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 futureand 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 departmentfaculty or studentto
own a microcomputer. He started setting it up at 1 oclock on a Saturday
afternoon, and when he next looked at the clock it was 2but dark
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 genomes mortar. Most everyone
assumes that when we talk about sequencing a genome, were 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 childs
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
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 genomeand making up most of it in complex organismswere
known collectively as junk DNA.
one molecular biologists junk is anothers treasure. Schisler
is among scientists taking a closer look at non-coding DNA, including
introns. It turns out that its 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 were 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 theyve
been conserved, that means theyre important. What theyre doing,
we still dont 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, providingamong
other thingssupport 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. Im 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, theres a dark side to this knowledge
as well. The eugenics that we saw in the early part of this century is
a concernI 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. Theres 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 Schislers 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 didnt 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 weve come up with on our own, or is it something
thats happening in nature, and were 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 whats 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. Its only through an understanding
of the scientific method that we can discuss these ideas logically and
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 theres a lot
we can do to help.
Pomonas 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 summerBradley Akitake, Anna Bruett
04, Ambereen Kurwa 05, Ana Lizama-Price, Ganesh Devendra and
Grace Tancaktiong 04are co-authoring papers on two subjects:
Intron Sequence Conservation in Complex Eukaryotic Organisms
and Going, Going, Gone... Intron Streamlining in Complex Eukaryotic
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, its not computers
that make the advances, its not corporate groups that make the advances.
Its people. Its someone who has a question and is searching
for the answer.
Michael Balchunas is a journalist,
a former member of the PCM
and now a free-lance contributor.
Photos by Phil Channing; Photo illustration
by Mark Wood.