Last month, Beagle readers were offered the chance to forecast winners of this year's Nobel Prize in Physiology or Medicine. The last issue of HMS Beagle featured the winners of our own contest, who accurately predicted the Nobel winners.

Who would have won the Nobel Prize if the vote had been up to Beagle readers rather than the Nobel committee? One of our top ten choices (Robert Furchgott) actually did win this year. The nine who did not (including, interestingly, Salvador Moncada, who ranked above Furchgott in Beagle voters' estimation) profess to be grateful, proud, and pleasurably abashed that BioMedNet members think so highly of their past work.

Here's the countdown, and what they say about their present and future endeavors:

"All along I've been motivated by an interest in human biology, trying to figure out what the fundamental questions were and how we could approach them in a model system like yeast. But humans are outbred, every individual is different, we have this tremendous genetic diversity. Yet all the model organisms we work with are inbred and we change only one gene at a time. That's very powerful because of its simplicity, but if we want to understand humans we're going to have to start coping with diversity," Hartwell told HMS Beagle.

What interests him now is how biological circuits are designed so that they tolerate variability but still function. How much variation can exist before it becomes lethal or we call it disease? "Because of the DNA damage checkpoint, for example, cells can tolerate a lot of defects in their DNA replication apparatus," Hartwell notes.

Nurse also won a Lasker this year, and is also a pioneer cell-cycle researcher, as well as a yeast fancier. He now heads London's giant Imperial Cancer Research Fund, but swears he is ruthless about spending at least half his time on research. Nurse's lab identified the same crucial cell-cycle gene in fission yeast that Hartwell's group had found in brewer's yeast, and then, in 1987, reported the human version, CDC2, which they mapped to chromosome 10.

"This was perhaps striking and unexpected, that the mechanisms worked out in yeast turned out to be universal and applicable in all living things, and also to have medical relevance, to cancer in particular," Nurse told HMS Beagle. "It's yet another example of how curiosity-driven biomedical research can often illuminate problems in ways one did not imagine beforehand."

Folkman is no stranger to scientific notoriety as well as scientific fame, especially this year. A surgeon/cell biologist at Children's Hospital in Boston, Folkman has plugged the notion of angiogenesis for a quarter of a century, and for a large part of that time was derided for it. Now it is conventional wisdom that tumors survive by tricking the body into sprouting new capillaries to feed their growth.

On May 3, 1998, New York Times reported on its front page that Folkman's lab had used the growth inhibitors angiostatin and endostatin to cut off mouse tumors' blood supply, thus preventing their growth and eliminating established cancers. The inhibitors are less toxic than standard treatments, and they had worked perfectly every time. The mice were 100 percent free of cancer.

No human patient had ever been given either of these drugs, so their therapeutic effects, if any (to say nothing of their toxicity, if any) were entirely unknown. The Times's story included the caveats, but the article's prominent position, and the uncritical enthusiasm of other print and broadcast media, convinced some cancer patients that researchers had discovered the magic bullet at last. Patients besieged their dismayed physicians and demanded it. One woman even wanted it for her cat. She was disappointed, but Phase I clinical trials are planned for a few specimens of Homo sapiens next year.

Vogelstein heads the Howard Hughes Medical Institute (HHMI) research labs at Johns Hopkins University in Baltimore. His work on tumor-suppressor genes has made him the world's most highly cited scientist. Between 1990 and 1997, reports the Institute for Scientific Information (ISI) in Philadelphia, 190 of his papers appeared among the scientific literature's references nearly 28,000 times.

A high citation rate may mean a researcher is one of the giants upon whose shoulders other scientists stand, but it doesn't mean the Nobel committee will admire one's research deltoids. For example, among the 11 scientists on ISI's 1990-1996 most-cited list, only David Baltimore (No. 5) is a Nobel laureate. ISI's David Pendlebury, who analyzed the list, has suggested that the Nobel committees simply haven't caught up yet. Nobelists abound on ISI's earlier most-cited lists, he said.

Capecchi invented targeted gene replacement, a form of genetic engineering that has sparked a revolution in mammalian genetics. That makes Capecchi, who professes biology and human genetics at the University of Utah in Salt Lake City, the intellectual father of the proliferating multitude of knockout mice.

In addition to building designer mice to order - "You draw it on paper, it can be done," he says - Capecchi is developing technology that might revolutionize genetics once again. First, he wants to find ways of controlling genes in time, learning how to turn a gene off at a certain point in development to observe its effects, then turn it back on to observe its effects in later life. But he also wants to control genes in space, asking, for example, whether a gene active in reproduction is also active in limb formation. Then he wants to control genes in time and space together.

As if temporal and spatial gene switches weren't enough, he's also trying to control gene amplitude - how much a gene is operative. Capecchi compares the process to using a rheostat to turn voltage up or down. His lab also continues to investigate the HOX genes that govern the extravagant variations-on-a-theme found in metazoan body plans. "There are 39 genes and the interactions of all possible combinations of them, so it's going to take us 20-30 years," he notes happily.

It is sometimes said that neuroscience has revealed more about the nervous system in the past couple of decades than in the whole of its previous history. No one has contributed more to this development than Eric Kandel. Kandel is another HHMI senior investigator; his professorships straddle several Columbia University departments, and his most recent administrative accomplishment is putting together Columbia's new interdisciplinary Center on Mind, Brain, and Memory. Furthermore, he is the author of not one but two highly regarded textbooks of neural science.

But Kandel is best known to other scientists for laying bare the entirety of a single nervous system (that of the formerly unprepossessing sea slug, Aplysia), and for pioneering the molecular biology of learning and memory. Last May, his lab and another at Columbia reported to readers of Cell that their research had uncovered a single family of ion channel genes responsible for the rhythmic pacemaker impulses of both heart and brain. That is, genes that regulate, among other things, heartbeat, the sleep-wake cycle, and perception. Oh, and breathing.

Wyllie, a coiner of the vexatious term "apoptosis" and a founder of that field of study, has just moved to Cambridge University from the University of Edinburgh. Research on programmed cell death is definitely Nobel-worthy, he says: "It has made a truly major contribution to the way we think about cells and tissues, cancer treatment, development, and possibly, to a surprising extent, disease processes that we attributed to other mechanisms in the past."

But Wyllie has his own short list of Nobel candidates who've worked on apoptosis: Robert Horvitz of the Massachusetts Institute of Technology, Stanley Korsmeyer of the Dana-Farber Cancer Institute, Peter Krammer of the German Cancer Research Center in Heidelberg, Shigekazu Nagata of Osaka University Medical School, and Suzanne Cury of the Walter and Eliza Hall Institute. Wyllie himself is probably best known for elucidating apoptosis's method of DNA fragmentation via endonucleases.

Since he was present at the creation of the word "apoptosis," HMS Beagle consulted him on how to pronounce the damn thing. With or without that pesky second p? "A-pop-TOE-sis," an American favorite? Or "a-po-TOE-sis," a bow to its concoction from the Greek?

Wyllie uses the latter, but insists he doesn't really know what's correct. In fact, a Scots professor of classical Greek once told him that modern Greeks would say "a-POP-to-sis," a pronunciation nobody else uses. He concludes, with supreme tact, "I'll go on saying it the way I say it, but I don't think one should be excluded from saying it any other way."

Formerly president of the Fox Chase Cancer Center in Philadelphia, Knudson now cochairs the Cancer Genetics Working Group at the National Cancer Institute. Knudson was another Lasker winner this year, for clinical research. He is credited with the "two-hit" hypothesis that explains why some identical-appearing cancers are hereditary and others are not.

Beagle readers at last forecast the 1998 Nobel correctly, with choices that ranked Nos. 9 and 10. Or at least they correctly predicted the field of research - the demonstration that the gas nitric oxide (NO) is a signaling molecule in the cardiovascular system. But only No. 10, 82-year-old Robert Furchgott, professor of pharmacology emeritus at the State University of New York Health Science Center at Brooklyn (better known as SUNY Downstate) was actually one of this year's laureates. (He shared the prize with Ferid Murad of the University of Texas Medical School in Houston and Louis Ignarro of the University of California at Los Angeles, who were not among BioMedNet Ltd.'s Top Ten.)

Salvador Moncada (No. 9) arguably should have gotten the Nobel, too. Indeed, after Moncada was similarly excluded from the 1996 Laskers, which went jointly to Furchgott and Murad, Furchgott himself complained to a reporter that Moncada "certainly has done as much in developing the field as the two of us who received the award, or maybe more."

The most-cited paper in NO research is the 1987 demonstration by Moncada and his colleagues that NO is endothelium-derived relaxing factor. ISI reports that Moncada has consistently been among the world's most-cited biomedical researchers for two decades or more. He's No. 2 on ISI's 1990-1997 list, with more than 20,000 citations, topped only by Vogelstein's 27,901. But he is the author of many more highly cited papers (342) than Vogelstein (190).

Moncada politely sidesteps the debate. "Recognition of the work on nitric oxide by the Lasker, and now by the Nobel, is well justified. It's a very, very important piece of work, and the only thing I can say is that I'm extremely happy and extremely proud that our work was so significant for the birth and later development of the field," he told HMS Beagle.

Like the others on the BioMedNet Ltd. list, Moncada looks forward. He heads the new Wolfson Institute for Biomedical Research at University College, London. This institute pursues interdisciplinary research into chronic degenerative disease, especially in the cardiovascular and central nervous systems. "It's a combination of basic biology and chemistry, to try to understand the diseases and then make prototypes that might be future medicines," says Moncada.

Endlinks

Paul Nurse - outlines the past, present, and future work of his lab on eukaryotic cell cycle control.

Bert Vogelstein - describes his work on cancer genes

Judah Folkman - explains how to fight cancer by attacking its blood supply in the September, 1996, issue of Scientific American

Mario Capecchi - on gene targeting

Descriptions of seminal research - by this year's Lasker winners Hartwell, Nurse, and Knudson, and RealAudio interviews with them

Eugene Garfield - editor-in-chief of The Scientist, discusses Salvador Moncada's exclusion from the 1996 Laskers