Originally created 04/03/00

DNA research opens era



There is no sign in Amy Varnell's face, and only when she speaks in a slightly hoarse voice is there a clue she is somehow different.

Among the 100,000 genes that formed her in the womb -- and now regulate functions in her body every second of every day -- was a defect in a single gene that controls how her body handles the common chemicals sodium and chloride.

And thus Mrs. Varnell was born with cystic fibrosis, which causes thick mucus to build up in her lungs and interferes with her digestion. It is a disease that years ago would have killed her before she became an adult.

But Mrs. Varnell, 26, lives in a new era. Later this year, scientists finally will catalog all those genes in her DNA, where they have -- in fits and starts -- begun to understand how those genes make proteins and how they interact. And already she has seen the fruits of part of this new understanding: her 7-month-old daughter Malori.

Her husband, Brooks, was able to take a genetic test to see whether he also carried the gene. Finding out he was not a carrier greatly lowered the odds Malori would inherit the defect, which she didn't.

"I already feel like that has given me so much because when they isolated the gene, that allowed Brooks to be tested," Mrs. Varnell said.

Yet these past few months have also seen a storm of controversies descend upon the 1,300 biotechnology companies and hundreds of academic institutions involved in gene research, such as the Institute for Molecular Medicine and Genetics at Medical College of Georgia. A few examples:

A patient who died during an aborted gene therapy study at the University of Pennsylvania provoked calls to suspend such research until there is a greater understanding of how it works.

Private companies rushing to discover genes hidden in the code and then patent them have seen their stocks drop amid growing concern about allowing those patents.

European activists are working to ban genetically altered food from the United States and thousands of people protested against a biotechnology conference in Boston.

"Throughout history when there's been new scientific discoveries, there's been a period of adjustment for society and oftentimes people feel a little uncomfortable and that's what's happening now," said Michael Werner, bioethics counsel for the Biotechnology Industry Organization, which represents many of the companies and research centers involved in the field.

Deciphering gene work

For all the concerns about the misuse of the technology, however, there is even more optimism that the growing body of knowledge and new techniques will result in first screening, testing and eventually cures for diseases like Mrs. Varnell's.

There is both simplicity and complexity involved in how genes work in the body, said James Fick, neurosurgeon and gene therapy researcher at MCG.

Inside the nucleus of each cell is an instruction booklet for life, made up of 23 chromosomes that are woven out of interlocking strands of deoxyribonucleic acid or DNA. Each of those strands, like a long sentence, are made up of four letters: A, C, T and G, which stand for the bases they represent: adenine, cytosine, thymine and guanine.

As the two strands of DNA interlink, adenine always connects with thymine, cytosine with guanine. Scientists say there are 3 billion of these "base pairs" that make up the elaborate code of the human genome. And embedded in this code are specific segments called genes, which are instruction books to make proteins. Another chemical, messenger ribonucleic acid or mRNA, works as a template to carry the gene sequences to another area of the cell, where it is used to assemble the actual protein.

Those proteins control how cells function, how they respond or don't respond to changes in the body.

Errors in copying that code as cells divide and create new cells could be meaningless or devastating depending on where they show up. They could land in an area of the DNA that scientists believe does nothing, or they could land in a gene that does not then produce the correct protein or makes a mutated version.

"Increasingly, it's being determined that very small differences in the amounts of proteins can have very profound consequences," Dr. Fick said.

Instead of replacing an absent or defective protein with a pill or shot, the way diabetics inject insulin -- it may one day be accomplished by replacing the defective gene.

The problem is the system is extremely fine-honed, Dr. Fick said.

"Even though we provide replacement drugs, we really can't provide them in the proper amount or the proper timing required to mimic the body's normal function," he said. "If you think about this going on for hundreds of thousands of molecules at any instant, you can begin to understand how incredibly complex the minute-to-minute interplay between genes and proteins throughout the body are."

Scientist sees benefit

Some of the gene sequencing work is paying off in labs across the country, like William Dynan's at MCG. When he was a graduate student in the 1970s, there was speculation about what the sequence would look like but only slow progress in defining it because of a laborious manual process, said Dr. Dynan, chief of gene regulation at MCG.

Better understanding of DNA and RNA led to recombinant DNA, where copies of human genes can be inserted into things such as bacteria to make millions of copies available for study.

"Recombinant proteins were a big advantage and began to be really practical to the average lab in the mid- to late '80s," Dr. Dynan said.

The current explosion of genetic information can be traced to the advent of polymerase chain reaction in the late 1980s, which meant being able to copy DNA much more rapidly, making more available for analysis.

The process requires temperature changes -- hotter to first separate the strands so they can be copied, cooler so new primer pieces can be attached, then warmer to restart the copying process. It meant moving the test tubes from one tray of water at a specific temperature to another in the beginning. While he studied viruses in the lab with his wife, molecular biologist Dr. Rhea-Beth Markowitz, it meant applying the new technology by hand, Dr. Dynan said.

"We'd sit there for two to three hours with a timer, to move this stuff from one water bath to another," Dr. Dynan said. "My wife did this in the late stages of her pregnancy. Sitting at the desk was very difficult, to sit there for two to three hours."

Now, there are machines that cycle the temperature 30 times an hour and cut production down to about an hour, Dr. Dynan said. That process, combined with high-speed supercomputers, has allowed researchers at biotechnology companies and at academic and government institutions to process billions of pieces of DNA and reassemble them in the correct order, information that is then put into publicly available databases.

Dr. Dynan's lab is involved in studying the repair of broken DNA, whether from catastrophic injuries such as ionizing radiation or the natural process in the immune system, when DNA must be cut and pasted to add new antibodies against viruses or bacteria just encountered.

Discoveries will also be aided by technology such as the gene chip machine, where genes are encoded on a chip and then a sample is processed against the chip to see if the genes respond.

"You could look at 50,000 genes and see that under conditions when you're doing the repair or perhaps under conditions where part of this machine is not working right, how does the cell respond," Dr. Dynan said.

One of Dr. Dynan's students is studying a part of the repair machinery called a DNA ligase.

"In a direct fruit of the Genome Project, if you wanted to make a lot of this ligase in a test tube to study, in the old days this would have been very involved. You'd have to get a molecular clone of the protein (yourself)," Dr. Dynan said. "But in this case, the protein was a known protein sequence that was in the database. We were able to go to the Web, and for $20 order the clone off a public database of known clones."

Patenting genes troubling

It is the patenting of those protein sequences by biotechnology companies, which runs sequencing computers 24 hours a day -- and sometimes have only a rudimentary understanding of what the protein does -- that has caused much debate in the scientific community.

"Patenting the genome to me is anathema. It just makes no sense," said James Goldenring, cell biologist at MCG and staff physician at the Augusta Department of Veterans Affairs Medical Centers. "I don't know why we allow these patents to occur. Having said that, we're forced into a situation where every time we find something now, should we patent it?"

Dr. Goldenring and colleague Jeffrey Lee, a gastrointestinal pathologist, are working on a theory about how inflammation from a certain bacteria could give rise to stomach cancer. In the process of finding cells that could then go on to become the cancer, they discovered a small protein that could serve as the target for screening, a screening method they are forced to take time to patent now. The more mercenary hunt through the genome for potential genes that could turn into potential drugs could mean one company will stumble upon the answer, they said.

"Somebody is going to get lucky," Dr. Lee said. "They're going to hit the lottery."

But others, such as Dr. Fick, say the potential payoff spurring the advances may be the only way to attract the necessary investments. The high-risk research and the amount of capital needed to pull them off may be more than universities can provide on their own, Dr. Fick said.

The potential worth of those patents and not the actual value helped spur a meteoric rise this year in biotechnology stock prices, much like the other new-economy Internet companies whose values rise even as they lose money. President Clinton's call to make the raw gene sequencing information public -- which is already being done -- nonetheless spurred a selloff in some biotech companies that saw their stock price fall.

But some are not worried about continuing to invest in the companies or about them losing their patents.

"Intellectual property is one of the linchpins of the new economy," said Robert Burgoyne, technology strategist with Monument Funds Group of Bethesda, Md. " I don't see it being reversed because it's really one of the U.S.'s key assets."

It also means betting on the trend for health care spending to increase and for more of it to go to the new and more effective methods, Mr. Burgoyne said.

"As investors, we make judgment based on probabilities and that's a pretty good probability," Mr. Burgoyne said.

Success will ultimately help allay other fears as the technology proves itself, said Mr. Werner of the Biotechnology Industry Organization.

"In five years, I think people will be saying, `I can't believe we were so concerned about X,"' Mr. Werner said.

Still waiting for a cure

It is the wait for the technology to prove itself that has caused some concern. Mrs. Varnell was in ninth grade when doctors isolated the gene causing her disease.

"We were very excited," she said. "We all thought, `OK, the cure. The cure, the cure, the cure.' When I realized the cure wasn't coming right away, I didn't think about it until Brooks was tested."

There is still her hope that she will live long enough to see that cure, though it will not likely reverse the damage already done to her body. Yet she can see what the gene work has already done for her life in the chubby face of her daughter.

"Everybody says life is a gift, and I never really thought that until I had her," Mrs. Varnell said, watching Malori try to chew through a rubber ring toy. "I feel like I'm leaving something behind."

Reach Tom Corwin at (706) 823-3213.