../murre/Science Notes  -- Summer 1998
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SULLIVAN'S initial skepticism of the defect-toleration hypothesis has proved correct. The young embryo indeed monitors for damaged nuclei and expels them, thus assuring the integrity of its constituents. It does not, as had been suggested, allow sloppiness early and wait until stage fourteen to inspect.
      "Bill doesn't let the prevailing dogma affect his thinking at all," says Doug Kellogg, of the University of California, Santa Cruz. "He's not really bound by the way the rest of the scientific community looks at things."
      Sullivan's unconventional approach resonates with other aspects of his life. When he began working at UCSC as an assistant professor, his home was a boat. And as an undergraduate at the University of California, San Diego, he slept in his car for several years. "I think he didn't get around to making arrangements for living in campus housing," says Sullivan's sister Jeannie Sullivan. " It was easier to just buy a parking permit."
      At UCSD, Sullivan already knew he wanted to study science. He had become fascinated with the natural world as a child. Every week he tuned in the family TV to "The Undersea World of Jacques Cousteau."
      "At the end, the narrator would say something like 'and he solved the mystery of the Red Sea,' and I thought, 'By the time I'm old enough [to work as a scientist], Cousteau's going to have everything figured out,'" Sullivan recalls. "There got to be a point when I couldn't watch any more. At twelve, I was already worried about being scooped."
      In his office on the University of California, Santa Cruz campus, Sullivan sits at a desk with its drawers ajar. Piles of folders, a large glass flask, a box of computer disks, and a sweater litter his floor. A paper coffee cup and muffin wrapper lie on a tabletop supported by two sawhorses next to his desk. A thick black binder holds his scientific papers, neatly ordered and numbered.
      Sullivan, with the reds and blues of his different shirt arms peeking out from under one another, says he likes the formalism of genetics.
      "You have the analysis on paper and then do something simple like count the number of flies with a certain eye color, and you can learn something really profound," he says. "It's pretty amazing that Mendel got it all right--just by counting peas."
      More than 100 years ago, Gregor Mendel figured out the rules that govern the inheritance of many traits by mating plants of different colors and pea shapes.
      Sullivan sits up in his chair, nods his head, and leans forward as he talks. His eyes brighten. He seems a bit like a child, talking about his new Lego set.
      Anxious to get back to the lab, Sullivan glances at his watch, which is attached to its band with a strip of bright green lab tape.

AFTER Sullivan found out what happens to damaged nuclei in fly embryos, he dove deeper into the question of how they usually manage to divide correctly. He thought the answer would lie in the molecules that push and pull DNA, and package it into new nuclei. So he set out to find the embryonic components that shepherd the chromosomes.
      As his first step, he created strains of flies whose nuclei make more than the usual number of mistakes. These strains, he reasoned, should contain altered versions of molecules that normally make nuclei behave properly.
      This approach is similar to learning about how cars function by tying the hands of different workers in an automobile factory, Sullivan explains. The flawed cars that roll off the assembly line provide information not only about each person's job, but also about how the car works. When cars emerge without the round plastic devices on their front left-hand sides, one suspects that the incapacitated person installs steering wheels. And when those same cars are driven to the parking lot and fail to make the first turn in the road, one might conclude that the round plastic devices steer the car.
      In principle, by tying every worker's hands on different days and studying the emerging cars, one can match people with their jobs in the factory, and discover what the different components of the car do. In flies, each strain (or day in the factory) contains a defective gene (or worker with tied hands).
      "What's nice about [fruit flies] is that if there's a defect, you detect it because the nuclei are no longer evenly spaced in the embryo," says Kellogg. "There's an easy read-out."
      Sullivan looked at 76 strains of mutant flies. He found several that display an irregular pattern of too few nuclei on the embryonic surface and contain excess nuclei on the interior.
      His scheme succeeded, but, like many research projects, it easily could have failed. Daring experiments, however, don't daunt Sullivan, reports Kellogg. One Friday night about eight or nine years ago, Kellogg and Sullivan were walking up Tank Hill in San Francisco. "Bill stops in front of this big poison oak bush and tells me how he used to get these really bad cases of poison oak and he doesn't anymore and he's pretty sure he's become immune," says Kellogg. Sullivan reached out, grabbed the plant, and rubbed it on to the back of his hand.
      "Monday I come into work and Bill is sitting at the microscope. His eyes are nearly swollen shut, and he has big patches of poison oak all over his hands, his face, his arms," Kellogg says. "Bill really isn't afraid of trying radical experiments."

AMONG the fly genes Sullivan has found, one encodes a relative of a protein scientists already knew about. This protein resides in yeast cells, and gives them time to repair damaged DNA. When other molecules report problems, the protein pulls the brakes on cell division. Like mature animal cells, yeast correct errors, presumably because serious blunders are a matter of life and death for each of these single-celled organisms.
      Fly embryos containing a defective version of this gene contain clustered--instead of evenly spaced--nuclei. Because of the clumpy appearance, Sullivan named the gene "grapes."
      Embryos with a defective grapes gene contain higher than normal levels of DNA damage, Sullivan showed. A string of unbroken DNA usually composes each chromosome in a healthy cell. Although the chromosome is copied in small segments, the cellular machinery patches the resulting pieces together. Within the mutant embryos, almost five times the normal number of loose DNA ends exist. This result indicates that the nuclei don't have enough time to complete DNA replication before they start trying to divide, Sullivan says. Such DNA doesn't line up so it can divide properly, and these fragments of DNA pose a hazard to cells that contain them.
      Reasoning from these results and the resemblance of grapes to the yeast gene that suspends cell division, Sullivan proposed that the protein product of the grapes gene generates a pause that allows fly nuclei time to finish duplicating their chromosomes.
      "What's surprising is that the same genes are used [in yeast and flies]--just in different ways," Sullivan says. Yeast use their protein to counteract mistakes, while fly embryos use theirs as a normal part of nuclear division. The fly embryos don't really need the Grapes protein until cycle 11 because earlier, DNA replication occurs slightly more quickly and can keep up with the pace of nuclear division. In both yeast and flies, the relevant proteins generate a pause so the nucleus can ready the DNA for division.
      Once Sullivan decoded the fly grapes gene, Stephen Elledge's group at Baylor College of Medicine in Houston used the information to find its human counterpart. Although scientists had isolated the yeast gene four years earlier, their previous attempts to uncover the human version had failed because the two are too distantly related. "People have been looking for it [the human version] for a long time, but they couldn't pull it out," says Sullivan. Because humans genetically resemble flies more closely than yeast, Sullivan's gene provided the missing link that allowed scientists to nab the human gene.

GRAPES is one of two genes in yeast, flies, and humans that ensures that one portion of cell division is finished before the next one begins, says Sullivan. This means that scientists may be able to exploit flies to learn about humans. No one knows whether the grapes gene carries out similar jobs during human and fly development, but divisions early during embryonic development tend to differ from later ones in all higher organisms, so Sullivan's work may hold relevance for human pregnancy.
      In addition to informing scientists about embryonic growth, the grapes gene may provide information about the basic mechanisms of growth and tumor formation in a wide range of organisms. Genes such as grapes, which control the order and timing of events during cell division, have been implicated in the transformation of healthy cells into cancerous ones. "Cancer is a case of cells [growing] out of control," says Kent Golic, a geneticist at the University of Utah in Salt Lake City. "The cells don't know that they're not supposed to be dividing."
      The grapes gene may provide a powerful tool with which to investigate this process. Like yeast, flies are amenable to manipulation and experimentation. But their bodies, like those of mammals, are composed of specialized cells that carry out different jobs. Using flies to probe the function of grapes may well convey scientists to an understanding of humans that would not be possible by studying only yeast.
      Although Sullivan began this project searching for the components that shove DNA from one place to another within the cell, he wound up with a gene that plays a role in growth control.

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