DNAprint Genomics (DNAG)

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Gene map in hand, but hard road ahead

http://www.chron.com/cs/CDA/ssistory.mpl/front/2660085

Using knowledge to combat disease years away
By ERIC BERGER
Copyright 2004 Houston Chronicle Science Writer

Geneticists trying to decipher the "Book of Life" have found it to be more like the impenetrable Ulysses than The Cat in the Hat.

Four years after finishing the much-hyped first draft of the human genome at a cost of nearly $3 billion, scientists have had difficulty translating the genetics of common ailments like diabetes and high blood pressure into medical treatments.

New medicine for the most common diseases probably remains at least a decade away.

"The promises were made too quickly," said Eric Boerwinkle, director of the Human Genetics Center at The University of Texas Health Science Center at Houston.

"Both the scientific community and funding agencies thought we would get practical results more quickly. But I remain optimistic in the long run."

The goal for Boerwinkle and other geneticists is to discover all the genes that play a role in a person's susceptibility to a particular disease. An understanding of these genes, scientists believe, will give them insight into the biological causes of illness.

It is these causes, then, that new drugs and medical interventions can target.

But first, the scientists must find and interpret the genes, and that is proving to be a tough slog.

Researchers have spent the better part of two decades looking for genes that contribute to Type 2 diabetes, a rapidly growing health problem in the United States and a precursor to heart disease.

Although geneticists believe dozens of genes are involved, they have confirmed just one, Calpain-10, in 23 years. The completion of the human genome, and better scanning technology, has helped scientists look for genes, but the work remains in its infancy.

Hunt continues for gene variations
"At the beginning there was a high expectation that this would be easier," said Craig Hanis, a genetics professor at UT-Houston.

Hanis and his colleagues sift through some 30,000 genes in the body that contain the biological blueprint for life. A gene may make blue eyes, brown hair or, like Calpain-10, be responsible for making proteins that are part of a previously unknown mechanism for causing diabetes.

Genes vary in size -- some have 3,000 links in the DNA chain, others have 2.4 million. The most basic way for scientists to connect one of them to a disease is studying a large population with a particular illness and another without the ailment.

The hope is to find genetic variations, sometimes as little as just one link in a gene, between the two groups. When they find the differences in a gene, it becomes a "candidate" gene for causing the illness.

Hanis said there are more than 1,000 candidate genes for Type 2 diabetes that scientists would like to study further. He is pursuing a $6 million grant to study 500 of the best candidates. Before he retires, the 52-year-old Hanis says, every single gene in the human genome will be scrutinized for a possible role in diabetes.

Some say strategy must tighten focus

The same hunt continues with numerous other common diseases as well, prompting some researchers at the Texas Medical Center to question whether the hundreds of millions of dollars being spent by the federal government to scour the human genome is worth the investment.

"I'm not convinced this is the answer," said Dr. Arthur Beaudet, chairman of the department of Molecular and Human Genetics at Baylor College of Medicine. "The idea that the human genome project needs to solve every medical problem in creation is not realistic."

Beaudet said that, for the time being at least, geneticists may be better off concentrating on the 6,000 diseases each caused by a single gene, such as cystic fibrosis or sickle cell anemia.

This is a problem that can be tackled, he said. Scientists also may look at diseases with strong genetic links, such as autism; a child with a sibling who has autism is about 100 more times likely to have the illness than the general population.

The problem with diabetes, hypertension, heart disease and other common ailments is untangling the genetic factors from a person's lifestyle and environment. What causes an individual's diabetes -- overeating or bad genes?

Human habits make sift more challenging

Genetics certainly isn't the only factor in many diseases.

A hundred years ago, diabetes was much less of a problem, and in the last century human genes haven't changed much. What have changed, however, are eating habits and physical activity.

Still, genetics plays a part in nearly all illnesses. High blood pressure, diabetes and heart disease all run in families, a clear indictment of genes. But some genes play a major role, some a minor role, and perhaps some only affect Hispanics or men or Asian women. Parsing out the individual components is no easy task. It requires thousands of patients, millions of dollars worth of equipment, and an understanding of computers, statistics and biology.

Some researchers argue, despite the challenges, that this is a fundamental mess that must be sorted out.

"I would say the Human Genome Project was hyped, but appropriately so," said Richard Gibbs, director of Baylor College of Medicine's Human Genome Sequencing Center, which participated in the project.

"This is all we have -- everything that programs us -- so we had better deconstruct this machinery if we want to ultimately understand how we are put together."

New field could have more immediate impact

If new medicines for most of the common diseases remain a decade away, a more immediate impact may come from a new field called pharmacogenomics, or personalized medicine.

The premise behind pharmacogenomics is that a lot of medicine is trial and error. One patient with high blood pressure may respond to one type of medication, a diuretic, but receive no benefit from another, an ACE inhibitor. Finding the right drug for the right person can cost patients and the insurance industry billions of dollars a year.

If a patient's genome can be mapped, a treatment regimen can be tailored to be compatible.

"Within the next five years there will be examples where pharmacogenomics is not really a research tool, but it enters the standard of care," said Dr. Francis Collins, director of the National Human Genome Research Institute in Bethesda, Md.

"Your doctor is going to want to know your genotype before writing a prescription."

More than 100,000 people die each year from bad reactions to medicine. With pharamacogenomics, physicians can avoid prescribing medications that could cause such reactions. It might also allow some drugs that are effective at treating disease, but lethal to a small segment of the population, back onto the market.

Genes' effect on how drugs work studied

One common ailment that doctors may soon be able to treat with pharamacogenomics is high blood pressure.

A $140 million study of more than 40,000 patients with high blood pressure based at UT-Houston concluded earlier this decade that diuretics, a cheaper, generic alternative, were just as effective, on average, as more expensive alternatives.

That led the scientists to suggest that all patients start on diuretics.

Boerwinkle and his colleagues have taken the study one step further. Within proper protocols, they collected the genotype of each study participant -- the 3 billion unique DNA letters of their genome -- to see whether the effectiveness of a particular drug in a person is because of differences in about 50 different genes.

He says the results are promising but declined to discuss them before publication in a scientific journal, expected this fall.

What Boerwinkle is less confident about is using genetics to alter patient lifestyles and eating habits.

Will gene insight make us try healthier living?

Scientists are identifying genes that increase the risk a person will develop a disease. With enough genetic information, a doctor may eventually be able to look at a patient's genetic profile and say, perhaps, that a patient has a 75 percent chance of developing heart disease by a certain age if certain behaviors, such as a high-fat diet and smoking, continue.

Yet, if AIDS doesn't lead sexually active people to use condoms, or strong evidence against smoking doesn't drive people to quit, precise genetic information seems unlikely to prod people to live healthier lives, Boerwinkle said.

"Unfortunately I'm not hopeful that genetic testing is going to prevent these kinds of problems," he said.

Better genetic insight could lead to better vigilance on the part of some patients and doctors, however. A patient with a certain gene mutation for colon cancer might receive a colonoscopy every year, instead of every few years.

Pharmacogenomics and improved prediction of disease for patients are, of course, predicated upon being able to genotype a person's DNA for a reasonable price insurance companies might pay, maybe $1,000 or less, Collins said.

That too, geneticists say, will take time.

"We have to be a little bit careful about the euphoria that surrounds genetic research," said Dr. Stephen Turner, a high blood pressure specialist at the Mayo Clinic in Rochester, Minn., who collaborates with Boerwinkle.

"I would liken this to the debate over whether we should have gone to the moon. Some argued that we had enough things to spend money on here at home. But like then, there's a spirit of discovery that is driving us with genetics. You need to realize this is a long-term effort. It's very slow, and it's incremental."

End of article

Eric Boerwinkle was mentioned above. Here are some of Eric's previous publications:

Pfaff CL, Parra EJ, Bonilla C, Hiester K, McKeigue PM, Kamboh MI, Hutchinson RG, Ferrell RE, Boerwinkle E, Shriver MD. Population structure in admixed populations: effect of admixture dynamics on the pattern of linkage disequilibrium. Am J Hum Genet. 2001 Jan;68(1):198-207. Epub 2000 Dec 07.

Shriver MD, Jin L, Boerwinkle E, Deka R, Ferrell RE, Chakraborty R. A novel measure of genetic distance for highly polymorphic tandem repeat loci. Mol Biol Evol. 1995 Sep;12(5):914-20.

Ellsworth DL, Shriver MD, Boerwinkle E. Nucleotide sequence analysis of the apolipoprotein B 3' VNTR. Hum Mol Genet. 1995 May;4(5):937-44.

Shriver MD, Jin L, Chakraborty R, Boerwinkle E. VNTR allele frequency distributions under the stepwise mutation model: a computer simulation approach. Genetics. 1993 Jul;134(3):983-93.

Shriver MD, Siest G, Boerwinkle E. Length and sequence variation in the apolipoprotein B intron 20 Alu repeat. Genomics. 1992 Oct;14(2):449-54.

Shriver MD, Boerwinkle E, Hewett-Emmett D, Hanis CL. Frequency and effects of apolipoprotein E polymorphism in Mexican-American NIDDM subjects. Diabetes. 1991 Mar;40(3):334-7.