MAPPING THE GENOME: One year later

Published on February 17, 2002 - The Star Tribune, Minneapolis, MN

By Sharon Schmickle; Staff Writer

The celebrated publishing of the human genome sequence last February was no surprise at Bill Pederson's home in Eden Prairie. Like millions of other Americans, the Pedersons keep track of genetic research because they have a life-or-death stake in it.

Lupus killed two of Pederson's sisters, and now it's attacking him. No one knows why the disease hits, but genes are a factor. University of Minnesota scientists are using genomic tools to study Pederson, 53, and others to identify the culprit genes and learn how they work.

A year after scientists got access to the genome sequence, nothing so dramatic as a cure for a major disease is within reach. Breakthroughs of that magnitude weren't expected at this point. Still, scientists are exhilarated about the power the genome has given them to push into new frontiers on cancer, heart disease and other disorders.

"Every day is an adventure because you have so many genes to play around with," said Dr. Ashley Haase, who directs the university's Biomedical Genomics Center.

Graduate students are publishing results of genomic experiments that their professors couldn't have done even a couple of years ago.

"I don't like to sound cheesy, but this is a revolution," said Lisa Herron, a Ph.D. student at the university who is decoding the genome of a bacterium that infects hospital patients and cows.

Scientists are studying many of the tiny invaders that make people and animals sick. These microbes represent "the lowest hanging fruit in the genomics field," said Vivek Kapur, who co-directs the Genomics Center. Their genomes are relatively simple, and the goal is to learn how the microbes can be blocked from infecting people, he said.

Another rapid advance for the overall research is in diagnosing diseases, Haase said. In cancer, for example, genomic studies are making it possible to classify and diagnose tumors more accurately and thus target treatment more effectively.

"It hasn't reached clinical practice yet, but you can imagine it getting there reasonably soon," Haase said.

Also coming soon to the neighborhood clinic are prescriptions that are tailored to a person's genetic profile rather than the one-size-fits-all drugs that haven't worked for some patients.

`U' in gene race

Minnesota was not a real player in the genome project. Now, however, the state is jumping into the race against other research institutions to make use of the sequence for medicine and agriculture.

At the University of Minnesota, two new buildings dedicated to genomic research and related studies are expected to open within a year. More than 100 new scientists have been recruited. The Mayo Clinic in Rochester also is vying to play a prominent role.

At least a dozen Minnesota companies are trying to develop therapies and drug ingredients using genes and related proteins. For example, HTS Biosystems, based in Minneapolis, is making tools to help companies mine proteins for new drugs and diagnostic tests, said Doug Astry, vice president of marketing and business development.

The state Legislature pitched in to the overall effort last year by appropriating $10 million for the Biomedical Innovation and Commercialization Initiative, which seeks to help companies translate biotech discoveries into products.

Lupus studies

The lupus studies illustrate how researchers are investigating diseases.

In a refrigerator at the University of Minnesota, Pederson's DNA is stored in tiny wells on a laboratory tray. In all, researchers have obtained samples from 1,750 people for studies supported by the National Institutes of Health and the Lupus Foundation of Minnesota.

An initial goal for the research is to compare DNA from people with and without lupus in order to spot differences that could identify genes associated with the disease. For starters, that information could help improve diagnosis.

To understand why lupus patients pray for better diagnostic tools, consider Pederson's struggle to explain the problems that began in November 1996 with fatigue.

In January 1997, he was found to have double pneumonia and infectious mononucleosis. In February, doctors said his blood chemistry was out of whack. In June, his spleen was removed, and in August a blood clot almost stopped his heart.

All of this was mind-boggling to a busy electrical engineer who hadn't been hospitalized since birth. Life had been rich and full for Bill and Elaine Pederson, who reared three children while running a family business and hauling a mint-condition 1957 MG to auto shows.

The next crisis came in December 1997. He was in an airport in Denver trying to get home for Christmas when he started "feeling terrible and sweating like crazy." He made it to Minneapolis. But the next morning, he collapsed in the living room.

"He said, `I love you and the kids,' and then he stopped breathing," Elaine Pederson recalled.

It was another blood clot, but he survived.

It took two more frustrating years before doctors could definitely say his problems were caused by systemic lupus erythematosus. His immune system was attacking his body's connective tissue. The damage can occur in kidneys, heart, blood vessels or elsewhere. Because the disease takes many forms, it is tricky to diagnose. Thus, most patients struggle for years with no clear explanation or effective treatment.

"This disease is a huge puzzle," Pederson said.

Complicating his diagnosis was the fact that lupus typically strikes young women. Even though two of his sisters had died from it years earlier, doctors didn't expect him to get it.

Pederson believes that one of his sisters could have survived if her lupus been diagnosed earlier. So, he insists that doctors monitor his children for early signs of the disease. His greatest hope is that genome studies will produce results in time to help them.

Book of life

The microscopic genome that gives so much hope often is called the book of life because it holds instructions that every cell in the human body needs to communicate with other cells, produce proteins and perform other functions. The instructions are encoded in sequences of DNA's four chemical bases, usually denoted by the letters A, C, T and G.

The hoopla last February came because scientists had spelled out the exact order of most the 3.2 billion characters of the genome. The job won't be finished until 2003 because researchers still are filling gaps and checking for errors.

Meanwhile, the bulk of the sequence is available to other researchers. As with lupus, a leading goal for medical research is to locate genes that influence diseases. The genome project advanced that effort by several years, said Dr. Timothy Behrens, who directs the lupus study.

To grasp the significance of the change, think of the genome as if it were the United States as seen from a satellite, he said. It was largely an abstraction with few visible landmarks to show where and how to find a gene.

"We were doing the Lewis and Clark thing, and it was extremely time-consuming," he said.

Now, he said, the genome provides a road map on which scientists are filling in the genetic equivalent of county lines, towns and major landmarks. Much work remains to be done, Behrens said.

Sophisticated laboratory equipment and computer technology developed for the genome project is being used to further the research. Robots manipulate tiny drops of DNA, lending efficiency and accuracy to the work.

In the lupus study, researchers are closing in on six genome regions. Behrens predicts that some lupus genes will be identified in three to five years.

Another goal is to understand how the disease advances. With Pederson, for example, exposure to the sun triggers lupus flareups. Researchers have asked him to donate more DNA when that happens because they want to study what's going on inside his cells.

"We already are seeing certain inflammatory pathways that are turned on in lupus patients but not in other people," Behrens said.

If drugs could be developed to block such pathways, that would be welcome news for Pederson. He is holding his own with current drugs.

More remote, Behrens said, is the day when gene therapy might fix defective DNA, curing lupus and other diseases.

Another long-term goal is to search for genes that might explain whole groups of diseases. Lupus is one of several autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, juvenile (Type 1) diabetes and others. The university team is recruiting families with a history of at least two of those disorders for genetic studies to be done in collaboration with research groups in California and New York.

An ultimate goal for genomic research is to understand the nature of disease and to unlock mysteries of what happens in cells when the body responds, said Haase, who studies genes related to AIDS.

"You start to see whole patterns of things," he said. "Then you start to write about this, and it's a story that you've never done before. . . . It isn't a single story because it has serialized chapters. It's more like writing a novel or a symphony."

The big breakthrough stories, such as a basic understanding of cancer, won't be written for five years or more, he said, but some important chapters could come earlier.

"How soon that's actually going to happen is difficult to say," he added. "Maybe you'll get the data and all of a sudden you'll have great ideas. Or maybe you'll get the data and you'll sit there scratching your head for a while."