What story does the DNA tell us?

When I was a Ph.D. student in the late 1960s, a scientist determined the exact DNA sequence that encoded the plan for part of a protein. He and his team sequenced 23 bases of DNA and it took them a year. We thought it was marvelous in concept and execution — and it was.The DNA sequence is a code, just like writing is a code. DNA usually gets translated into proteins, as alphabets get translated into sounds. Both codes have punctuation and the information in a genome and a novel are arranged in a strict order. Novels have chapters, genomes have chromosomes. Reading either code must be quick to be useful. I loved Moby Dick, but if it had taken me six months to read the opening words, “Call me Ishmael,” I would have quit. The striking command that opens the novel contains the alphabet equivalent of 15 DNA bases, including spaces. Even in the 1960s we knew that the human genome contained billions of bases (letters), so sequencing it was unimaginable.But human cleverness intervened. In the late 1970s, two methods to sequence DNA emerged. The one that won out was designed by a modest man named Fred Sanger in the U.K., for which he won his second Nobel Prize. Sanger made it possible to sequence hundreds of bases — the A,C,T and G chemical subunits that make up DNA and, significantly, do it in a couple of days. My lab used to do it and I remember that it involved a lot of radioactivity. It was still a long way from sequencing hundreds of bases to sequencing billions. But the technology improved, the radioactivity dropped out, sequencing became automated and computing improved so that vast amounts of data could be stored and searched. By 1990 it was possible to contemplate sequencing the human genome. The genome from one person was finally sequenced in 2001 and cost $3 billion taxpayer dollars — when that was a lot of money.Now it is becoming possible to sequence a person’s genome for $1,000, which means that $3 billion would be enough for half the population of Connecticut. There are companies who will do it for you. They are making a profit from the idea that your destiny is in your genes. Swab your cheek, send the swab and they will tell you the probability that you will have Parkinson’s disease in 30 years. My advice is: don’t do it. If you suspect that your family harbors some troublesome mutation, call a genetic counselor at a medical center who will advise you on the benefits and risks of DNA sequencing in your personal case. You will get more than a dubious probability.But does this brave new world of DNA sequencing ever justify the $3 billion we spent on it?Yes, actually. To give one example among many: two of my colleagues, Laura Pasqualucci and Riccardo Dalla-Favera are experts in lymphoma, which is a cancer of the cells that make antibodies. The formal name for such tumors is Diffuse Large B Cell Lymphoma. B cells usually mature and stop dividing as they make antibodies that protect us from infection, but sometimes they do not stop dividing and instead form tumors. Only half of the cases can be treated. What makes the untreatable cases different? Do they carry mutations that we don’t know about? If so, what critical cellular processes do the mutations affect?u u uWhen a cell starts to become malignant, it loses control over the maintenance of its DNA. To return to the literary metaphor, it is as if some mad compositor put “Call me Ishmael” in the middle of Moby Dick, shuffled paragraphs and chapters and threw in a lot of typos. The scrambling and mutation of DNA can wreck the normally tight mechanisms that control cell division, which is what happens in lymphoma.What Laura Riccardo and a large team of collaborators did was to recover the tumors of a number of patients and to sequence the DNA of each. This takes a large group of talented people, with scientific and computational acumen, and incredible organization. It depends completely on the information and technologies that were developed for the human genome project.By sequencing the DNA of eight lymphoma tumors, the team was able to figure out what new mutations each tumor contained. (It is, by the way, essential to sequence each bit of DNA many times to avoid errors.) On average, there were 30 specific new mutations in each tumor that had not been known before and they deregulated known biological processes. The authors learned a lot about the biology of the previously untreatable tumors. There are potential therapies to treat the effects of these newly discovered mutations, but nobody knew to use them. Now they do. So that $3 billion paid off in this and many other ways. Richard Kessin, Ph.D, is Professor of Pathology and Cell Biology at the College of Physicians and Surgeons of Columbia University. He and his wife Galene live in Norfolk. He can be contacted at rhk2@columbia.edu.