Genetic code checks might yield new clues about disease, treatments

By Sue Goetinck Ambrose / The Dallas Morning News Wanted: the code that makes people tick. Wait, make that ... Wanted: the code that makes people sick. Spelling matters.

Monday, October 23rd 2000, 12:00 am

By: News On 6

By Sue Goetinck Ambrose / The Dallas Morning News

Wanted: the code that makes people tick.

Wait, make that ...

Wanted: the code that makes people sick.

Spelling matters. A letter can change the meaning of a sentence. And a few letters â€“ in the genetic code â€“ can mean the difference between ticking like clockwork or suffering from disease.

Scientists are in the midst of a spell-check of the human race, hunting down millions of letters of human genetic code that vary from person to person. The letters, known among researchers as SNPs, make some eyes blue or others brown, some hair curly and other hair straight.

Even more important, these genetic blips affect human health. Inherit a certain combination of SNPs (pronounced "snips") and you're more or less likely to develop many common conditions affecting Americans today: asthma, diabetes, high blood pressure or heart disease. And if you do have one of those ailments, other SNPs influence how well the medicines you take will work.

Scientists all over the world are cataloging SNPs to help identify which of the body's thousands of genes are involved in disease. And because all the SNPs that people carry are a legacy of the generations that came before, scientists can also use the genetic fragments to reconstruct the history of humanity.

Scientists hope that by connecting SNPs with diseases and treatments, medical care can become more precise and personalized. But SNPs' potential to transform medicine hasn't been tested. And researchers still don't have cheap and efficient enough tools to learn all the secrets that SNPs conceal.

"I think that the basic research that's being done will be incredibly useful for ultimately changing the practice of medicine," said Jeanette McCarthy, of Millennium Pharmaceuticals Inc. in Cambridge, Mass. "However, I don't think that it's going to happen tomorrow. A lot of work still needs to happen."

SNP is short for single nucleotide polymorphism, geneticists' way of describing the smallest possible change in the genetic code. The code is constructed of DNA, a long molecule made of chemical links called nucleotides. (These nucleotides come in four varieties, abbreviated A, T, C and G.) "Polymorphism" means that a link can come in more than one variety. So a single nucleotide polymorphism is a single link in the chain that can vary from person to person.

Scientists estimate that the human genetic code contains 3 billion links. For the most part, these links are the same in any two people. But at one spot every 1,000 or so links along the chain, there is a SNP. One person may have an A, another a T. These SNPs give everyone (except identical twins) a unique genetic code.

Some SNPs matter more than others. Certain SNPs fall inside genes, crucial segments of the genetic code that endow people with physical characteristics. SNPs in genes that affect how the body processes cholesterol, for instance, could make one person's cholesterol soar, and another's stay enviably low.

Other SNPs, however, fall outside of genes, in portions of the code that scientists generally regard as unessential. These SNPs don't affect health directly, but they can signal the presence of SNPs that do contribute to disease. So, either type of SNP can give scientists a more thorough description of a disease.

"If we understood the diseases better, we'd be in a better position to target therapies," said David Altshuler, a geneticist at the Whitehead Institute for Biomedical Research in Cambridge, Mass.

Traditionally, scientists have looked for disease-causing genes by studying large families afflicted with a certain condition. But given enough SNPs, researchers hope they won't have to rely on finding just the right family to study.Theoretically, researchers could simply compare the SNPs of unrelated people with high blood pressure, for instance, to those of people without the condition.

But researchers don't have proof yet that the new approach will work, said Eric Boerwinkle, a geneticist at the University of Texas Health Science Center in Houston.

"I think there's some skepticism," he said. "I don't know of an example where that's been carried out."

Being able to use unrelated people, rather than families, for genetic studies should also help scientists figure out how genes affect the way medications work. Testing the same drug on many family members is impractical, because not everyone in a family has the same illnesses at the same time, Dr. McCarthy said. Comparing genes from people who respond well to a drug with genes from people who don't is more feasible.

Still, scientists don't know how much genetics governs a patient's response to drugs. Nutrition, dose and timing of medications, among other factors, can all make a difference.

"I don't think we can generalize at this point," Dr. McCarthy said. "The reality is we may not be successful in every situation and for every drug therapy."

But researchers have uncovered a few drug-SNP connections. For example, an experimental anti-asthma drug worked better in people with a particular set of SNPs in a gene that affects inflammation in the airways.

As scientists use SNPs to pinpoint disease-causing genes, or genes that affect how well medications work, brand new genes will turn up, too, the Whitehead's Dr. Altshuler said.

The growing catalog of SNPs, scattered throughout the vast human genetic blueprint, allows researchers to focus on genes that haven't been studied yet, but may be the key to understanding certain diseases. Humans have between 30,000 and 100,000 genes, but most aren't understood.

"Only a thousand or so genes have been well-studied by biologists to date," Dr. Altshuler said. "We need an approach that is not focused on what we know. Because we know very little."

And having a catalog of SNPs freely available should make it more practical for researchers to embark on gene-finding journeys. Previously, Dr. Altshuler said, scientists had to find their own SNPs, or equivalent genetic tools.

"The amount of work it would take ... was so overwhelming that no one could ever do it," he said.

But having SNPs readily available may not be enough, said Dr. Peter Oefner, a geneticist at Stanford University in California. Scientists are planning to use SNPs to tackle very complicated diseases, he said. Diabetes, heart disease, high blood pressure and asthma, for instance, often develop when a particular combination of genes clashes with a particular lifestyle.

If there are a lot of genes each contributing just a little to a disease, it makes those genes very hard to find, Dr. Oefner said.

Even finding these types of genes in simple organisms is difficult. Dr. Oefner has tried to find genes that let a simple yeast withstand high temperatures. But although it's far easier to track yeast genes than human genes, Dr. Oefner and his colleagues have struggled.

"We could only identify one gene so far," he said. "Even there, we have tremendous difficulty really proving it."

Another challenge in finding disease genes is that many disease symptoms are hard to measure precisely.

Take blood pressure, Dr. Oefner said. Blood pressure varies from day to day, and even within a given day. If a gene affects blood pressure by only a few points, tracking the gene with SNPs may be impossible.

To take full advantage of SNPs, scientists may have to come up with better ways of measuring the ups and downs of the human body.

Still, the work with SNPs is a sign of great progress in genetics, Dr. Oefner said. But, he added, "it needs to be matched by great progress in physiology and biology."

Dr. Boerwinkle said connecting SNPs to disease might be more successful if scientists can develop different ways to gauge the severity of disease. In the case of high blood pressure, for instance, measuring compounds produced by the kidney â€“ the organ that controls blood pressure â€“ may be a better strategy than measuring blood pressure directly. It might be easier, he said, to connect SNPs directly to the kidney compounds than to the blood pressure.

Understanding how SNPs contribute to disease should help scientists solve another mystery about human life â€“ how the human genetic code arrived at its present state, Dr. Boerwinkle said. A recent study of his, for example, has found that SNPs that protect against Alzheimer's disease and heart disease have been steadily replacing harmful SNPs in the last 200,000 years.

No one knows why that should be, he said. It's tempting to think that the harmful SNPs are disappearing because they cause disease. But heart disease and Alzheimer's strike late in life, long past the probable life span of human ancestors. So the harmful SNPs probably didn't contribute to disease until recently, when people started to live longer.

Scientists will probably face many puzzles like this one, Dr. Boerwinkle said, in trying to reconstruct the forces that shaped people's genetic blueprints.

"We're all fascinated in how we got to be who we are today," he said.