June 26, 2000 -- It's been called the body's instruction booklet, the human blueprint, the book of life -- and its mapping has been called the biggest scientific leap since Neil Armstrong skipped on the lunar surface more than 30 years ago. The rough draft of the human genome, all the 3 billion or so chemical letters in the human body's DNA, is complete, thanks to the contributions of researchers around the world.
Vice-President Al Gore recently proposed doubling cancer research funding to $2.5 billion over the next five years. By then, he says, genetic blood tests, based on the Human Genome Project, should be available to detect nearly all cancers in their early, treatable stages.
Expectations are high. But how might the project eventually affect your family's health? Researchers agree that labeling each of the human DNA molecules is one thing; putting that information to work in fighting diseases is another.
For the big picture, WebMD went to W. French Anderson, MD, director of Gene Therapy Laboratories at the University of Southern California Keck School of Medicine. Anderson, who headed the first approved clinical trials of human gene therapy, has been called "the father of gene therapy."
Over the next 10 years, Anderson says, we can expect to see profound changes in our understanding of the human body. "Over time, as investigators all over the world work out how specific genes are involved in normal human metabolic pathways, and then in abnormal pathways, that information will revolutionize ... our understanding of how the body works."
Virtually everything in the human body is regulated by genes, says Anderson. While environment plays a role in whether we get sick, "the basis for the defense mechanisms in our bodies depends on our genes. So as we learn how our body functions, what our defenses are, what makes them strong or weak -- all that information can be used to provide better health, both in the sense of treating disease [and also] just in how to live more healthy lives."
Think of your body as a car, says Anderson. "If you have a car and all you know how to do is drive it, you can't do anything much more than drive. But when you understand the engineering principles behind it, you can make it go faster, like a race car at 200 mph or a rocket car at 600 mph."
But for now, only researchers will be able to make use of the Human Genome Project data, says David Altshuler, MD, PhD, a research scientist at the Whitehead Institute Massachusetts Institute of Technology Center for Genome Research in Cambridge, Mass.
"There are two phases to doing this kind of work," Altshuler tells WebMD. "The first is to identify which of the vast number of these differences in DNA sequence are relevant to given diseases. Then there's the whole clinical side: So you've found that there's some inherited gene difference. Now how do you make that relevant to the patient?"
That, researchers agree, will take a while. Genetic tests to diagnose various diseases may appear quickly, but most treatments are likely five to 10 years off.
"Biology is tough; life is complicated," Richard Gibbs, PhD, director of the Baylor College of Medicine Human Genome Sequencing Center, tells WebMD. "There are very few disorders that have a simple underlying biochemistry or ideology."
Some common inherited diseases are caused by a single gene, he says, including Huntington's disease (which causes dementia) as well as cystic fibrosis and muscular dystrophy. But "the real challenge is to crack the common disorders like heart disease, cancer, diabetes, hypertension, schizophrenia, and other psychiatric disorders," he says. Some are caused by multiple genes that are defective; in some cases, environmental factors also play a role. Geneticists not only must identify the many genes involved, but their function in creating the disease.
"The rationale is, you find the gene, you understand the disease, you find a better way to cure it, and that's definitely a viable pathway," he says. "But it's a long, slow, hard pathway."
Fixing a defective gene requires inserting another gene in its place to take over the replication process. In early experiments, that has not proven easy.
Studies of muscular dystrophy illustrate the complexity of this process. The gene was identified in 1992, but researchers still haven't found a way to tweak the gene and halt the disease -- much less prevent it. The inherited gene causes damage to leg muscle. "How do you undo that damage?" asks Gibbs. "With muscular dystrophy, it's necessary to introduce a protein that can restore the wasted muscle."
So far, researchers have focused on using viruses as a "Trojan-horse" way to sneak in a virus (with a "good gene" riding piggyback) to "infect" a "bad gene." That has been problematic because the infection does what infections do -- infects or damages surrounding tissue. Viruses are still considered the best medium for gene therapy, but researchers are working hard to perfect the process.
They are making headway, though. A recent study found that "microbubbles," which can take the viruses through the circulatory system and deliver them right to diseased organs, showed promise for heart disease and cancer treatments, says Paul A. Grayburn, MD, professor of internal medicine at the University of Texas Southwestern Medical Center in Dallas and chief of cardiology at the Dallas VA Medical Center.
Once the bubbles reach their destinations, ultrasound technology is used to pop them so they can deliver gene therapy or drugs to the targeted tissues, resulting in more effective treatment with fewer side effects. Grayburn says this technique might also be used to treat diabetes because it could deliver genes directly to the pancreas, which produces insulin.
As for cancer treatment, gene mapping will provide more precise diagnoses of the many variations of tumor formations -- "very powerful" information, says John McPherson, PhD, co-director of the Genome Sequencing Center at St. Louis' Washington University.
"Then you know how aggressive that cancer is, what drugs it responds to. You're then better able to tailor treatment targeted at that specific cancer. Right now, doctors start with a broad-range approach [with chemotherapy] and see what works. "
Genetic information should also make it easier to determine which patients will respond to chemotherapy or other treatments, and which might suffer serious side effects, he says. Many researchers believe people will eventually carry I.D. cards encoded with genetic information that will help doctors make these decisions. "With more genetic testing, with a card I.D. that carries your genetic profile, they will know which drug will be best for you," McPherson tells WebMD.
Adds Altshuler, "In a sense, with this terrible problem of cancer, we actually have a leg up. One of the hallmarks is that mutations that occur in the cells that form the cancer control the cancer's growth. So people are studying that as well -- where specific genes are turned on or off in the cancer, and that might affect how virulent is or how hard to treat. ... Until you knew what the genes were, that was a much harder question to ask."
And, of course, successes are already being seen in treating patients with gene therapy, including:
- A "cure" for Severe Combined Immunodeficiency Disease (SCID), the illness that keeps children in sterile "bubbles." By transfusing them with a corrected gene, French physicians restored the immune systems in five of these children
- Good results in patients with head and neck cancer who were given gene therapy in conjunction with chemotherapy.
- A treatment for cardiovascular disease in which a gene was injected directly into heart muscle, creating new blood vessel growth and "allowing bedridden patients get back to normal life," Anderson says.
Just like the space program, which introduced us to Velcro and other technology spin-offs, the Human Genome Project will lead to other developments, Gibbs says.
Recently, the Department of Energy sequenced an entire enterococus bacteria, "some bad bug that could be used in a bioterrorist attack," he tells WebMD. "And as a result, in one day of actual laboratory work, they were able to decipher the entire genetic complement of this bacteria. So if anybody ever puts it in a subway system, the chances of taking this bug and disarming it genetically are pretty good."