Indiana University Research & Creative Activity

25th Anniversary

Volume XXV Number 1
Fall 2002

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Rudolf Raff
Rudolf Raff
Copyright © 2002 Tyagan Miller

Michael Conneally
Michael Conneally
Copyright © 2002 Tyagan Miller

Thomas C. Kaufman
Thomas C. Kaufman
Copyright © 2002 Tyagan Miller

Myers Hall
Myers Hall, completed as the Medical Building in 1936, is well known on the Indiana University Bloomington campus for its limestone carvings and exterior design. After an extensive interior renovation, Myers Hall was rededicated in April 2002. It now provides modern laboratory space for Indiana Molecular Biology Institute researchers and also houses joint use facilities for imaging, DNA sequencing, and genomics as well as conference rooms and a large lecture hall.
Photo courtesy Rudolf Raff

A Research (R)evolution

by Eric Schoch

Today, scientists work with DNA, even whole genomes, in ways that now seem no more exotic than a chef working with eggs and flour. In February 2001, they announced the working draft of the human--what once seemed an impossible task now is old news. Twenty-five years ago, things were different.

About the time this magazine was entering the world, a revolution was underway in the biological sciences. The techniques of molecular biology were fundamentally altering the ways biologists and biomedical scientists would go about their work.

For three veteran Indiana University researchers, the revolution gave them new tools and affected the kinds of hypotheses they could test.

But it didn't have much impact on what they wanted to know.

For Rudolf Raff, Distinguished Professor and director of the Indiana Molecular Biology Institute in Bloomington, the DNA revolution broke biology apart and now is putting it back together again.

For Michael Conneally, Distinguished Professor at the IU School of Medicine in Indianapolis, the tools meant the difference between frustration and helping to map, and then clone, the gene for Huntington's disease.

For Thomas Kaufman, Distinguished Professor at IU Bloomington working with his stocks of fruit flies in IUB's Jordan Hall, it meant being able to open a genetic "black box" and peer inside.

Raff, whose interest is in evolutionary developmental biology, has adopted the new tools in his research. But when asked about the impact of molecular biology, he first looks at the big picture.

In the 1960s and 1970s, says Raff, many departments of biology began their own processes of division, though not replication. On the one side were those focusing on molecular, cellular, and developmental questions. On the other were the evolutionary, ecology, and organismal biologists.

"There were some who thought it would be a good thing to shed the 'dead wood.' They weren't interested in organisms, they were interested in molecular biology, what's happening at the cellular level," he says.

Harvard University, for example, has a department of molecular and cellular biology and a department of organismic and evolutionary biology. Nor has the trend stopped--the biology department at the University of Michigan was "reorganized" into two units just last year: the department of ecology and evolutionary biology and the department of molecular, cellular, and developmental biology.

But the techniques of molecular biology are equal-opportunity tools, and over time, they've been adopted by a broad range of biological scientists, says Raff.

"What's happening now is a reunification of biology, a reunification of discovery," he says. "What there is, is biology, and it makes wide use of new and old tools."

Raff describes his own research interest as "the history of evolution of the big patterns of life. How do all these innovations come about? Why aren't we all still single cells? How do you evolve a big brain?"

To work on answers to these big questions, Raff turned to a small creature--the sea urchin. Recently he's been looking at two sea urchins that are quite similar when mature, but which have radically different reproductive methods. He and his colleagues were able to identify the small number of genes that are responsible for such profound effects, which in turn has implications for the evolution of these developmental processes. That sort of analysis would not have been possible some two decades ago, but that didn't mean Raff wasn't looking for ways to find answers to the same big questions.

"You focus on the questions that are available, and do science," Raff says. "People are not thinking, 'how primitive things are!'"

When Michael Conneally was looking into the genetics of Huntington's disease in the late 1970s, the tools were primitive. Conneally had left his native Ireland to study animal genetics at the University of Wisconsin. A mentor there, Newton Morton, convinced Conneally to turn his attention to human genetics. He came to the IU School of Medicine in 1964. Fifteen years later, finding a gene for Huntington's disease or any such hereditary illness seemed a long way away.

"We had essentially no tools to find these genes," Conneally says. "We had about 30 landmarks throughout the genome, and they weren't very good."

Those landmarks, or genetic markers, are like road signs in the genetic highway that help point researchers to the likely location of genes. But they were crude, things such as blood types and a few known proteins. From his bookshelf, Conneally pulls out a thesis written by one of his students in 1979, "Genetic Studies in Huntington's Disease." It used 27 markers to look for likely gene locations. With such blood-related markers, Conneally says, "we got nowhere."

Working on single-gene diseases like Huntington's disease was difficult and frustrating enough. Working on complex diseases that involve many genes and environmental factors seemed out of the question.

"We couldn't touch complex diseases. We couldn't think about asking about osteoporosis or alcoholism," Conneally says.

But more, and better, genetic markers were on the way because of a series of breakthroughs in the 1970s, starting with the discovery of restriction enzymes. These enzymes, used by bacteria to protect themselves, cut DNA at specific locations. By the end of the decade, researchers found they could use these molecular scissors to cut and splice sections of DNA, then place the recombined sections of DNA into bacteria where they would be biologically active.

When scientists studied the pieces of DNA produced by restriction enzymes, they found that they were not always the same length. A section cut from one area of DNA in one person might be longer or shorter than the section cut from the same area of another person's DNA. These differences in length--called polymorphisms--turned out to be useful in tracking down the locations of genes. (They also led to the development of "DNA fingerprinting" techniques used by police and forensic investigators.)

While these new techniques were being developed, Columbia University researcher Nancy Wexler was collecting a mountain of genetic and family history data from the residents of a Venezuelan village with a high rate of Huntington's disease. Conneally, meanwhile, was collecting similar information from families in the Midwest.

And at the Massachusetts Institute of Technology, researchers David Housman and James Gusella began testing their newly developed markers with Wexler's and Conneally's samples from the Huntington's disease families. It was a project they expected to last years as markers were painstakingly analyzed and discarded. Instead, they struck gold almost immediately, and were able to map the gene to an area on chromosome 4 in 1983.

"We were lucky. We had markers in the right place," says Conneally. "That helped get rid of some of the melancholy."

Once the gene was mapped, it seemed likely that the gene itself would be found and cloned within a year or two. It didn't happen--in fact it would be another decade before they could announce that the actual gene had been cloned.

During that time another breakthrough helped overhaul biological research: polymerase chain reaction, or PCR. The technique, developed in the mid-1980s, enabled scientists to "amplify" a section of DNA--creating millions of copies of a section of DNA. This enabled technicians to quickly produce a large sample of DNA for research, diagnostics, and other uses even when only a tiny amount of the original DNA was available.

"That was the No. 1 revolution in biology," says Conneally.

In the late 1970s, scientists had developed ways to sequence DNA--to identify each nucleotide (the A, C, G, or T) in a section of DNA. In the 1990s, the Human Genome Project--the international effort to map and sequence the human genome--prompted the development of technologies that could sequence DNA faster, cheaper, and using more automated techniques.

Thomas Kaufman came to IU around 1976 from the University of British Columbia, where he was a postdoctoral researcher and lecturer. His specialty was--and is--Drosophila, the fruit fly. It's a creature with a long history in the study of genetics, yet researchers such as Kaufman were discouraged by the distance between what they wanted to know and what the technology could tell them.

"It was such a long way between genotype and phenotype. We had no idea what was going on in between," he says. "It was a black box.

"What is this gene? What is its product? How does that product work? The questions were always there, but the technology didn't exist to answer the questions," Kaufman continues. "We were frustrated."

For Drosophila researchers, just as for Huntington's disease researchers, the dam broke when people realized the potential posed by restriction enzymes and the ability to clone genes and grow them in bacteria. By 2000, the first release of the Drosophila genome had been completed and made available to researchers.

"Now that we have the sequence, anything is possible. If you can imagine it, you can do it," says Kaufman. "It's changed utterly. There's no comparison."

It has not, however, all changed for the better, in Kaufman's view. Science goes through stages, he says, "and there are stages where the technology is more important than the question being asked."

We're now in a stage that Kaufman calls "the industrialization of biology." With high-speed robotic equipment, computer chip-like gene arrays, and accompanying powerful computers, people are collecting massive amounts of data with no real hypotheses to pursue. At some scientific meetings, there are laments "that hypothesis-driven research is dead," Kaufman says. "We're in the stamp-collecting stage.

"It's not as much fun, because of all the industrialization. It's gotten kind of cutthroat, I'm afraid. People are behaving badly, and one reason for it is because there's a potential to make a lot of money.

"But then, I'm old school," Kaufman adds.

And yet, says Raff, there is something to celebrate at IU, where the Bloomington biology department never splintered and now is reaping the rewards in Jordan Hall and the new, extensively renovated Myers Hall. As one example, Raff points to last year's arrival of Michael Lynch, who came to IU from the University of Oregon with a training grant and other substantial funding. Lynch's work is a synthesis of evolutionary biology, developmental biology, and genomics. He found Bloomington to be fertile territory for such work.

"Biology has this life in it again," says Raff. "I don't know if people realize how vibrant an environment we have here."

Eric Schoch is a science writer at the IU School of Medicine.

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