Sunday, August 1, 2004

Lung cancer findings cap arduous hunt


UC medical detective's path to success took surprising turns

By Tim Bonfield
Enquirer staff writer

Dr. Marshall Anderson grew up in tobacco country. He even picked tobacco as a boy.

But even though he lived with the causes and casualties of lung cancer - America's leading cancer killer - all around him, his interest in the battle has never been personal.

He never smoked. No close relative of his died of the disease.

Instead, the man who led a national coalition of medical centers in a landmark hunt for a genetic link to lung cancer says his interest in the subject was much more akin to the challenge and satisfaction of solving a massively complex puzzle.

"A lot of people said it couldn't be done. But one thing we surely showed is that these families do exist," Anderson says.

Last week, the Genetic Epidemiology of Lung Cancer Consortium, which was headed by Anderson, published a major lung cancer study.

By analyzing blood and tissue samples from families that had as many as eight cases of lung cancer, the group reported that such families share a probable genetic trait that makes them much more likely to develop the disease.

In fact, the group pinned down the location of the probable genetic trait to a narrow region of about 50 genes along chromosome 6, one of 22 chromosome pairs in the human body.

No one has come so close to proving a genetic link to lung cancer.

Not only did the study offer hope of better treatments in years to come for millions of people affected by lung cancer, it was a moment in the sun for the University of Cincinnati Medical Center, which has steadily increased its medical research capabilities.

And it could be the pinnacle career achievement for Anderson, a 65-year-old professor of environmental health who actually started out as a math professor in the mid-1960s.

Marshall Anderson has a strong Southern drawl that traces to his birth in Lynchburg, Va., and spending most of his career in North Carolina. He has a kindly professor habit of ending every other sentence he speaks with "Right?" or "OK?"

His casual nature, colleagues say, belies an exceedingly sharp mind.

Anderson has contributed to more than 120 scientific publications and has traveled as far as China to give talks about genetic science.

"To be effective, a scientist must have good instincts,'' says Dr. Ranjan Deka, a fellow genetics expert at UC. "Marshall is one person with very, very strong instincts. He can catch things right away."

Anderson, however, didn't start out with any deep interest in lung cancer. He isn't a medical doctor.

He started out with degrees in math and chemistry in 1961 from Emory and Henry College in Emory, Va. He went on to earn a doctorate in mathematics from the University of Tennessee in 1966.

Even then, he wasn't planning a career in medicine. After a brief stint as an assistant math professor, he worked for two years in communications technology at Bell Telephone Laboratories.

Then Anderson became interested in the emerging concept of biomathematics, or applying advanced statistical methods to understanding how the body works.

He took post-doctorate training in the field at North Carolina State. Ever since, his days of number crunching were tied to the fast-growing field of health science.

In 1971, Anderson was among the scientists who got in on the ground floor of a new federal agency called the National Institute of Environmental Health Sciences, located in North Carolina's now-famous Research Triangle Park.

He spent 22 years there, rising to chief of the agency's Laboratory of Molecular Sciences. He spent years there studying how mice, rats and rabbits were affected at the genetic level by exposure to cancer-causing agents, including tobacco smoke.

To Anderson, and many others, lung cancer offers a model for studying how an environmental factor (smoking) can affect the most basic genetic functions of the body.

Understanding this interplay between the environment and the body has the potential of opening doors far beyond lung cancer, Anderson says.

From mice to people

It was only after becoming the director of research in 1993 at the Cancer Research Institute at St. Mary's Hospital in Grand Junction, Colo., that Anderson shifted his focus more directly on people with lung cancer.

At about that time, he also started collaborating with Dr. Joan Bailey-Wilson, then a professor at Louisiana State University, who also was interested in the genetic roots of lung cancer.

For years, scientists have searched to explain why some smokers never get lung cancer while others who get lung cancer never smoked. So the two researchers launched an effort to find families with multiple cases of lung cancer.

The project seemed feasible because so many technical advances had led to the Human Genome Project, which mapped out the entire genetic blueprint of the human body.

In recent years, that project has inspired many medical centers to pump hundreds of millions into improving their ability to collect, process and analyze DNA in hopes of finding new ways to cure disease.

So even though the idea of a genetic link to lung cancer dates at least to 1955, only recently had it become possible to find such a link.

The project might have started earlier, Anderson says. But it was sidetracked briefly when Bailey-Wilson moved to the National Human Genome Research Institute and Anderson was named director of UC's Department of Environmental Health in 1996.

After resettling, they had to try twice to win funding from the National Cancer Institute for the project. They got the money - a five-year, $5.9 million grant - on the second try in 1999, after Anderson recruited a dozen medical centers to join the consortium.

Politically, the team approach was vital to winning the grant. But practically, it was necessary, Anderson says.

Finding 52 families to study turned out to be a needle-in-a-haystack hunt that started with more than 26,000 lung cancer patients referred to the project.

Much of that detective work was coordinated by Dr. Susan Penney, a UC epidemiologist who also is known for her work in studies of breast cancer and cancer risk for people who lived and worked near the former Fernald uranium processing plant in northwest Hamilton County.

Doing the complex analysis required the work of powerful computers and top experts at several well-known medical centers, including the Mayo Clinic in Minnesota and the MD Anderson Cancer Center in Texas.

"There was no way the University of Cincinnati or any other single medical center could have done it all. This took a whole bunch of people working together," Anderson says.

In fact, experts from the National Cancer Institute and other centers questioned whether it could ever be possible to sift out an inherited genetic link to lung cancer from the many direct ways that genetic damage was known to be caused by cigarette smoke.

Many more experts questioned whether such a quest would be worth the bother because the leading cause of lung cancer - smoking - was already well-established.

Advocates ranging from the American Cancer Society to community doctors have said repeatedly that money spent hunting for a genetic link to lung cancer would be better spent on anti-smoking programs.

Experts also questioned whether it would be technically feasible to obtain high-quality DNA from tissue samples of deceased lung cancer patients that had been encased in paraffin for years.

But work performed primarily at UC proved that adequate DNA information could be obtained. In fact, some techniques were invented for this study and will become subjects of other scientific papers, Anderson says.

Unfinished work

Anderson acknowledges that the genetic findings likely will have far-reaching influence on how people are tested and treated for lung cancer. But he remains uncomfortable talking about how the project was done - in large part because the job isn't done.

Researchers are confident - but not certain - that the actual lung cancer gene is hiding somewhere in those 50 genes discussed in last week's paper. But there's plenty of work to do because the target segment of chromosome 6 that includes those genes has about 20 million base pairs of DNA yet to be analyzed.

So even though others have given high praise to his work, Anderson isn't patting himself on the back just yet.

"I think we should wait until we find the gene for that," he says.

E-mail tbonfield@enquirer.com


Marshall Anderson file

Title: Professor, department of genome science, University of Cincinnati Genome Research Institute.

Age: 65.

Born: Lynchburg, Va.

Residence: Campbell County, near Cold Spring.

Family: Married to Elena. Has two grown children: Dr. Andy Anderson and Melissa Cooper, a speech pathologist; and a 10-year-old step-daughter, Maria.

Education: Doctorate in mathematics at the University of Tennessee and a fellowship in biomathematics at North Carolina State University

Career highlights: Has written or co-authored more than 120 scientific papers. Worked 22 years at the National Institute of Environmental Health Sciences in Research Triangle Park, N.C.; moved to St. Mary's Hospital Cancer Research Institute in Grand Junction, Colo., in 1993; moved to Cincinnati in 1996 to become director of UC's Department of Environmental Health. Became a professor at the genome institute this year.


Major milestones in genetics

The National Human Genome Research Institute is based at the National Institutes of Health in Bethesda, Md. Research, however, has been conducted at numerous universities throughout the United States, Europe and Asia.

With the completion of the Human Genome Project in 2003, scientists now have the ability to read nature's complete genetic blueprint for building a human being.

Humans have about 30,000 genes.

As scientists learn to read the instructions in our genes, they are discovering that much of our DNA is riddled with errors. Fortunately, most of these errors are harmless.

Problems arise only when an error in DNA alters a message that tells certain cells to manufacture a particular protein.

To date, scientists have identified gene mutations linked to some two dozen disorders, including cystic fibrosis, Tay Sachs disease, colon cancer, breast cancer, Lou Gehrig's disease, Huntington's disease, thyroid cancer and prostate cancer.

Following are major genetics milestones:

1984: The DNA fingerprinting technique is developed.

1989: The gene responsible for cystic fibrosis is discovered.

1990: The Human Genome Project, an international effort to map all of the genes in the human body, is launched.

1990: Mary Claire King, epidemiologist at the University of California-Berkeley, reports the discovery of a gene linked to 5 percent to 10 percent of breast cancer cases. The cancer is the result of a mutation to a gene on the long arm of chromosome 17, the BRCA1 (Breast Cancer 1) gene. BRCA2, a first cousin to BRCA1, is found on chromosome 13.

1994: The BRCA1 gene, previously implicated in the development of rare familial forms of breast cancer, also appears to play a role in much more common types of non-inherited breast cancers.

1996: The gene associated with Parkinson's disease is discovered.

1996: Researchers identify the location of the first major gene that predisposes men to prostate cancer.

2000: The Human Genome Project announces a major milestone: It has assembled 90 percent of the sequence of the human genome, the genetic blueprint for a human being.

2000: Scientists discover a genetic "signature" that may help explain how malignant melanoma - a deadly form of skin cancer - can spread to other parts of the body.

2002: Scientists find a gene on chromosome 1 associated with an inherited form of prostate cancer in some families.

2002: The National Human Genome Research Institute launches the International HapMap Project, a new venture aimed at speeding the discovery of genes related to common illnesses such as asthma, cancer, diabetes and heart disease.

2003: The federal government announces that 99 percent of the genome map is complete.

2004: Researchers at the University of Cincinnati identify a region of genes that can sharply increase a person's risk of developing lung cancer - America's No. 1 cancer killer.

Source: Chemical Heritage Foundation, National Cancer Institute, National Human Genome Research Institute.




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