National Post Feature

The National Post features the Genome Sciences Centre in a 3-day exposition on the status and implications of the Human Genome Project in its "Writing the Book of Life" addendum.

So obscure he won the Nobel Prize

Michael Smith founded a genomics centre in Vancouver, reversed the brain drain and kept Canada in the gene hunt

National Post (Margaret Munro) Michael Smith believes there are limits to the power of genetic alchemy. Do not, he says, hold your breath for scientists to take bits of ancient DNA and recreate dinosaurs or mastodons as some researchers have suggested.

"Now that's acute science fiction," says the 67-year-old Nobel Prize winner.

Michael Smith won the Nobel Prize for chemistry in 1993. (Photo courtesty Nick Didlick, National Post)

Still, with the human genome largely in hand, "there's going to be no end of things to do," he says.

Smith's latest venture is the creation of a $25-million Genome Sequence Centre at the B.C. Cancer Agency in Vancouver. Not that he had a burning desire to take on more administrative duties, "but I feel so strongly that Canada get involved that I agreed to become founding director," says Smith from behind a desk piled high with reports, proposals and grant applications.

The only evidence of his celebrity status is a framed copy of the certificate he received along with his Nobel Prize in 1993. It is propped on top of the bookcase where it will collect dust until someone has time to find a hammer.

Dinosaurs aside, Smith expects genomics to have a profound impact. It should enable scientists to understand the chain of genetic aberrations that set cancer on its deadly course. It should allow them to devise probes to identify infectious microbes in a matter of minutes instead of days. Genomics may even explain why some individuals are immune to flu, helping to create new drugs. Longer term, Smith envisions treatment for diseases like Huntington's and cystic fibrosis caused by to gene mutations.

And that's just in medicine.

Genomics applies to all forms of life. It should, he says, allow scientists to find plant genes linked to drought, heat and pest resistance, and help them to engineer new crops and trees that can handle global warming.

The idea of decoding the entire human genome sounded like science fiction when Smith first started tinkering with the biologically active molecules that later turned out to be key to genetics. Back then, in the late 1950s, the notion that life was controlled by strings of molecules called DNA was brand new. Smith's work was critical to understanding how DNA actually works its magic, and how it could be manipulated in the test tube.

He arrived in Vancouver in 1956 as a post-doctoral student from England to work for famed biochemist Gobind Khorana and was put to work synthesizing molecules, known to be active in genetic processes, from scratch.

Some of the compounds Smith cooked up -- at times with such abandon that resulting explosions left large orange stains on the lab ceiling -- are still in use by the scientists now routinely synthesizing DNA.

It was in 1976, while on sabbatical in England, that Smith hit on the idea that would earn him the Nobel Prize. He was at Cambridge University learning how to read or "sequence" genes by determining the order of the nucleotide molecules that make up DNA. He helped sequence the first complete genome of a living thing -- the tiny virus PhiX174.

"It had 5,386 base pairs," Smith recalls as if he had counted them yesterday. "We did everything by hand," he says, and were lucky to sequence 100 nucleotides a day. (The assistants in Smith's new lab now read close to 200,000 a day, with the help of $500,000 DNA sequencing machines.)

When he returned to Canada, he decided to try a bit of chemical sleight of hand to alter -- or mutate -- genetic codes deliberately. He soon succeeded and called the process "site-directed mutagenesis." The rest of the story is legend in Canadian scientific circles.

Smith's technique -- which was considered so obscure it was rejected by the editors of the leading journal Cell -- became a fundamental tool in genetic engineering labs, enabling scientists to alter the sequence of genes deliberately and turn on and off the production of proteins. In effect, Smith's discovery enabled scientists to rewrite the language of life.

It also helped him make a small fortune through a company in Seattle, Zymogenetics Inc., which he co-founded in 1981.

But it was an early morning phone call in 1993, with news that he was co-winner of the Nobel Prize for chemistry, that changed Smith's life. Overnight he became the poster boy -- and ambassador -- for Canadian science.

Everyone, it seemed, wanted a piece of him. For several years Smith maintained an exhausting schedule of guest lectures and meetings. He used to lament that he was never home long enough to even do his laundry.

Smith used his fame to focus attention on areas that he felt were neglected -- such as schizophrenia research, promotion of women in science and the need for better public understanding of science. (He feels the current debate over genetically engineered food is largely based on ignorance and unfounded fear.) As Martha Piper, president of the University of British Columbia, put it recently: "You can find Nobel laureates, but to find a Nobel laureate who also believes so strongly in the importance of giving back and contributing to society ... Mike is just so generous at all levels.''

Smith has managed to slow down, a bit. He has been ordered to stop flying by his doctors, who are worried about a medical condition that he would rather not discuss. Suffice it to say infectious microbes, which are all too common on airplanes, could worsen the condition. But he still gets around. Last fall he spent two stormy weeks being tossed around on a 71-foot ketch off the Alaska-B.C. coast with friends.

To his regret, Smith is too busy to spend time at the lab bench. (He is also too valuable a draw for research dollars to spend his time puttering with molecules.) But he has managed to pull off the next best thing. He has attracted a team of bright young scientists to Canada to work at the new genome centre, which will concentrate on pinpointing the genes involved in cancer. "We're reversing the brain drain," says Smith.

Marco Marra, a native of northern Alberta, has been lured back from Washington University in St. Louis where he was a key member of one of the big U.S. teams racing to decode the human genome. Marra, a genetic fingerprinting expert, never thought he would be able to work in Canada again. Then Smith came courting with an irresistible offer to make him associate director of Canada's first comprehensive genome sequencing centre. Marra, who was also wooed by two large U.S. genome labs, opted for Vancouver and working with Smith, whom he describes as brilliant, gracious and "amazingly forward-thinking."

Smith also lured back Steven Jones, a "bioinformatics" whiz, who studied at Simon Fraser University before heading to the Sanger Centre at Cambridge University in England, the world's largest centre of genomics research. Jones' job is to make the overwhelming volume of new genetic information accessible and meaningful. He and his colleagues are working on systems to enable scientists worldwide to quickly find out everything known about a gene, from its molecular structure to its relation to similar genes found in other lifeforms, be they worms or monkeys.

Not only did Jones and Marra bring back their brains, they have brought a big piece of the next big international sequencing project -- to decode the entire mouse genome. By completing this, scientists expect to better understand the function of genes and DNA on the human genome, most of which are completely unknown. The B.C. team has a $1.8-million contract with the U.S. Human Genome Research Institute to get the first chunk of the mouse genome fingerprinted by the end of June. If they deliver, they will be in line for another $2-million contract.

"It just shows we have world-class talent in Canada and we can get involved in world-class projects," says Smith, who hopes to have time to return to the lab bench some day.

The moon walk of medicine

The human genome project is almost complete. It's what you might call 'a giant leap for mankind.' It will revolutionize medicine and may extend our lifespans

National Post (Margaret Munro) It is officially known as the Human Genome Project, but scientists like to say they are writing the book of life.

Human life that is, and the 80,000 genes that make it possible.

Dr. Marco Marra, the Associate Head of Sequencing and Mapping at the Genome Sequence Centre in Vancouver. (Photo courtesty Nick Didlick, National Post)

Some say the human genome is one of the most profound things ever created. It is a detailed biochemical description of the genes that control how the human body carries out its duties from conception until death -- everything from the colour of your eyes to when your heart starts beating.

The impact of knowing the human genome is expected to be enormous. On a par, say many eminent scientists, with the development of the atom bomb and the landing on the moon.

It will help prevent, tame and, with a lot of luck, even cure cancers and many genetic diseases. It will enable scientists to tailor drugs and treat diseases according to people's genetic profiles. Biofactories will be able to grow an endless supply of replacement organs for transplantation. Some even believe the genome contains the secret of eternal youth.

Hundreds of scientists, most of them in the United States and Britain, have spent 10 years and close to $5-billion on the project. They have isolated the long strands of DNA found on the 23 pairs of chromosomes cradled inside each human cell, snipped them into manageable pieces, and set about reading -- or sequencing -- their genetic codes, molecule by molecule. The information has been recorded in a giant data bank -- the so-called book of life -- that is available to anyone with access to the Internet.

The genome is likely to be finished in the summer. Scientists have passed the half-way point. The further the project advances, the more the pace of progress accelerates. But even before completion, it is already transforming our understanding of the human condition and challenging notions of what can and should be done with the genes that help determine what we look like, how we act and think, and what diseases we will get.

Scarcely a week passes without some research team announcing it has found a gene that "may" help cure heart disease, or baldness, or boost intelligence. Or that yet another biotech company is joining the race to put these genes to work.

Celera Genomics Corp., led by maverick U.S. scientist and millionaire Craig Venter, has fuelled the race to finish the genome by claiming his team will finish the job before the publicly funded effort. Venter's team has been working overtime filing for thousands of patents on human genes they have found and charging $5,000 to $5-million a year for the right to access the company's data base -- leading to growing concern that the essence of human life is being crassly commercialized.

In response, the publicly funded scientists have stepped up their work and expect to finish the first draft of the genome within months, years ahead of the original schedule. "It is imperative that the genome sequence, the fundamental building block of biomedical research, be made rapidly available at no cost to scientists around the world," said Francis Collins, director of the U.S. National Human Genome Research Institute, in a recent paper in the New England Journal of Medicine.

The promise the genome holds for unravelling the mysteries of human life are seemingly endless. The biggest impact will be in medicine. But scientists say it also gives them a new tool for studying how humans evolved from rat-sized primordial mammals and how early human beings populated the globe. As the journal Science reported recently, there may even be revelations about the politics of the sexes: "Who left home and who moved in with the in-laws, can be traced through the evolution of the X and Y chromosomal sequences."

But the big money -- almost every major pharmaceutical company in the world is involved -- is banking on the human genome revolutionizing medicine. And a chorus of scientists in this country -- from Nobel Prize winner Michael Smith to medical doctors trying to treat people with genetic disorders -- say Canada must wake up to genetic reality.

Every developed country has a genome program up and running. The United States government is spending over $500-million a year on the human genome, and Germany, France, Britain and Japan are investing huge amounts to exploit it and come to terms with its implications. Canada's Liberal government, after much prodding from scientists who have been watching colleagues and opportunities slip away, has just agreed to spend $160-million on Genome Canada, which will create five new research centres across the country.

But like many technical feats -- especially where profits ride on the outcome -- the decoding of the human genome is nothing if not over-promoted.

"There is a lot of hype," says Thomas Hudson, a leading geneticist who splits his time between McGill University and the Massachusetts Institute of Technology, where he is assistant director of MIT's genome centre.

There is clearly a lot of excitement, say Hudson and his colleagues, but progress is often painfully slow.

"The gene for Huntington's was first mapped in 1983, it was cloned in 1993 and today is 2000, and we haven't found a cure yet," says Hudson. "We certainly understand a lot more about the biology, but it's very difficult."

Gene therapy is also progressing slowly. What is moving quickly is the development of genetic tests, which are proliferating and are now available over the Internet. The tests require only a few drops of a person's blood or a few of their cheek cells. They can identify, with often quick and chilling accuracy, who carries gene mutations that have been linked with dozens of disorders.

Scientists are already using human genes to create bizarre human/animal hybrids, such as pigs that produce human proteins in their semen. There are also labs full of "humanized" mice that have been engineered with disease-causing human genes to give scientists a better understanding of what the genes do. It's not much of a leap of imagination to conjure up visions of designer babies.

Reading the human genome is often compared to mapping the route from San Francisco to New York City and documenting every hill and valley along the way. The mass of data generated is enough to fill 200 telephone books. And the reading is a lot less interesting. But scientists say writing the book is just the start. The revolution, and revelation, will be in the way the information is interpreted and put to work. "It's the beginning, not the end," says Marco Marra, associate director of the Genome Sequence Centre in Vancouver.

Learning the language of an undiscovered country

National Post (Margaret Munro) Steven Jones scrolls down a long column of As, Gs, Cs and Ts on his computer screen and scratches his head.

"This is an anonymous gene," says Jones, head of the informatics group at the Genome Sequence Centre in Vancouver. "We've no real clue what it does."

Dr. Steven Jones, the Head of Bioinformatics at the Genome Sequence Centre in Vancouver. (Photo courtesty Nick Didlick, National Post)

The same can be said of most of the human genome.

Huge teams of scientists in labs around the world have spent close to a decade cataloguing the three billion letters -- the As, Gs, Cs and Ts representing the long chains of DNA cradled inside every human cell. But "the words don't make a lot of sense to us," says Marco Marra, associate director of the centre. "We've written the book. Now we have to figure out what it says."

The job will keep scientists busy for decades. Only a fraction of the genome -- about 3% -- is thought to be genes, which instruct cells to make proteins. Scientists are at a loss to explain what the other 97% of the DNA is for.

As for the genes, scientists are not sure just how many are embedded in the genome. Estimates vary from 70,000 to 120,000. And the function of most of them is unknown.

"We're also missing large chunks of genes," says Jones. "More important, we're missing the things that control genes -- the things that switch them on and off."

To try to make sense of the human genome, scientists have turned to the lowly round worm, known as C. elegans, which has also had its chromosomes read from start to finish. It has thousands of genes in common with humans and other animals. By eliminating the tiny worm's genes one by one, and watching what happens, scientists hope to find the trigger genes.

There is also a race underway to complete the mouse genome, which, like C. elegans, shares thousands of genes with humans and should shed light on their function.

Others teams are taking a more sweeping, high-tech approach. They use gene chips and arrays to monitor thousands of genes at once. The gene chips, some no bigger than a quarter, cost $500 to $2,000 a piece. But some teams can make them for a fraction of that cost. Each of the chips have thousands of tiny gene sequences hooked on to them.

The chips allow scientists to see which genes are turned on and off when normal cells become cancerous. Researchers can watch the genes involved as viruses cause disease and watch drugs in action.

Until recently scientists could study only one gene at a time. Now, "we can take a cell and give it a drug -- such as a steroid drug for asthma -- and see the effect on the 6,000 genes," says Thomas Hudson, a leading geneticist whose team at McGill University in Montreal uses the chips. "And all of a sudden we are starting to see the big picture, the global view of biology."

Meanwhile, as dizzying quantities of information flow out of the genome project, biologists face a pretty steep learning curve. So they are lining up for crash courses on how to use the vast new data bases.

"We getting twice as many applicants as we can accept," says Stephen Herst of the Canadian Genetic Diseases Network, which has been holding week-long "bioinformatics" workshops across the country. The students, who run the gamut from hip, young graduate students to grey-haired university department heads, pay $1,250 to spend five days (and often much of the night) poring over computer screens learning to navigate genome data bases that are doubling in size every 12 months.

Putting the human genome "in the public domain opens whole new avenues of investigation. It's a massive door opening," says Jones.