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Editor's Note: Earlier this month, the 2000 Nobel Prize in Physiology or Medicine was awarded to three scientists: Eric Kandel, Paul Greengard, and Arvid Carlsson.
As we did last year, we invited HMS Beagle readers to guess this year's Nobel laureate, and we're pleased to announce that one prescient reader, David Jarmul, did just that. For his clever and correct prediction, he will be awarded a copy of Images from Nature, a beautiful book from the Natural History Museum.
Of course, many Beagle readers had their own ideas of who should have taken home the medal this year. So, in our own exclusive "ceremony," we here present the Not-Quite-Nobels.
We are gratified to observe that your voices are being heard at last in Stockholm. Twice before, in 1998 and 1999, HMS Beagle has asked readers to pick the scientists they thought merited a Nobel Prize. Eric Kandel, Columbia University's neuroscientist extraordinaire, has been on your list in both years. This year, as everybody knows, the Nobel selection team agreed. Columbia's Kandel has been awarded the 2000 Nobel Prize for Physiology or Medicine, which he shares with two other world-class neuroscientists, Rockefeller University's Paul Greengard and Arvid Carlsson, emeritus at the Göteborg University. (Greengard and Carlsson have not been among your selections, but, hey, one out of three ain't bad.)
Now that you've got Stockholm's ear, the world will be watching, and your responsibilities are awesome. We know you don't take them lightly, and neither do we. So here are your Nobel Top Ten for the Year 2000. This is the third appearance for five of them, numbers two through six, which makes them the ones to bet on in October 2001.
1. When we told Sydney Brenner he was number one on your Nobel Top Ten list this year, he asked, "What was I last year?" We were flustered to realize that he was not on last year's list (nor, shamefully, the year before). You have finally rectified this appalling oversight by zooming him straight to the top, although we suspect your tardy embrace may have been triggered by the unusual Award for Special Achievement in Medical Science that the Lasker Foundation bestowed on Brenner recently. (The regular Lasker came ages ago, in 1971.)
Is there anyone in these precincts who doesn't know of Sydney Brenner? A highly condensed CV: Brenner proved that messenger RNA existed and deciphered the codon. He invented biological-containment methods for microbes and demonstrated that they worked by drinking the disabled strain. Bored, he announced, "I would like to tame a small metazoan organism." Thus, tiny transparent Caenorhabditis elegans became a star; Brenner and his colleagues nailed down a complete wiring diagram of its nervous system and sequenced its DNA, the first genome project to be completed. Just recently, he published his new microbead method for plucking particular expressed genes out of a soup of thousands.
His talks are legendary, and even his offhand comments are a marvel of complete sentences, perfect wit, and rat-a-tat ideas. His regular column for Current Biology is a must read. The one project that has gone less than swimmingly is the Molecular Sciences Institute he founded in Berkeley a few years ago, where he sought to sequence the junkless DNA of the pufferfish. "I'm not doing very much there now," he reports. "I closed my lab at the beginning of this year, owing to lack of money and excess of age." For Beagle readers, however, he forecasts permanent employment, having estimated that each human gene will require 40 years of study and that the human genome itself will inspire at least 50,000 professorships.
2. Mario Capecchi, Howard Hughes Medical Institute neuroscience investigator at the University of Utah, was second on your Top Ten List last year, too, and among your nominees the previous year as well. Best known as the inventor of targeted gene replacement and the progenitor of the now-essential knockout mouse, Capecchi and his colleagues have for the past several years perambulated purposefully through the apparently infinite intricacies of the 39 Hox genes that govern the mammalian body plan. In February 2000, Nature published yet another of his group's landmark papers. Capecchi and his colleagues showed that even though two mouse Hox genes separated 530 million years ago and perform entirely different jobs today, chunks of them can be swapped and settle right down to carry out the other's function.
This startling finding confirmed what some researchers have suspected: what matters in evolving new functions for a gene is not mutations that change the gene's structure, but alterations in the way the gene's performance is regulated. As Capecchi explains: "It says that if you want to make new body forms - new animals - through evolution, it's easier to do that by changing where, how much, and when certain proteins are made by genes, rather than by changing the genes themselves." One unsettling implication is that the DNA sequencers need to get cracking on a project so stupendous that it dwarfs all the genome projects to date. Up to now (partly at the urging of your number one candidate, Sydney Brenner), they have concentrated on protein-coding sequences. But lots of regulatory action is believed to reside in those immense, annoying, endlessly repetitive miles of noncoding DNA, which the genome projects have largely omitted. Are you ready for the Junk Genome Project?
3. This is the third year on the list for Paul Nurse, too. Now Sir Paul, he helped illuminate the workings of the cell cycle by identifying checkpoint genes in fission yeast and H. sapiens, and then moved on to head the gigantic Imperial Cancer Research Fund in London. Like many others, Nurse has been mulling over the radical structural changes that are coming to biology. "I'm interested myself in the potential contributions of physicists and mathematicians," he says. He wants to see space and time dynamics incorporated into the description of molecular reactions. "That's a bit beyond our normal intuitive thinking, and I think the sort of methodologies used by physicists and mathematicians will help us work out the dynamics and underlying patterns of what's happening to molecules in the cell." He stresses that this does not mean Big Science or the end of biology-as-we-know-it. "I'm suggesting innovative interactions between a typical biomedical scientist and his colleague across the campus. No threat, all opportunity."
4. Bert Vogelstein's Howard Hughes Medical Institute lab at Johns Hopkins moved in September. In the process, the lab fridge was stripped of the sign that proclaimed it "The Most Highly Cited Refrigerator in the World." That was his postdocs' wry comment on the fact that Vogelstein is always introduced by mentioning that his landmark papers on the p53 tumor suppressor and colon cancer are cited by fellow scientists more often than any other. Which helps explain why this is his third appearance among the HMS Beagle Top Ten.
Or maybe it's the band. Wild Type is a real rock and roll band available for real gigs at real science functions and consists of five Hopkins cancer researchers, Vogelstein on keyboard. Why Wild Type? Vogelstein explains that they had three options as geneticists: Wild Type, which means the normal state, or Pathogenic Mutations, or Rare Variants. "I was in favor of Rare Variants, since none of us is quite normal, but other members of the band liked Wild Type. I think the 'wild' word was attractive, like a real rock band. I'm not making this up; we really took a vote." For your listening pleasure, MP3 files of selected cuts - including the classics "Bitch" and "Hush" - can be found on the Web.
5. For a change, Judah Folkman, another three-time nominee, has been keeping a low profile, unless you count the lawsuits over patent rights with giant drugmaker Abbott Laboratories. Abbott charged in May that Folkman and Children's Hospital in Boston, where he does his famously controversial research on starving tumors into submission by attacking their proliferating blood supply, have conspired to claim credit for developing the anti-angiogenesis drug endostatin. In July, Folkman and the hospital countersued, accusing Abbott of fraud and defamation. Endostatin has had a checkered career. Reports of its near-miraculous destruction of mouse tumors have been passionately disputed. Clinical trials began last year, and in May a National Cancer Institute official said he was not aware of any major clinical response so far.
6. Lee Hartwell is also making his third appearance herein. Hartwell's name is often coupled with Paul Nurse's because Hartwell's lab first identified the cell-cycle checkpoint gene in baker's yeast, as Nurse's did with fission yeast. And, like Nurse, Hartwell now heads a large cancer research institute - The Fred Hutchinson Cancer Center in Seattle - while thinking big thoughts about the future of biology. This has plunged him into the thicket where interdisciplinary teams of scientists struggle to make sense of complex systems, and so he wants to entice physicists into the field. "What physicists bring to biology is the ability to step back from details of molecules and ask what the properties of processes are, what ideas would be needed to explain the behavior of the system," he says. "Population geneticists would say most mutations are neutral, but they're neutral because of the way biological systems are built, not because they don't affect the protein or the gene." In his lab, he and his colleagues are striving to understand what they are calling "buffering relationships," biological circuits that are built to be robust - for example, fail-safe systems such as redundancy. "We've submitted a paper that comes to some conclusions about the relationships between genes and buffering," he reports. "Already some principles are apparent in gene interactions in yeast and other organisms that tell us something about how molecular biology is organized to accommodate these variations."
7. Michael Berridge, a newcomer to the HMS Beagle Top Ten, is best known for his 1984 discovery of the widespread cell-signaling system based on inositol trisphosphate. His lab at the Babraham Institute near Cambridge, England, concentrates on the role of calcium as a universal signal in cell regulation, and he has recently developed a new idea of how neurons work. "I refer to this as my neuron-within-a-neuron concept, the idea being that the endoplasmic reticulum forms an internal membrane network that has properties similar to the outer plasma membrane," he says. "I believe the two membranes function in tandem to carry out a lot of neural processing." Recently dubbed Sir Michael, he also recently acquired a remodeled water mill as living quarters, and is happily renovating its neglected garden. He is also a self-described keen golfer. Golf is not a terribly common sport among scientists, but Berridge belongs to a foursome with a distinguished history: it was founded by Ernest Rutherford. And how does he feel about being often mentioned, in venues other than this one, for a Nobel Prize? "It's always nice to feel that you've been nominated. In a way that's what we're all in science for, getting acknowledgment from our fellow scientists."
8. It's also a first for Ronald Levy, of Stanford University, who has been applying monoclonal antibodies to non-Hodgkin's lymphomas and tumors of the immune system for a very long time, and who is also trying to develop vaccines. In 1999, the General Motors Cancer Research Foundation awarded its Charles F. Kettering Prize to Levy for demonstrating that monoclonal antibodies can produce objective clinical responses in patients with B cell lymphomas. Levy has stuck with monoclonal antibodies since 1980, the days of wild hopes that here were true magic bullets that could carry out search-and-destroy missions against tumors. A decade later, companies and many researchers had lost faith, but a few, such as Levy, stuck it out. These persistent pioneers finally achieved some success, and monoclonal antibodies are slowly coming back into favor. Nine monoclonal-antibody drugs have now been approved, including rituximab, which Levy has worked with.
9. Another newcomer is Piet Borst, of the Netherlands Cancer Institute in Amsterdam. Borst and his colleagues illuminated the metabolism of mitochondria, and have been credited with the discovery and characterization of circular mitochondrial DNA in animal cells and yeast. The work helped generate one of the most important methodologies in molecular biology: gel electrophoresis. That alone is reason enough to be among your Top Ten. He has moved on to the molecular biology of trypanosomes, which cause sleeping sickness, in the process laying bare new kinds of RNA behavior. He is also exploring genes involved in multidrug resistance in cancer cells and the structure of amplified DNA.
10. This year's final nominee, also a first-timer, is Ernest McCulloch, now professor emeritus of medical biophysics at the University of Toronto. From McCulloch's work stems a research area much in today's news: stem cells. Way back in 1961, he and colleague James Till discovered that all blood cells come from hematopoietic stem cells in the bone marrow. That discovery paved the way for bone-marrow transplantation and today's much-improved survival rate in childhood leukemia, plus a seemingly endless list of other extraordinary biological possibilities. Some of these - genetic engineering of human embryonic stem cells, for example - are not generating universal approval.
Tabitha M. Powledge is a longtime science and medical writer-editor who keeps an eye on the intensifying fusion of genetics and neuroscience.
Andrzej Krauze is an illustrator, poster maker, cartoonist, and painter who illustrates regularly for HMS Beagle, The Guardian, The Sunday Telegraph, Bookseller, and New Statesman.
Endlinks
Maintenance of Functional Equivalence During Paralogous Hox Gene Evolution - abstract of paper from Nature. Free registration required for access.
Paul Nurse - A Scientific American interview.
Lee Hartwell - Biographical information from the Lasker Foundation.
Michael Berridge - a press release describing his accomplishments.
