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Fall 2002
Volume 39, No. 1
Issue Home

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PCMOnline Editor: Sarah Dolinar


Reading Between the Lines (in the Book of Life)

Between the sparse lines of meaningful code in the human genome lie volumes of what was once thought to be nonsense. That is, until Nick Schisler and his students began to read between the lines.

In 1980, before most of his current students were born, Nicholas Schisler caught a glimpse of his future—and theirs. He was an undergraduate at The University of Western Ontario, a leading research institution in Canada, when he stopped by a new kind of shop called The Computer Circuit. There he had an epiphany.

“They had an Apple II computer playing the Sargon II chess program,” says Schisler, who was a biology student. “When I saw that computer playing chess in a store, I knew that computers were going to be a major player in scientific endeavors.”

Two years later, as a doctoral student, he splurged, paying nearly $5,000 for an Apple II-plus with 48K of RAM and a 120K floppy disk drive, plus a printer. He was the first person in the department—faculty or student—to own a microcomputer. He started setting it up at 1 o’clock on a Saturday afternoon, and when he next looked at the clock it was 2—but dark outside.

“Needless to say, I was hooked,” says Schisler.

The hook was deeply embedded. Schisler wrote the software he needed for the computer to crunch numbers and analyze statistical data as part of his studies in biochemical genetics. He became a pioneer. The new ground he was treading is now known as bioinformatics, the still-emerging field in which biology and computer science intersect.

“Bioinformatics has taken off tremendously in the last couple of years,” says Schisler. The surging interest has been driven by huge volumes of data resulting from the sequencing of the DNA of complex genomes —a treasure trove of information about the genetic history of life that is just beginning to be mined.

Many molecular biologists are “going for the gold ring,” as Schisler puts it, by focusing their studies on the protein-encoding genes in complex, or eukaryotic, organisms such as humans. But although genes are the building blocks of life, determining hereditary characteristics, they are dwarfed in volume by the genome’s mortar. “Most everyone assumes that when we talk about sequencing a genome, we’re talking about the protein-encoding genes,” says Schisler. “But the genes that make the proteins are only 3 percent of the genome. The other 97 percent is non-coding DNA, which we know very little about.”
A genome has aptly been described as a book of life, but it is a very curiously written tome.

The story of each of the 30,000 to 40,000 human genes might be considered as a set of how-to instructions for creating one or more specific proteins that act in some way to help make us what we are. It was thought that when they were decoded, each of these sets of instructions would read as a continuous string, something like the manual for assembling a child’s bicycle: a cotter pin connects to a nut that is threaded on an axle attached to a wheel, and so on. In simple-celled prokaryotes, such as bacteria, the sequences do follow such a continuous, linear pattern.

But in 1993, two U.S. scientists were awarded a Nobel Prize for having discovered an odd fact that turned this view on its head. In humans and other eukaryotic organisms, the coding sequences that might be considered analogous to a how-to manual are interrupted by non-coding passages that might be considered something like the genetic equivalent of Finnegans Wake.

These unexpected interruptions, called introns, did not appear to their discoverers to make much sense. In fact, when our cells transcribe genes as part of the process of creating a protein, the introns are most often edited out and the coding portions of the gene that are interspersed among them, called exons, are joined to make a continuous string. Until very recently, introns and other seemingly meaningless DNA sequences found throughout the genome—and making up most of it in complex organisms—were known collectively as “junk DNA.”

But one molecular biologist’s junk is another’s treasure. Schisler is among scientists taking a closer look at non-coding DNA, including introns. It turns out that it’s far from junk.

“I hate that term,” says Schisler. “Nothing in the genome is necessarily junk.” The key to understanding and proving this, he says, is comparative genomics. Because DNA mutates over time, and beneficial mutations are conserved through natural selection, non-coding DNA sequences that are meaningless would not be conserved through the evolutionary process.

Using a specialized computer program, Schisler and some of his Pomona students have been exhaustively combing through enormous databases of genomic data, aligning and comparing strings of introns from species at varying evolutionary stages. The results of this work, also being confirmed by other scientists, have been astonishing.

“We compared every intron with every other intron in the database,” says Schisler. “As an example, we found that roughly one-third of the introns found in the mouse had some similarity to other introns in the mouse, and a smaller percentage had a similarity to introns in other species. This was absolutely unheard of.

“The human and mouse are separated by about 40 million years of evolution,” Schisler explains. “What we’re finding is large structures of DNA that are virtually identical in these species. If they are identical, that means the sequences have been conserved through evolution. If they’ve been conserved, that means they’re important. What they’re doing, we still don’t know. But at least we have the tools now to separate the wheat from the chaff.”

Other studies suggest that some of these non-coding DNA sequences may act in some vital way to regulate how genes order the development of an organism. This summer, Schisler and five students working with him have been examining this topic further. DNA sequences called transcription factors are known to regulate the expression of genes, so Schisler and the students have begun looking for sequences of this type within the long stretches of non-coding DNA.

Another very specialized type of computerized analysis that Schisler and the students are planning would look for particular three-dimensional molecular structures among the intron databases. If those are found, it would suggest the possibility of some functional purpose for the molecules.

Underscoring the potential of his work, the National Institute of Health in July awarded Schisler and his collaborator, Dr. Arlin Stotzfus of the Center for Advanced Research in Biotechnology, part of the National Institute of Standards, a grant of $800,000 to study intron evolution, providing—among other things—support for at least four students to conduct research in Schisler's lab and to attend international scientific meetings over the next three years.

Schisler was not certain of his own eventual purpose in life when he received his undergraduate degree from The University of Western Ontario. “I had a choice like everyone else faces, it seems, in biology: Should I go to medical school? Should I become a teacher? Or should I go into graduate school?” he says. Graduate-level study attracted him in part, he adds, because “research is something that is thoroughly fascinating and constantly changing.”

His career trajectory resembles in one way the discontinuous DNA strands that he studies: Sequences directly involving biology are interspersed with sequences related to computers and programming. From 1990 to 1995, for example, Schisler served as director of research and development for Autodata Marketing Systems Inc., writing software for the start-up company, which has had marked success in applying computer technology to various aspects of the automotive sales industry. But, “I really wanted to get back to academic software development,” he says, and he has remained in academia since.

Schisler, who joined the Pomona faculty in 2000, is keenly interested in the ethical considerations attending genetic studies. He notes that his doctorate in zoology from Canada states that it is conferred with “all its rights, privileges and obligations,” and says that he regards those obligations very seriously. At Pomona, Schisler has taught a Critical Inquiry Seminar for first-year students called Contemporary Issues in Biology, Biotechnology and Medicine.

The potential benefits of a thorough understanding of genomes are almost unbounded, he says, though he expects a full functional analysis of genes to take decades to complete. In the meantime, new discoveries are having dramatic effects already. “I’m sure in five to 10 years your doctor will become very adept at using this technology to give you some very good advice regarding your health and what to indulge in and what to avoid,” says Schisler. “The therapeutic applications are just tremendous. Of course, there’s a dark side to this knowledge as well. The eugenics that we saw in the early part of this century is a concern—I shudder to think of what Hitler would have done with this sort of data.” In addition, there is not yet equitable distribution of therapies developed through the increased understanding of molecular biology. “We have the luxury in North America of being in perhaps the most technologically advanced society on Earth,” says Schisler, “but the poor man in sub-Saharan Africa who has contracted the virus that causes AIDS has no chance at all. There’s a real disparity in First World versus Third World application of our knowledge.”

As the use of genetic data increases, not just for medical purposes but in a variety of other ways, an array of other ethical issues must be dealt with, Schisler notes. Some law enforcement jurisdictions, he believes, have begun sampling the DNA not just of people convicted of crimes but of all of those arrested. Also still subject to fierce debate is the increasing use of genetically modified organisms, including food crops and animals. One of Schisler’s concerns is that the biological processes involved are not well understood by many members of the public. The genomes of plants and animals have long been manipulated by people through selective breeding, he notes, and there is increasing evidence in nature of the “lateral transfer” of genetic information between seemingly unrelated organisms. For example, some human genes appear to be of bacterial origin. “Where did those genes come from?” Schisler asks. “We certainly didn’t put them there.”

“When I consider the arguments of people who are opposing any genetically modified organisms, I try to get them to ask the question, ‘Is this something that we’ve come up with on our own, or is it something that’s happening in nature, and we’re just starting to understand and exploit these properties?’” says Schisler. “You really have to have an understanding of the science involved to make an informed decision. Evolution is wrapped up into this package, and unless people have a firm understanding of the concepts of evolution, they will not be able to make sense of what’s going on in biology at any level. I think we really have to do more to ensure that students get a strong science education in our high schools. It’s only through an understanding of the scientific method that we can discuss these ideas logically and dispassionately.”

Living on campus as a faculty resident, Schisler has many opportunities outside of the classroom and lab to discuss his ideas with Pomona students. “My wife and I are really trying to integrate our lives with those of the students,” he says. “Some students have difficulty adjusting to this sort of residential college lifestyle, and there’s a lot we can do to help.”

Pomona’s need-blind admissions and the opportunity to work with student collaborators helped draw him to the College, Schisler says. The five students working with him this summer—Bradley Akitake, Anna Bruett ’04, Ambereen Kurwa ’05, Ana Lizama-Price, Ganesh Devendra and Grace Tancaktiong ’04—are co-authoring papers on two subjects: “Intron Sequence Conservation in Complex Eukaryotic Organisms” and “Going, Going, Gone... Intron Streamlining in Complex Eukaryotic Genomes.”

“Our student body is second to none,” Schisler says. “Three of the five students working with me are on scholarship. The other two said, ‘Hey, I can afford to do some summer research until funding comes through, so I just want to be part of it.’ That really speaks to the motivation that many of these students have. When we talk about scientific progress, when you get right down to it, it’s not computers that make the advances, it’s not corporate groups that make the advances. It’s people. It’s someone who has a question and is searching for the answer.”

—Michael Balchunas is a journalist, a former member of the PCM staff
and now a free-lance contributor.

Photos by Phil Channing; Photo illustration by Mark Wood.