Marc's DNA, a web of molecules each too small to see with the naked eye, entwined into a single shining thread. The secret of his life.
You can do a similar experiment with any living tissue-even if you don't have a laboratory to hand you can get pretty good results in the kitchen using an onion as the source of tissue, and washing-up liquid, salt and vodka to extract the DNA. It will look exactly the same as human DNA, for a very good reason: from a chemical point of view it is exactly the same kind of molecule. DNA is the common thread that links every living thing with a single primeval ancestor.
But your DNA also makes you different from an onion, and from every other human being. The DNA molecule carries a code, and the instructions that dictate whether an egg or a seed grows into a human or an onion are written in that code. Much smaller differences in these coded instructions determine the infinite variety of hair color, facial features, body shape and personality that make each of us a unique individual. Each instruction, or gene, has a small part to play in making the whole, and the overall outcome is determined in part by the environment, but the combined power of the information contained in the whole genome, the entire complement of an organism's DNA, is truly awesome. The project that is now under way to harness that power through reading and understanding the complete set of instructions that makes a human being-the human genome-is one of the most momentous enterprises in modern science. It could transform our lives, for better or worse depending on how we apply the knowledge.
Everyone seems to understand this, if the razzmatazz that greeted the June 2000 announcement that the draft human genome was complete was anything to go by. But despite the fanfares, the job isn't remotely over yet. The reading process will be largely complete some time during 2003, but the understanding will take decades and will encompass all of biology. And the generation that really understands the human genome, or the onion genome for that matter, will understand life.
I never meant to get involved in the three-ring circus of the Human Genome Project. Only ten years ago I would have laughed if anyone had suggested I would soon be directing a research center with a staff of 500, plunging into the politics of an international project and engaging in a war of words in the press. What I wanted to do was to read the genetic code of the nematode worm. I didn't imagine that the worm was going to lead us directly to the human genome. Certainly, reading worm DNA is a good preparation for reading the DNA of any other species, and that includes humans; but when we started to read the worm genome we had no thoughts of other species. We simply wanted to fill in the background to the ever more elaborate picture of the biology of this tiny creature that had developed over the previous twenty-five years.
I first met the worm in 1969, when I arrived at the Medical Research Council's Laboratory of Molecular Biology in Cambridge-universally known as the LMB-to work as a staff member in Sydney Brenner's group. Sydney was joint head, with Francis Crick, of the cell biology division at the laboratory. Physically they were a study in contrasts-Francis was tall and sandy-haired, while Sydney was short and dark with penetrating, deep-set eyes beneath startlingly bushy eyebrows-but both were great talkers. Born and educated in South Africa, Sydney had come to Oxford as a graduate student in 1952, with a medical degree but determined to work on the biology of the gene. He had quickly established himself among the international group of scientists working on the genetics of bacteriophage-tiny viruses that infect bacteria-who together were laying the foundations of modern molecular biology.
In 1953 Francis Crick and Jim Watson had discovered the double helix structure of DNA, and Sydney had been one of the first to visit Cambridge and hear about the discovery at first hand. He had moved to Cambridge permanently in 1957 and had worked with Francis on deciphering the genetic code and understanding how cells translate it into the protein molecules they need to carry out their functions. By the mid-1960s Sydney considered the work of understanding how genes make proteins almost done, and wanted to move on to the next stage. His ambitious plan was nothing less than to understand how a complete animal was encoded by its DNA. Naturally he wanted to start with something simple, and the animal he chose was the nematode worm. `We propose to identify every cell in the worm and trace lineages,' wrote Sydney in his bid for support for the project. `We shall also investigate the constancy of development and study its genetic control by looking for mutants.' Sydney later recalled that some people thought the idea was crazy. `Jim Watson said at the time that he wouldn't give me a penny to do it,' he said. `He said I was twenty years ahead of my time.'
Why did Sydney pick a worm? There is a long tradition in biology of studying simple organisms in order to discover mechanisms that are at work in all living creatures. At the time Sydney embarked on his project, most geneticists worked with bacteria or the fruit fly Drosophila melanogaster. But neither of these suited Sydney's purpose. Bacteria are single-celled organisms; one of the main objects of his program was to look at how the genes control the successive cell divisions that turn an egg into an adult in a multi-cellular animal. The fly, on the other hand, with its compound eyes, wings, jointed legs and elaborate behavior patterns, was too complicated to be susceptible to the sort of exhaustive analysis Sydney had in mind. Nematode worms, or roundworms, were not as well studied as either, but they were far from unknown to biology. They constitute a large family that includes both parasitic and free-living varieties. The species that interested Sydney was a free-living soil-dweller, Caenorhabditis elegans: a long name for a tiny creature only a millimeter from nose to tail.
In the wild, C. elegans lives in soil and feeds voraciously on any bacteria or other micro-organisms it can find. It grows from egg to adult in three days (one-third of the time for a fruit fly), except when food is scarce, when it can hang about in a non-breeding larval form for several months. Most adults are hermaphrodites and produce several hundred offspring through self-fertilization. Males arise occasionally, perhaps at a rate of one in a few hundred, and mating provides the possibility for genetic mixing which allows for more rapid evolution. The worm's anatomy is quite simple, but although it lacks many of the physiological features of higher animals, such as a heart, lungs and bones, it can still carry out many basic tasks: moving, feeding, reproducing, sensing its environment and so on. It consists basically of two tubes, one inside the other. The outer tube includes the skin, muscles, excretory systems and most of the nervous system; the inner tube is the gut. It moves by contracting its dorsal and ventral muscles alternately, arching its body into a series of S-shaped curves.
The worm is, moreover, well suited to the kind of investigation Sydney had in mind. It is easy to keep and breed in the laboratory, living happily in petri dishes that have been sown with lawns of Escherichia coli bacteria. You can even keep them in suspended animation in the freezer for years at a time, allowing you to preserve stocks of different strains of the animal. Both larvae and adults are transparent, so that, given a good enough microscope, you can see not only the internal organs of living animals but even individual cells. The adult hermaphrodite usually has exactly 959 cells, not counting the egg and sperm cells. (For comparison, a fruit fly has more cells than this in just one of its eyes, and the human body has 100 trillion.) Its genome is made up of 100 million bases divided into six segments, or chromosomes.
Sydney hoped that he would be able to establish direct links between the worm's genes and its development from egg to adult, following the classic route of geneticists, in use since the first decades of the twentieth century. With a fast-breeding species, such as a worm or a fruit fly, occasional changes arise in the DNA that make the animal look or behave abnormally. These changes are known as mutations, and the altered animals as mutants. Geneticists soon developed a variety of techniques to increase the normal mutation rate. In the 1960s there was no way to analyze the DNA directly, but by cross-breeding mutants and looking at the patterns of inheritance in later generations you could map the relative positions of the mutated genes on the chromosomes. The closer together two mutations lay on a chromosome, the more likely they were to be inherited together. As well as mapping the genes, Sydney hoped, through careful microscopy and biochemistry, to discover exactly what was going wrong in mutant worms at the level of cells.
Assisted by a succession of young researchers, most of them American, Sydney was initially very successful in finding mutants and mapping the affected genes along the chromosomes, confounding those skeptics who had said that the worm was so boring in appearance and behavior that he would never be able to distinguish the mutants from the rest. But the timescale of the whole enterprise turned out to be longer than Sydney anticipated. Genes almost always work in concert, rather than solo-only very rarely is it possible to follow a direct line through from one gene to one function. Even so, the whole thing took off in a larger way than Sydney could have predicted because his intuition led him to an animal with tremendous potential for research.
As was typical of Sydney's style-indeed, the style of the LMB as a whole-on my arrival I was given about a meter of space at the bench in a crowded lab and more or less left to get on with it. Sydney and Francis believed that keeping the lab tightly packed encouraged people to interact, and that `desks encouraged time-wasting activities.' I found myself among a group of young researchers, astonished that we were being paid to do what we wanted to do anyway, and knowing that we had no-one to blame but ourselves if we did not succeed. I compared notes with another new arrival, amazed like myself by the pride, to the point of arrogance, that we found at the lab. `Who do these people think they are?', I remember him saying. But gradually we realized that they had a right to be proud, and as time went on we acquired some of that pride ourselves, though personally I was convinced that I could never do well enough to live up to the past glories of the LMB.
The laboratory was then and still is one of the world's top centers for research into the molecular basis of life. This was the place, more than any other, where the field of molecular biology had been invented. Its unique ethos undoubtedly played a role in shaping my development as a scientist. It grew out of a fortunate combination of circumstances in the years after the Second World War. Many academic scientists had engaged in war-related research, and the results were spectacular: radar, high-speed computing, antibiotics, and nuclear technology all had their origins in wartime research. It dawned on the government of the day that investment in science could have a long-term payoff. Up to the end of the 1930s there was little opportunity to do research in Britain if you didn't have a university teaching appointment or a private income. But ten years later it suddenly became easier to get grants, generous ones, from government-funded bodies such as the Medical Research Council (MRC) or the Department for Scientific and Industrial Research. This sudden largesse coincided with one of the most exciting periods in the history of biology, as more and more people began to apply the methods of physics and chemistry to biological problems.
Lawrence Bragg was a physicist who headed the Cavendish Laboratory, the physics department of Cambridge University. As a young man, Bragg had pioneered the technique of X-ray crystallography that made it possible to study the three-dimensional arrangement of atoms in molecules, including biological molecules. Among his staff was a meticulous, quietly spoken Viennese émigré chemist called Max Perutz. Perutz, together with a young colleague, John Kendrew, also a chemist, was trying to decipher the structure of the blood protein hemoglobin. X-ray crystallography worked well for small molecules, but proteins contained thousands of atoms and progress was slow. Bragg, an extremely influential figure in British science, was an enthusiastic supporter of Perutz's work. In May 1947 he wrote to the Secretary of the MRC asking for the funds to establish Perutz's group `on a more permanent basis.' Within months the MRC agreed to support a Unit for Research on the Molecular Structure of Biological Systems, with Perutz at its head.
Excerpted from THE COMMON THREAD by JOHN SULSTON GEORGINA FERRY Copyright © 2002 by John Sulston and Georgina Ferry
Excerpted by permission. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.