Science & Technology: Genetics
It's All in the Genes? Ha!
Protein shapes are key to heredity, says Susan Lindquist
It was in a high school biology class in the late 1960s that Susan L. Lindquist first encountered the science of heredity and the world of DNA. "It seemed unbelievably beautiful," Lindquist recalls.
Too beautiful to tell the whole story, it turned out. Lindquist went on to challenge conventional genetics and evolutionary theory with studies showing that mere proteins could carry inherited traits from one generation to the next. This was just short of heresy to many geneticists, who believed that the nucleic acid DNA and its cousin, RNA, were the sole agents of inheritance.
Now, as research on exotic proteins spills from laboratories around the world, Lindquist's theories have struck a chord with many biologists, who hail her as one of the field's leaders. "In biology, she is clearly in the upper echelons of thinkers," says Richard A. Young, a principal investigator at the Whitehead Institute for Biomedical Research in Cambridge, Mass. In 1997, Lindquist's work was recognized with her appointment to the prestigious National Academy of Sciences.
Beyond challenging scientific orthodoxy, Lindquist's ideas could one day lead to new treatments for ailments such as Parkinson's disease and Alzheimer's, as well as mad cow disease. All of these scourges involve alterations in the normal behavior of proteins. And the 49-year-old Lindquist, head of a 20-member molecular genetics lab at the University of Chicago, is laying the scientific foundation for understanding those changes.
Sidestepping the global stampede to discover new genes, Lindquist has homed in on two classes of proteins: so-called prions, which are thought to cause mad cow disease, and "chaperone" proteins, which manage the inner workings of cells. In yeast cells, she has proven that prions can transmit structural characteristics from one generation to the next--without any changes in DNA. "There could be many proteins capable of undergoing these remarkable, self-perpetuating changes," Lindquist says. "And I think they will prove to have fundamental roles in human biology."
Even in their normal forms, proteins are enigmatic. Known as the basic building blocks of life, proteins are polymer chains consisting of up to 20 different kinds of amino acids. These acids are alternately attracted to and repelled by each other, and also by elements in their environment. So the instant a protein is produced in a cell, it twists and turns, folding into shapes of breathtaking complexity. There may be hundreds of billions of possible combinations. But in a matter of seconds, proteins manage to find their optimum configuration, called the "native state."
Once folded, proteins usually remain intact. Trouble may arise, however, if a protein--such as a prion--can exist comfortably in more than one shape. Indeed, even in normal circumstances, cellular proteins tend to unfold as cells grow old or are stressed by heat, viral assault, or toxic chemicals. That's when molecular chaperone proteins step in, prodding malformed or unfolded proteins back into shape and shepherding them to wherever they are needed in the cell.
These prion and chaperone proteins inspired Lindquist's most radical theories. In 1994, after reading a paper on yeast prions by National Institutes of Health biologist Reed B. Wickner, Lindquist and colleague Yury O. Chernoff--now at the Georgia Institute of Technology--described how a specific chaperone could switch off an inherited alteration in a yeast protein called Sup35 (table, page 100). "It was like a lightning bolt," Lindquist recalls. "We could show that this inherited trait was due to a protein changing its shape, not a change in DNA sequence. And the new trait persists for thousands of generations."
Lindquist calls this "an uncharted mechanism for heredity." And she credits Reed Wickner for first suggesting the idea. Wickner, now head of a biochemistry lab at the National Institute of Diabetes & Digestive & Kidney Diseases in Bethesda, Md., is just as emphatic. "Individual proteins can be genes," he says. And there could be key therapeutic implications. In the Feb. 26 issue of Science, Wickner showed how a yeast prion called Ure2, when it changes shape, becomes a pathological form of protein called amyloid--the basis of waxy deposits found in the brains of mad cow, Alzheimer's, and Parkinson's victims.
There are many mysteries to unravel here. In yeast cells, for example, the strange, hereditary protein changes aren't necessarily bad. They may enable the yeast cells to grow in new, nutrient-poor environments. That's a stark contrast to prion-linked diseases in mammals, where infective proteins seem to reduce whole sections of the brain to sponge. Nonetheless, Lindquist points out, "there's an uncanny biochemical similarity" between yeast and mammalian prion proteins.
Lindquist and Wickner aren't the first scientists to propose outlandish new roles for proteins. Decades before James D. Watson and Francis H. Crick solved the structure of DNA, Nobel laureate Linus C. Pauling suggested that antibodies might derive their unique shape from the antigens they target. The theory was wrong--though it very smartly anticipated prion-like capabilities.
The idea of proteins as genes surfaced again in 1967 when British mathematician J.S. Griffith suggested that a protein agent might be responsible for an infectious disease in sheep called scrapie. He believed that misfolded proteins in the sheeps' brains might be acting as templates, inducing deformation in other proteins.NOBEL STRUGGLE. Fifteen years later, Stanley B. Prusiner, a biochemist at the University of California at San Francisco, invoked a similar theory, arguing that rogue proteins (he dubbed them "prions") were responsible not only for scrapie but for mad cow disease and similar diseases in humans. His meticulous efforts to prove this theory brought him a Nobel prize in 1997--but only after a bitter, 15-year struggle with a scientific orthodoxy that balked at the idea of infectious diseases transmitted by proteins, without the aid of nucleic acids.
Lindquist's work in yeast prions did much to validate Prusiner's theories about mammalian prions. And since then, imaginative leaps have become her stock in trade. Last summer, in a paper published in Nature, Lindquist and collaborator Suzanne L. Rutherford showed how chaperone proteins can allow fruit flies to acquire small, subtle variations in the way proteins fold, without allowing these variations to harm the fly. Then, when some stress occurs in the environment, the chaperones are called away to take care of other proteins that are starting to misfold. "Perhaps the army of chaperones is stretched too thin and can no longer attend to those subtle, hidden variations," Lindquist says. So the variations are suddenly uncovered. As a result, over a single generation, the fly appears to undergo changes in form and structure that usually take many generations.
Paleontologists quickly seized on her study as a plausible explanation for certain mysterious phases of rapid evolution that are evident in the fossil record--a phenomenon dubbed "punctuated equilibrium" by evolutionary biologists Niles Eldredge and Stephen Jay Gould. "Now, evolution has a plate filled with a larger number of hors d'oeuvres to select from," says Northwestern University biochemist Richard Morimoto. "Susan is a remarkably creative individual."
Lindquist is the first to caution that her theories don't nullify a half century of molecular genetics and evolutionary theory. In the case of the fruit fly, genetic changes are occurring but they're hidden till an environmental change exposes them. "DNA and [Austrian geneticist Gregor] Mendel may explain 90% of what we observe," she concedes. But as her own work shows, minor miracles lurk in the remaining 10%. As they come into view, it's a safe bet that chaperones, prions, and other agents of protein folding will be at center stage.By Neil Gross in New YorkReturn to top