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CRAIG VENTER: AT THE HELM OF THE GENETIC REVOLUTION.

In the galaxy of genetic discovery, Dr. Craig Venter is a bright star whose pioneering spirit has set the pace in the race to reveal mankind's genetic makeup.

As we enter a new millennium, a revolution in science and medicine is taking place. We are on the doorstep to the future of biology and medicine. And genetics holds the key. Today, leading geneticists from around the world are scrambling to decode the entire human genome--the blueprint for humanity. In the process, scientists are writing the first chapter in a new human understanding of the process of life.

In the final laps of the race to reveal humanity's genetic blueprint, the iconoclastic gene hunter Dr. Craig Venter remains firmly in the lead.

Dr. Venter has been challenging the scientific establishment and rattling the world of molecular science since the early 1990s. While Venter's candor may not endear him to his contemporaries, they cannot argue with his unparalleled achievements.

Dr. Venter is an unlikely success story in the hallowed halls of science. After graduating from high school, he pursued the life of a beach bum, surfing and sailing until drafted into the Navy and sent to Vietnam. At 21, Venter was stationed at the Naval Hospital in Danang, Vietnam. Tending to the critically wounded, he learned a lesson that shaped his future outlook--life is short and every day counts. Returning from Vietnam, Venter enrolled in medical school to become a doctor and work in Third World hospitals. But after finishing his coursework, he realized that his passion lay in medical research.

The young scientist joined the National Institutes of Health in 1984, working on gene expression in the central nervous system. But during the early days of the molecular revolution, discovering genes was a painstaking process, typically taking researchers years to locate and decode a single gene.

Enter computer technology. While reading the journal Nature, Dr. Venter learned about a new machine that could decode genes rapidly and automatically. He met with the machine's creator, later introducing the first automatic gene sequencer, or decoder, to the NIH in 1986. But when he couldn't get the necessary funding for his project, Dr. Venter left the NIH to join the private sector in 1992, founding The Institute for Genomic Research (TIGR) to continue his ambitious study.

Armed with even faster equipment, Dr. Venter completed gene maps with unprecedented speed. Using a rapid method of decoding gene sequences at TIGR, Dr. Venter and fellow scientists discovered and published one half of all the human genes that have been sequenced. Later, Dr. Venter left TIGR to form Celera in a joint partnership with biotechnology firm Perkins-Elmer.

One of the most cited biologists in the world, Dr. Venter has set the pace for human genome sequencing. The Post spoke with him in his office in Rockville, Maryland.

Q: Much is written about genetics and the genome project, but its implications are hard to grasp. Recently, for example, you announced the completion of the genetic makeup of the fruit fly, or drosophila. Why is this accomplishment considered important ?

A: We are genetically closely related to fruit flies. Basically, every human disease gene that has been characterized has a counterpart in fruit flies. The fruit fly is also the first organism that has been completely genetically mapped with a central nervous system. Mapping this DNA sequence opens the door to a better understanding of the human genome.

Q: The media have depicted the challenge to sequence the human genome, for good or for bad, as a race between private enterprise and government-funded projects. Your challenge certainly stepped up the process at the government and private levels. Is your prediction that you will have assembled the entire human genome by 2001 still on target?

A: It's at least on target and possibly ahead of that target.

Q: On Labor Day 1999, Celera announced that it was switching its focus onto the human genome. How far have you progressed?

A: We are close to having 50 percent of the human genome already done and in our databases. By the end of December, we expect to have completed 70 percent. Even though we just recently started, we get most of the information early in the process, using the whole genome "shotgun" method that we developed at TIGR. Information collected at the end of the process is more a guarantee that we have the genome completed and in the proper order.

Q: How can one picture the complexity and magnitude of this project?

A: If we decoded your genome--the sequence of the DNA in your chromosomes--and you could read one letter of the genetic code per second, it would take you over 100 years to read your own genetic code.

Q: What tools are you using to help accomplish that daunting task?

A: We are building one of the largest supercomputers in history here. The computing power is massive.

Q: Can you offer us a simple analogy to help people understand how Celera is deciphering the human genome ?

A: It's like solving a jigsaw puzzle. Existing technology only allows us to get about 600 letters of genetic code at a time. So our strategy has focused on how you construct a sentence that is 3.5 billion letters long when you can only get 600 letters at a time.

We do that by breaking the chromosomes down into little pieces of 600 letters, performing that process over and over again about 60 million times. Over time, we will actually sequence the human genome 10 times. And we get the overlaps between the pieces to help build back a mosaic of what the original chromosome was. That is what the massive computing is here for.

Q: What are the medical and scientific benefits of deciphering the human genetic map?

A: Fundamentally, there is going to be a very, very dramatic change in the way research goes on around the world. Presently, researchers only look at one gene at a time, and only about 5 percent of the human genes have been well studied. Cancer, for example, involves the complex interactions of tens of thousands of genes working together. The only hope we have to understand what really goes on in cancer is to understand the integration of all this genetic information.

Deciphering the human genome will be catalytic in moving forward what scientists are able to do in research. Over time--not in six months but over years and decades--this information will change everything that we know about medicine and will impact everybody's life.

The future of medicine will change. For example, if we determine your genetic code, you will know whether you will have an increased chance of developing cancer in life. So instead of treating a disease after it already develops, we will be able to use this information to develop successful strategies for preventive medicine.

Q: Aren't we using genetic discoveries already in colon cancer screening of high-risk families, breast cancer, and sickle cell disease?

A: But we have only known a piece of the puzzle. Our research will provide the understanding of where those genetic diseases fit into the broader scheme of biology. We have a good idea of some of the genes that are involved in those diseases, but that is very different than understanding how to do something about it. All diseases have a genetic origin--whether it's cancer, heart disease, or schizophrenia--so we are going to have the basis to try and understand all of these diseases.

Q: Your project, then, is really just a first step?

A: It is not even the first step. To us, mapping the human genome is the absolute beginning. That is why we are trying to do it so quickly, because we can't go forward without that information.

Q: Many times people read stories about genetic discoveries, and there is a general feeling that a cure won't be far behind.

A: Discoveries are presented that way because well before Celera started its project, there has been a multibillion-dollar project launched to get the sequence. Unfortunately, many have raised expectations that cures are right around the comer, when in fact they are not. If you had a 15-year, $3 billion project, you would start to look at every phase as the all-important key step when, in fact, it's not.

Q: Can you foresee a time when treatment, drugs, and preventive measures will be tailored to an individual?

A: That is exactly what we predict. The chromosomes that you inherited from your mother differ from the ones received from your father in about three million letters of the genetic code, or about one every thousand letters. The difference, then, between you and me is roughly three million letters. Those minor spelling differences, however, have much to do with why you look, act, and sound different than I do. As we begin to understand each person's individual genetic code, we will be able to tailor drugs for him or her. You will get drugs that are compatible with your genetic system, where that same drug might be toxic to someone else. Existing drugs only work, on an average, in 30 to 60 percent of the population; the rest either don't work or cause problems for people. In the future, we will be able to tell the difference between the ones that are compatible with your system versus ones that aren't.

That is why we are trying to build the paradigm for individualized medicine. In the future, I predict that everybody wanting to understand their genetic differences, whether determined by us or somebody else, will log on to our computer Web site to understand the spelling differences in their genetic code and what it means for their lives.

Q: You are working with Hamilton Smith, M.D., a Nobel Prize winner. What is he bringing to the project?

A: Dr. Smith worked with me to do the first genome in history in 1995--the Hemophilus influenzae. He was then at Johns Hopkins University. We did that work at TIGR. When I announced that I wanted to sequence the human genome, he was the first volunteer. He wanted to come over and help me. Hamilton Smith does the very first step in the process where we take the chromosomal DNA, and we break it down into millions of tiny pieces. It is a real art form, and Dr. Smith is the person who does this with his own hands.

Q: Will this information gathered from you and others serve as a collaborative database?

A: Our database will work like The Saturday Evening Post does. You wouldn't say that because the Post is by subscription, it is a secret set of information. I could go out and buy The Saturday Evening Post. Our database subscription will be available to all researchers around the world.

GENOMICS 101

In nearly every cell of every living organism, there exists a complete set of instructions for creating that organism and regulating its cellular structures and activities over its lifetime. That set of instructions is called a genome.

A genome is organized into distinct, microscopic units called chromosomes. Chromosomes are coiled threads of deoxyribonucleic acid--DNA--that is composed of two long chains of nucleotides bound together in pairs to form a double helix. Three and a half billion of these nucleotide pairs make up the human genome.

Specific sequences of nucleotide bases within a DNA strand--called genes--are the cells' instructions for producing proteins. Scientists estimate that 80,000 to 100,000 of these basic units of heredity exist within the human genome. Proteins perform a wide variety of physiological tasks. They facilitate processes such as digestion, breathing, immune responses, the production of heat and energy, and the movement of fluids in and out of cells.

While most members of a species have the same collection of genes, each individual's unique characteristics stem from slight variations--called polymorphisms--in the sequence of nucleotides that comprise the genes of that individual. On average, the DNA of any two individuals will differ by about 0.1 percent.

Other types of variations--called mutations--also occur. Both polymorphic and mutagenic variations may be harmful to an individual by inhibiting the production, or altering the normal function, of a protein. Most diseases result from these types of genetic variations.

The goal of genomic inquiry is to identify the sequence of nucleotides, understand the function of every gene they comprise, and clarify the genetic variations that define individuality and create disease. --www.celera.com
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Author:Perry, Patrick
Publication:Saturday Evening Post
Article Type:Interview
Geographic Code:1USA
Date:Jan 1, 2000
Words:2078
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