Medicine's Springboard: Perceptions from a Few Consummate Geneticists

by Marjorie Centofanti

When Aravinda Chakravarti invited seven leading members of his field to campus to talk about their work, the result was a look into the future of human genetics. Here's an overview:

Francis Collins

Eric Lander

Edward Rubin

Lee Hartwell

Susan Lindquist

Svante Paabo

Barton Childs

Svante Paabo, Max Planck Institute for Evolutionary
Anthropology Founder of a new institute dedicated to shedding light on human origins, Svante Paabo has embraced the findings of the Human Genome Project, using it to map evolutionary relationships between humans and the great apes.

"We're looking for patterns of gene mutation and gene combination unique to

humans," he said. For now, Paabo's work focuses on the genetic makeup of gibbons, gorillas, orangutans, chimpanzees, bonobos and humans.

One comparative study of part of the X chromosome—an area that's remained remarkably unchanged genetically for thousands of years—has led scientists to conclude chimpanzees and humans were more recently evolved from a common ancestor than chimps and gorillas. Another study revealed the chimp genome to be four times more varied than the human one and the orangutan genome to be 10 times greater than ours.

Paabo also described an intraspecies look at humans, comparing a set segment of DNA, again, on the X chromosome. But which humans to study? He chose 17 people, each a representative of a fundamentally different language "phylum" or linguistic origin: Beginning at the point where language diverges, he says, let us skip the last 10,000 years of history. Key similarities in the volunteers' patterns of DNA bases confirmed Africa as the cradle of modern humanity.

Paabo described new directions in genome-based anthropology. They include studies of great apes' susceptibility or non-susceptibility to human diseases, like AIDS, that can help reveal origins of disease. In other studies using microarray technology—a system that reveals which of thousands of genes are turned on at a given time—Paabo's colleagues are comparing gene expression in brain and other tissues of humans and the great apes.

Susan Lindquist, Whitehead Institute, MIT
"Saccharomyces is man's best friend," said Lindquist, a molecular biologist who explained how yeast is providing humans with a window on "self-perpetuating" proteins. Also called prions, the molecules underlie a new concept in how certain cell phenomena are controlled—one, she said, that could vastly change the way we view biology and disease.

Lindquist described work on an inherited trait in yeast affecting characteristics from color to antibiotic resistance. Remarkably, it's inherited through a change in the three-dimensional structure of a protein and doesn't involve nucleic acids. The protein in question, called Sup35, exists in two physical states, one soluble, one not. The insoluble form assumes the shape of long, amyloid filaments in cells. Only the tiniest speck of one of those filaments can act as a seed that, at lightning speed, converts the insoluble Sup35 to filament form.

Lindquist believes the same protein folding phenomenon underlies a number of neurological problems, such as Huntington's disease, or affects non-pathological events such as the changing shape of chromosomal material.

Edward Rubin, The Lawrence Berkeley National Laboratory
"The non-coding sequences of the genome remain a vast, mysterious sea,"said Edward Rubin. In his talk titled "Jewels in Junk," Rubin gloried in metaphors in hopes investigators would give sequences of DNA that apparently don't code for genes a closer look.

Focusing on an especially large stretch of chromosome five that carries interleukin genes, Rubin showed the value of a comparative approach to flush out useful non-coding areas outside of the genes. He pinpointed the non-coding sections in human, cow, dog and rabbit DNA—sections long preserved by evolution—and showed they held similar sequences. Deleting those preserved bits in mice strongly reduced the activity of nearby interleukin genes. "That means, in short, that we've found a genetic switch outside of the genes."

Lee Hartwell, Director, Fred Hutchinson Cancer Research Center
Hartwell, a yeast geneticist who's unraveled many knots in cancer's tangled biology—and just received a Nobel Prize for it—has stepped back for the larger perspective on an important but overlooked cell phenomenon. He's exploring ways the genes for cells' large, interconnecting chemical pathways can interact to produce previously unsuspected cell effects.

In his talk, "Natural Genetic Variation, Gene Interactions and Complex Diseases," Hartwell said "we're fooling ourselves" if we assume a given gene behaves the same way in a different individual. To ignore the interactions of genes within cell circuits, he said, is to miss an underlying principle of human disease, one that helps understand why some people succumb and others don't.

The scientist explained that much variety persists in particular circuit genes because biological systems exert a huge buffering effect on them. Unless what they do is really dramatic or critical, the effects of certain genes are hidden, overshadowed by their environment. Those different varieties hang around, in essence, by hiding out.

But, using yeast secretory pathways as an example, Hartwell's shown that even "quiet" genes with no apparent cell effect of their own still interact with other genes—sometimes lethally. "In the right combination with other genes, they begin to express themselves in a new way." That idea's crucial to cancer research, accounting, for example, for variety in DNA repair systems and, accordingly, for peoples' different vulnerability to cancer.

Barton Childs, Johns Hopkins

"It's easier to move a graveyard than bring revisions in medical thinking," said Barton Childs in his talk on how genomics should be integrated into medicine's approach to disease. But Childs made an eloquent case for doing the latter, saying it would "let us advance an overall concept of disease, as opposed to the present-day focus on molecular and genetic errors in specific diseases."

Childs said an enlightened view of disease would use genome information to understand how a patient's overall gene makeup relates to getting a particular disease. Important to include—by looking at which genes are turned on—would be where patients stand on the road to maturity and what their genetic background is like. Finally, "if the epidemiologists can get inspired," he said, genomics will let them link the effects of a person's environmental exposure to illness.

Pooling these data "would give a coherent picture of an individual's disease—something we've never had in medicine. We could understand disease in the context of the humans who suffer it. That would keep us from reorganizing a patient's molecules at the expense of his sense of self, something, Childs said, that's all too common with modern drug therapy.