Good science and good fortune take Dennis Vance to the Weiland Medal podium

In this age of instantaneous communication — of e-mail and cellular phones, video conferencing and satellite links, overnight couriers and faxes — it is becoming increasingly rare for news of consequence to arrive via the daily post. But that is how Dennis Vance learned last summer that he had been selected for the highest international honor in his field.

"It just came in the mail," recalls the biochemistry professor who has headed the University of Alberta's respected Lipid and Lipoprotein Research Group since its inception in 1986. Inside the envelope with the German postmark was a letter informing the University of Alberta scientist that he had been selected to receive the 1995 Heinrich Wieland Medal, created as a memorial to the celebrated German biochemist who received the Nobel Prize in 1927..

The award, which he shared with a co-winner American biochemist Jean Schaffer (for unrelated work), was created in 1964 to recognize outstanding contributions in the field of lipid science. Selections are made by a panel of prominent German scientists and previous winners including some of the world's top biochemists. Among them are Nobel Prize winners such as Michael Brown, Joseph Goldstein and Bengt Samuelsson.

Opening the envelope and learning that he would be joining this elite group — the first Canadian to do so — was "a surprise, a very pleasant surprise, said Vance, who travelled to Munich to accept the award and a cheque for $15,000. He was accompanied by his wife Jean, who not only shares in his life outside the laboratory, but is herself a member of the Lipid and Lipoprotein Research Group — her lab is across the hall from his in the University's Heritage Medical Research Building.

Vance received the Wieland Medal at Munich University on 27 October 1995. "It was a very formal occasion," says Jean. The hall was decorated with flowers, a flute quartet played music by Mozart, and the medal winners were introduced by Wieland's son Theodore. Following the presentation of the medals and cheques and addresses by Vance and Schaffer, the medalists were guests of honor at an impressive banquet where Bavarian hospitality tempered the formality of the occasion.

A tall, spare man with grey hair and a trim grizzled heard, Dennis Vance is known for his calm demeanor and his organizational skills. He has an easy manner with his students and research assistants and a reputation for being ever ready to give them a hand, whether with problems arising front their work or personal lives. After his family (he and Jean have two university-age children) and his work, Vance's great love is the outdoors. He enjoys hiking and fishing, and as a golfer he can lay claim to having made a 'hole-in-one. ("He's not really all that good agoIfer - he just got lucky," contributes Jean.

He may be only a middling-good golfer, but Vance is a very good scientist. Before coming to Alberta he was the head of the Department of Biochemistry at UBC, and he is a former president of the Canadian Society of Biochemistry and Molecular Biology. His many professional honors include the Boehringer-Mannheim Canada Prize of the Canadian Biochemical Society and the Bristol Lipoprotein Research Award, which he and Jean shared.

He has a rock-solid record of research accomplishments, hut Vance is the first to admit that — like his hole-in-one— the work that led to the Wieland Prize owes something to luck. But it is no less important for that: his identification of an enzyme that appears to be capable of suppressing tumors in the liver could someday have major implications for the treatment of liver cancer, an important primary form of cancer in many parts of the world.

Fortune, they say, favors the prepared mind, and Vance's mind has been prepared by a long-standing curiosity. "I've always had an interest in disease," says Vance, who was born 54 years ago in a small town in southeast Idaho, hut grew up on the U.S. east coast. After earning a baccalaureate degree in chemistry at a small liberal arts university in Pennsylvania called Dickinson College, he went on to the University of Pittsburgh, where he earned a PhD in 1968.

It was while he was a graduate student at Pittsburgh that Vance began studying lipids. It was an interest that arose out of his work related to Fabry's Disease, a rare inherited genetic disease that causes sufferers to accumulate a lipid that clogs their kidneys and arteries. "Lipids are by definition insoluble in water, so they tend to gum up the works," points out Vance, using language more descriptive than scientific.

The most famous lipids are cholesterol and fat, but lipids comprise a broad spectrum of compounds that differ markedly in their chemical nature. Their one defining characteristic is that they cannot be dissolved in water. (On the other hand, lipoproteins complexes of lipids and protein — have the solubility characteristics of proteins: they are soluble in water or aqueous salt solutions.)

When he graduated from Pittsburgh, Vance's interest in lipids and the changes they go through as they are utilized by the body took him to Harvard University, where he spent two years as a research fellow with Nobel laureate Konrad Bloch. In 1973, following a year at the University of Warwick as a fellow of the British Heart Foundation, he accepted a faculty position at the University of British Columbia. He spent 13 years there, serving as associate dean of medicine (research) from 1979 to 1981. In 1986, with the help of funding from the Alberta Heritage Foundation for Medical Research, he was recruited to Alberta to develop a world-class lipid and lipoprotein research group.

While the high profile of cholesterol and fat tends to give them a tarnished image, lipids play an essential role in almost every body function and structure. The lipid that occupies the spotlight in Vance's lab is the building block of cells. Known as phosphatidylcholine — or PC, for short — it is a major component of cell walls, providing the substratum into which proteins are inserted to give cells their integrity.

The nine members of the U of A Lipid and Lipoprotein Research Group have diverse interests within their field, hut they have in common that each is engaged in some project that relates to cardiovascular disease. Every member of the group is supported in part by money from the Heart and Stroke Foundation of Alberta.

In Vance's case, the connection to cardiovascular disease arises from his interest in PC's involvement in the structure of the lipoproteins that carry cholesterol and fat in the circulatory system. "We are interested in the role of PC in the assembly of lipoproteins in the liver and the secretion of these into the bloodstream," says Vance. The liver, he explains, serves as a factory for the manufacture of the fat- and cholesterol-carrying lipoproteins. Somehow it assembles the components, taking the lipids, which are insoluble in water — and therefore insoluble in plasma — and combining them with proteins in such a way that the particle which results has different solubility characteristics. "The liver makes these sticky molecules and puts them into a particle that is soluble in water, so they can be transported through the blood stream to different tissues in the body." he says.

The discovery that led to the Wieland Medal arose out of Vance's curiosity about the pathways through which PC is manufactured in the liver. There are two of these. The first is found in all animal cells and is known as the CDP:choline pathway. The second pathway — the one in which Vance is most interested — is found almost exclusively in the liver. Through this pathway, a lipid known as phosphatidylethanolamine (or PE) is converted to PC.

"We have been interested in what regulates that pathway — what decides how much PE gets converted to PC," says Vance. As part of their studies into this very fundamental question, Vance and his research team were successful in purifying the enzyme responsible for the PE-to-PC conversion. When they accomplished the purification they found — as they had expected — that this enzyme with the unwieldy name phosphatidylethanolamine N-methyltransferase (which is commonly abbreviated to PEMT) is found virtually only in the liver.

"At that point we then decided to clone the DNA that encodes for PEMT," remembers Vance. The task was handed to a bright young postdoctoral fellow from China who had just joined the lab after a stint at the Harvard Medical School. Zheng Cui, now a research associate with Vance's group, was able to meet the challenge and presented Vance with the cloned DNA.

It was then that a series of completely unexpected findings began. It soon became clear that the enzyme that Cui had cloned was PEMT, all right, but not the PEMT they had expected. This became evident when the cloned enzyme was used to create an antibody and the antibody was then introduced to different fractions of the liver — all done simply out of curiosity. Vance was interested in seeing where in the liver PEMT is active — wherever PEMT was present, the antibody would react to it.

Vance and his colleagues were amazed to find that the enzyme they had cloned was not to be found where it should have been, but it was active where it had no right to be. What they had, it turned out, was a new, previously unknown form of PEMT, to which they gave the name PEMT-2.

"This was completely serendipitous," says Vance. The discovery, he points out, would likely never have happened if not for the fact that his wife happened to have a lab across the hall from his. "Over the years," he says, "Jean has developed a procedure for fractionating liver into its different components. It's only because she had these different components in the freezer, and we had this antibody, that we did the experiment." And if they hadn't, says Vance, they would have gone on thinking they had cloned the known form of PEMT

A second Surprise was to Come during further experimentation with the new form of PEMT In file Course of investigating various cell lines for evidence of the enzyme,

Vance tested some rat hep,uoma (liver cancer) cells that happened to be available. While lie had fully expected to find PEMT-2 in liver tumor cells, there was none. It was a surprise and also an opportunity. Because there was not any PEMT-2 present in the hepatuma cells there was, in effect, a clean slate - Vance decided to introduce the DNA for PEMT-2 into the cell line and see how that would affect PC metabolism. "Again this is just a fundamental question; `curiosity-bascd research' is another way I talk about it," says Vance.

Zheng Cui was once more involved. In his experimentation, Cui noticed that some cell lines he obtained after he introduced PEMT-2 were growing exceedingly slowly. It was an observation that Vance considered worthy of further investigation, and in a series of studies published in 1994, Cui, Vance and Martin Houweling (a postdoctoral fellow who had come to Vance's lab from the Netherlands), show that expressing the PEMT 2 enzyme in rat hepatoma cells slows the rate of cell division threefold. This was a landmark finding and the scientific world - including the Wicliand Medal panel - took notice.

Vance's lab has since thrown further light on this historic finding. Their research shows that PEMT-2 is probably slowing cell division by inhihitim, the primary PC biosynthesis pathway, the CDP:choline pathway. Studies that Vince has done in collaboration with a French scientist, Francois Terce of Toulouse University, back this up by confirming that blocking the CDP:choline pathway slows cell division.

"Mv hypothesis, at least, is that the PEMT-2 functions to regulate the CDP:choline pathway, and that there is something very important about this pathway - and the PC made by this pathway -for cell division," says Vance. "What that is we Jon't know. And that is where one of the frontiers is at the moment."

Vance's research has demonstrated a direct link between PEMT-2 and the growth of the liver. When the liver is growing rapidly, as it is before birth, there is no evidence of PEMT-2. When cell division slows after birth, the PEMT-2 level rises. Having revealed this inverse relationship, Vance collaborated with an Italian scientist to determine PEMT-2 activity at various stages of liver canccr. Based on those investigations, he and Luciana Tessitore of the University of Turin are about to publish a study that clearly show., that in the early stages of liver tumor ,~rowth PEMT Z all but disappears.

"We think there is a lot of evidence now to implicate PEMT-2 as a liver-specific tumor suppressor," says Vance. While this is exciting Vance remains Cautious about predicting a future for PEMT-2 in liver cancer therapy. The challenge, he says, will be to find a way to deliver the DNA for the enzyme to the tumor site. "That's a major problem. Labs all over are looking at how something like this could be done."

HecAu>e of the high incidence of liver cancer in parts of the world, Vance's work has excited a great deal of interest. While cancer ot the liver as a primary site is rare in C<+na,la and other western countries - in our part ut the world, liver cancer is usually a rc,uLt of metastasis from another site - in certain regions of Asia and Africa the incidence ot primary liver cancer is as high as 150 per 100,000 population (compared to four per 100,000 in North America). Around the glube, liver cancer causes more than ' 250,000 deaths each year.

Naturally, Vance hopes that his discoveries will help to one day prevent many of hose deaths, but that wasn't what he set out to do when he began studying PEMT. He simply was following his curiosity about the enzyme, and when he delivered his address to the Wieland awards audience, he titled it "Unexpected Findings from Curiosity Driven Research." The need for society to continue funding such research is something Vance feels strongly about. "Supporting fundamental research is a very important part of the health-care system," he says. "It's an investment in the future - if not for ourselves, for our children.

"Aside from the fact that we are developing basic knowledge about life, the record has shown that there are spinoffs that are important to medicine, and these keep coming. Our example is one- if I had put in a grant application even five years ago that what I was planning to do was relevant to cancer, the [scientific review] panel would have had a good laugh."

Those panels that supported Vance's work didn't get that laugh, but they now have every reason to smile. His success demonstrates that scientific excellence — the basic criterion for awarding Medical Research Council grants — can go a long way when combined with a large measure of curiosity and just a little bit of luck. As far — in Vance's case — as the Weiland awards stage in Munich.

Published Spring/Summer 1996.