The Human Genome Project: 10 Years Later, Progress but Still a Puzzle

Ten years ago this summer, President Bill Clinton announced that the first draft of the Human Genome Project was complete. Standing next to the president, the lead scientist on the project at the National Institutes of Health, Dr. Francis Collins, said the draft would reveal the keys to treating common diseases like Alzheimer’s in just 10 to 15 years.

That hope turned out to be wildly optimistic. A decade after those six billion letters making up the human instruction book were plotted in digital form, scientists are still just scratching the surface of the fundamental mystery of why some people get sick and others don’t. Pharmaceutical companies have spent hundreds of millions of dollars yet they’ve found it frustratingly difficult to design effective gene-specific drugs.

“There are layers and layers of complexity and this is why it takes such a long time to figure out what’s going on,” says Dr. Chris Roman of Downstate Medical Center, who studies the genetic underpinnings of Lupus and other auto-immune diseases. “Before the Human Genome Project it was like the tip of the iceberg—now we’ve pulled the iceberg out of the water but it’s much bigger than we thought. All of a sudden we have this huge body of information, how do we make sense of it?”

Roman describes genes as “blueprints,” because they’re sequences of DNA that instruct cells to produce specific proteins, all of which have jobs in the body. People get sick when there are tiny, subtle mutations in the genetic blueprints that change the way proteins act. And reading those blueprints isn’t so simple. At this point, scientists have identified about 21,000 protein-coding genes in humans, but they only know the function of about 6,000 of them.

In an attempt to maximize the results of the genome project, the NIH took an ambitiously broad approach to the research. “Like every scientific discovery, there was hype in the beginning. In this case the hype was extreme, and it extended into the NIH,” says Dr. John Pappas, MD, a clinical geneticist at NYU Medical Center. Enthusiasm, and perhaps hubris, led the NIH to spend millions of dollars in studies on the genetic roots of common diseases like diabetes and cancer, in which researchers compared sections of the genomes of hundreds of people, looking for common variations. “These were very expensive studies with very low yield,” says Pappas. A decade later, few treatments can be traced back to these studies, and scientists have found the evolution of common disease to be highly complex and often traced to environmental triggers and a combination of rare genetic variants.

Still, while researchers work to use the genetic map to find effective treatments for disease, the Human Genome Project has already revolutionized the way those scientists, along with doctors and genetic counselors, do their work.

“We can imagine disease like we never could have before,” says Roman, the auto-immune researcher.

One of the biggest advances to come out of the project is the ability to rapidly scan the genome to find  “look alike” genes. If scientists know that “gene A” has the blueprint for an important protein in the immune system, and they find a new gene that looks similar but has a tiny difference in its blueprint—we’ll call it “gene B”—they can use gene A to help them figure out what exactly the proteins created by gene B are doing in the body, and see if they are problematic in people with an immunological illness. If gene B’s proteins are causing problems, with luck scientists could then develop a drug that blocks those proteins. Roman says that’s in essence how scientists were able to develop a treatment for Lupus, a devastating disease in which a person’s immune system attacks their own tissues and organs.

Many of the discoveries to come out of the Human Genome Project have been in the realm of rare genetic diseases like Tay-Sachs and dwarfism that are tied to one gene, or section of the genome. That’s meant a sea change for the work of clinical geneticists in New York like Dr. Pappas at NYU.

“The Human Genome Project gave us the capability of looking in a lot of detail to see if a little batch of DNA is missing or duplicated,” Pappas says. “This can have associations with mental retardation, autism, and psychiatric diseases—this was very hard to see before.” Ten years ago, Dr. Pappas says he could make a probable diagnosis of a patient’s disease. Now he can back that up with a precise test.

In the waiting room of Pappas’ office at NYU, an adolescent orthodox Jewish pair, chaperoned by an older woman, were filling out forms. The discoveries of genes tied to rare diseases has led to an increase in pre-nuptial genetic testing, particularly among the Ashkenazi Jewish community in New York. Before an arranged marriage is allowed to progress, young people are often required to get tested to find out if they are both carriers of a particular disease like Tay-Sachs.

With each new discovery of a link between a gene and a disease, Pappas says the popularity of genetic testing among the general population has increased. “New Yorkers are well informed,” Pappas says, pausing to laugh. “They are test-seekers.” But he says the information gleaned from those tests often leads to ethical questions, such as the decision to terminate a pregnancy.

That’s why for clinical geneticists like Pappas, one outcome of the Human Genome Project has been increased counseling. He says it’s often hard for people to process the test results, particularly if there is no treatment. “Some people don’t want to know if they’re going to develop dementia 20 years from now,” he said.

Unless there’s a clear medical benefit, Pappas suggests that a test is sometimes more trouble than it’s worth. Even if a person tests positive for a genetic mutuation, it doesn’t necessarily mean that they will end up with a disease. That’s where environmental factors come in. “So how much do we want to test and for what?” Pappas asks. “These limits need to be set.”

Setting those limits may become even harder as the cost of testing continues to drop. Dr. John Danias, also at Downstate, suspects that when the cost of mapping a human genome decreases to $1,000 (from about $10,000 currently) we’ll see a flurry of people signing up. But because testing and treating remain very different things, Danias says some fundamental genetic questions must still be answered before we achieve a world of personalized, gene-based medicine. He offers one example: “There’s large areas of our genetic material that seems to encode for ‘junk,’” he says. “It doesn’t seem to encode for any protein, it seems to have no function, or very little function. But we sense that there must be another layer of control that we don’t understand at this point. And I think that’s the next big thing, is understanding how this so-called junk DNA regulates actual expression of genes.”

“Today, we are learning the language in which God created life,” said President Clinton when he announced the completion of the first map of the human genome. Ten years later, the scientific world can see the letters that make up the code, but it is still trying to decipher its meaning. There are many different approaches to the data, some of which are focused on human variation—what makes us unique—and others focused on finding cures for diseases. If billions of dollars are going to be spent in continuation of the project, for many clinicians, the latter is the more important. “That’s why we do all this—eventually to be able to treat people,” says Pappas. “Not only to give them a prognosis, not only for prenatal testing, but also to be able to provide medical treatment.”