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An Enterprise of Discovery

Five hundred years ago, the man whom we in the English-speaking world call Christopher Columbus (although there is no record that he ever referred to himself by that name — Ferdinand and Isabella of Spain knew him as Cristobal Colon) set foot on the soil of the New World. It was to be the signal event of an age of discovery. From the harbors of Europe, ships set sail for unknown lands on voyages that would eventually lead to the mapping of the shorelines of an entire planet.

Five centuries after Columbus, later-day explorers are involved in an enterprise of discovery every bit as intimidating in scope as the explorations of that earlier age. In laboratories around the world, men and women are at work mapping the structure of the human genome laboriously determining the location and composition of the genes that prescribe every physical aspect of the human animal.

At the University of Alberta, chemist Norm Dovichi is part of this quest. And while most of his fellow explorers are — metaphorically speaking — sailing aboard wind-driven brigantines, Dovichi is travelling by jet thanks to technology being perfected in his own lab.

Even to one who recognizes that scientists fit no stereotype, Dovichi doesn't quite fit the mould. In some ways (eyeglasses aside) it would not be hard to picture him as a sea-faring explorer of that earlier age. He has the physique for it, trim and athletic, but the same sprightly humor and relaxed approach to life that set him apart from many of his scientific colleagues, mar this image, as well. An explorer in search of new worlds should take himself more seriously, shouldn't he?

Dovichi, whose office door on the fourth floor of the west wing of the Chemistry Centre boasts above it a large flying corncob, admits that he enjoys what he is doing. "From the time I started university I knew exactly where I was going. I knew I wanted to be where I am today. I very quickly figured out I wanted to be a faculty member and I also knew I wanted to be a chemist — the rest is sort of gravy."

Dovichi not only takes pleasure in his work, he is extremely good at it. Only 38 years old, he is a full professor in the chemistry department recently rated the best in Canada by the Philadelphia-based Institute for Scientific Information. He heads a research group that currently comprises 11 graduate students, three postdoctoral fellows and assorted undergraduate students and is growing rapidly as a result of the research funding that is coming his way — some $1.6 million to date, including a recent $375,000 grant from the Human Genome Initiative in the U.S.

The recognition accorded Dovichi by his peers includes the WAE McBryde Medal. Bestowed upon him last year by the Chemical Society of Canada, this award recognizes outstanding achievement in pure or applied analytical chemistry by a young scientist.

More honors have already come his way in 1992. From the Chemical Society of Canada came the Noranda Lecture Award. From the Natural Sciences and Engineering Research Council came unprecedented recognition for an Alberta scientist: Dovichi became the first U of A researcher to collect both a Steacie Fellowship and the Steacie Prize in the same year.

The Steacie Awards, named in honor of Edgar William Richard Steacie, president of Canada' s National Research Council from 1952 to 1962, are presented annually by NSERC. Each year four Steacie fellowships are awarded to the best and most promising of Canada's younger scientists — researchers who are establishing national and international reputations for original work in their respective fields. The fellowships cover the salary and benefits of the recipient for up to two years, freeing them from teaching and administrative duties to allow full attention to their research.

The Steacie Prize is generally regarded as Canada's highest honor for young scientists and engineers and carries with it a cheque for $7,500. In honoring Dovichi, NSERC noted his development of "new, extremely sensitive methods to separate minute quantities of biological compounds such as amino acids."

There are, it is estimated, about 4,000 diseases known to be inherited — their occurrence directly tied to the information contained in the twisted strands of DNA which make each individual unique. Little wonder then the scientific interest in completing a map detailing the composition of human DNA, even though it is an undertaking of awesome proportions.

Consider the complexity. Each cell of the human body contains a nucleus with 23 pairs of chromosomes. These are threadlike packets of compressed and entwined DNA, the genetic material containing the blueprint necessary for reproduction of the cell through to future generations. The blueprint — the genetic code — is created on each strand of DNA by a particular sequence of bases (which are also called nucleotide units). A series of these bases with sufficient information to be capable of determining an inherited characteristic is considered a gene. There may be as many as 100,000 to 300,000 genes — nobody really knows for sure — in the 23 pairs of chromosomes each of us has. Altogether, the human genome consists of something like three billion pairs of DNA bases — that's about as many bases in our individual DNA as there are currently people on the earth.

It is a gargantuan task, but a complete accounting of all these bases would prove of immense value for such things as the artificial duplication of genes, and the identification, prediction and elimination of genetic diseases. To date, the base sequences for only about 500 human genes or parts of genes have been determined. Another thousand or so human genes, although not yet sequenced, have been mapped to their respective chromosomes.

Obviously there is a long way yet to go, and in the United States an organized approach to the elucidation of every chemical base in all the DNA that makes up human genetic material is being instituted. This is the Human Genome Initiative, which recently ranked Dovichi's submission at the very top of 100 proposals it evaluated for funding. The support given to his group — $375,000 over three years to further develop his sequencing technology — was only the second grant awarded by the Initiative to a group outside the U.S.

Being at the top is not an uncommon position for Dovichi and his research team. In 1990 Science magazine listed nine "Hot Tools" for biological science; in three of these (micro-protein sequencing, capillary electrophoresis, and laser-based detection) Dovichi's U of A group leads the world.

Looking back on his remarkable success, Dovichi says that vigilance and serendipity have contributed immeasurably. "You have a vague idea of what you want to do, but you always find something unexpected along the way," he says. He also points to personnel as being an important factor: "Someone calls and says ‘I can do such and such' and you say ‘Great, come in and we'll see what happens."' The research into DNA sequencing really got going, he says, because of a postdoctoral fellow from the University of Utah.

Utah was where Dovichi did his own graduate work. The choice, as he tells it, was not exactly a considered one — "They were the school that had the prettiest picture on their recruitment brochure," he quips — but it proved fortunate, nonetheless. "I had a wonderful graduate career there. I was my mentor's first student and got to help set up the laboratory and to see how to set up a research group."

Fate, or something very much like it, seems to have been prepared to step in at several important junctures in the life of the researcher, who shares with Columbus not only a penchant for discovery but an Italian ancestry. Dovichi's forbearers came to America in the late 19th century from the Italian heartland of Tuscany, the home of Chianti wine. (The terminal ‘chi' letter combination in his name has the same k pronunciation as the first three letters in the name of the wine.)

The future U of A professor was born in "a small city at the south end of Lake Michigan — called Chicago." There he grew up and, following his high school graduation in 1972, went to work for a machine shop while he considered his future. As late as August of that summer, he remained uncertain as to his career plans. His family was of modest means and the only university to which he had applied, Marquette in Milwaukee, proved out of reach financially, and the paycheque he was receiving from the machine shop seemed awfully attractive. On the other hand, 1972 was the last year of the draft˜.

As he teetered between remaining a wage earner and continuing his education, Fate gave a gentle nudge toward Northern Illinois University, where a number of his friends were headed. Located in De Kalb, Illinois (the home of DeKalb Hybrid Seeds and its flying corncob) Northern Illinois was "the least expensive place to go to school that wasn't in Chicago,"

Dovichi recalls. He never looked back, earning the College of Arts and Sciences' Dean's Award and university honors when he received his undergraduate degree in 1976.

Fate would take a hand in Dovichi's career again when, following his graduation from Utah, he accepted an appointment as a post-doctoral fellow at Los Alamos National Laboratory in New Mexico. "I went to work for a laser-jock," recalls Dovichi, who had gained considerable experience with lasers at graduate school. "At that time his lab required security clearance just because they were really hurting for space and the space available happened to be in a secure building."

Arriving at Los Alamos a couple of weeks before processing of his security clearance was complete, Dovichi spent some time with the biophysics group located in the local hospital. There, researchers were studying individual cells and the young post-doc became interested in finding out how small an amount of material could be detected. From that curiosity has evolved the world's most sensitive fluorescence detector, which is integral to the DNA sequencing work Dovichi is now doing.

The detection of sub-microscopic quantities of materials typically involves marking them in some way, often with radioactivity. An alternative approach is to use fluorescent dye — any one of a number of dyes commonly found in such products as fluorescent "highlighter" pens — to mark the material so that it will absorb light of one wave length (when the wave length is in the visible spectrum this will be a color) and in its place emit light of another wave length (color).

At the time Dovichi was awaiting his security clearance at Los Alamos, the most sensitive fluorescence detectors were capable of measuring "attomoles" of material (one attomole contains 600,000 molecules.) The detector that Dovichi has developed for use in his University of Alberta lab measures well into the sub-attomole range, quantities so small that it is only in the past year that they have been given an official name — scientists now talk about quantities in the "zeptomole" range.

Dovichi refers to his Los Alamos experience as "the most important step in my career. I was able to spend half my time learning totally new things, especially in biophysics, and it was the first time I did collaborative work."

From Los Alamos the chemist went to the University of Wyoming, where he began to attract the attention of the wider analytical chemistry community. By 1986 many in the U of A's chemistry department had noticed the good work he was doing, and when a position for an analytical chemist came open in their department a letter describing the position was dispatched to Dovichi.

"Their timing couldn't have been better," recalls the chemist. While he had had productive years at Wyoming, he felt constrained by department politics there and believed he could be doing better things elsewhere. The letter from Alberta arrived on his desk at a particularly opportune time — he had just had a confrontation with his department head — and he lost no time packing his degrees, texts, notes, papers and skis and heading for Edmonton.

"The reason I came here was the strength of the analytical program that was started by Walter Harris," says Dovichi, who praises as well the contributions of colleagues such as Gary Horlick, Fred Cantwell, Liang Li, Jed Harrison, Ron Kratochvil, and Paul Kebarle.

Ron Kratochvil, who was on the committee that hired Dovichi and is now the chair of the Chemistry Department, certainly hasn't had any second thoughts about inviting Dovichi to Edmonton. He says that his younger colleague has been "a delight to work with." He adds that not only is Dovichi's research truly at the state of the art, but his enthusiasm is infectious and he has contributed significantly to department administration and to teaching. "He's exactly the kind of faculty member a department likes to have," says Kratochvil.

The department chair makes particular reference to the Steacie Prize winner's breadth of expertise: "Not only is he able to understand biochemistry, he has a sound fundamental knowledge of both physics and chemistry. This is unusual in many ways, and it is this background that has allowed him to devise his extraordinary techniques."

Gene sequencing — the determination of the order of bases of the DNA molecule making up a gene — involves what Dovichi describes as "some extremely clever biochemical tricks." Because the entire stretch of human DNA is too big to work with, it is broken into smaller pieces, usually sequences of 1,000 or so nucleotides (bases). The sequencing of one of these pieces involves the manufacture of numerous copies — these are not exact copies, explains Dovichi, but constitute a "nested set of complementary fragments." By this he means that while each copy starts at the same point (the beginning of the sequence) the copies will vary in length in such a way that there will be some ending at each nucleotide base along the way.

Each base has one of four possible identifications — A (adenine), C (cytosine), T (thymine) or G (guanine). The complete set of complementary fragments is obtained by (the really tricky part of the whole process) making the enzyme used to synthesize copies of the original sequence always stop its manufacture at a particular base identity — 'A' for instance. This produces fragments which will always have an endpoint of that identity — 'A' in our example.

Conversely, for each base of that particular identity in the original DNA section there will be a copy which ends at that point. Repeating this synthesis for the remaining three identities ensures that there will be fragments of every possible length — that is, for each step in the DNA sequence there will be some fragments which have a corresponding endpoint. To obtain the sequence for the section being studied, the fragments are separated according to their length and their end identification read, moving from shortest to longest, to give the complete sequence.

The traditional method by which separation and identification is accomplished is known as electrophoresis. It was devised by British biochemist Frederick Sanger (earning him the 1980 Nobel Prize in Chemistry, his second of these) and involves the radioactive marking of the DNA fragments. These are combined with a gel and smeared onto a large glass plate. The passage of a low-level electrical current through the smear causes the fragments to migrate, their velocity directly related to their length. Because their speed of travel determines their final position, at the end of the electrophoresis the fragments have been separated in such a way that the sequence of the original DNA section can be read.

"Traditional electrophoresis is tried and true and involves low capital cost," says Dovichi. But it is also tedious and slow. "Horrendously slow," is how he puts it. The sequencing of a small section of DNA takes the better part of a day. "It has been calculated that it would take perhaps a century of person time to sequence the entire human DNA using this technology," says Dovichi.

The method his U of A group is pioneering is much, much faster — several orders of magnitude faster. His people place DNA fragments in a gel mixture which is forced into the hollow core of tiny capillaries, scarcely wider than a human hair. These tiny tubes, made out of the same transparent quartz as are optical fibres, are very efficient dissipators of heat, making possible the use of extremely high electrical fields for the rapid separation of the DNA fragments.

Once the separation is complete, Dovichi's laser-based, ultra-sensitive fluorescence detection technology is employed to read the base sequence. The whole process is computerized and Dovichi has plans for a third-generation detector that can collect information from 30 to 100 capillaries simultaneously.

In search of fame and fortune Columbus risked the perils of unknown seas five centuries ago. Fame he found in a measure few men have. Fortune was also his — contrary to the widespread belief that he died penniless, Columbus was, in fact, one of the richest men in Spain when he died in 1506.

Norm Dovichi doesn't see himself as a later day Columbus, but he admits that the fame and fortune part sounds pretty good to him. To illustrate the fame which DNA sequencing can bring, he points to the publicity surrounding the recent discovery of the gene responsible for cystic fibrosis. "With tremendous patience, a number of groups using the classic electrophoresis technology were able to determine the sequence of the piece of DNA which makes a protein which is defective in people who suffer from cystic fibrosis," he says. That discovery will likely result in a Nobel Prize.

On the fortune side, Dovichi gives the example of the large — perhaps $100 million or so — industry which has resulted from the deciphering of the sequence of about 1,000 nucleotides for the human growth hormone. "It's remarkable how a string of letters, if they are the right letters, can lead to fortune indeed," comments Dovichi.

Fame and fortune aside, there is a very basic reason for the scientific interest in DNA sequencing, suggests Dovichi. "We know that much disease has a genetic nature associated with it; so if you were able to discover what genetic defects cause these diseases you would have some hope of curing them. But that's not the real reason why people are interested in the human genome — it's not to cure genetic diseases, although that's a nice, simple, clean system to describe. What you want to understand is the molecules of life: how do human beings work on the cellular level? That's the whole point."

Published Summer 1992.

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