The medical revolution: Where are the cures?

Health and medicine explained.
Aug. 24 2010 7:10 AM

The Medical Revolution

Where are the cures promised by stem cells, gene therapy, and the human genome?

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Sometimes our expanding knowledge does reveal new avenues for therapeutic interventions, as it also taunts with its complexity. Dr. Bruce Stillman, president of the Cold Spring Harbor Laboratory, says medical progress would be stuck without the advancements made in molecular biology over the past 40 years. * He cites the successes of Herceptin for breast cancer and Gleevec for chronic myeloid leukemia, two drugs made possible by our growing understanding of how cells work. We've also learned, he says, that cancer is not one disease but many subtypes, so there will never be a single penicillin-like cure. "If anything, cancer has become a bigger problem because of the nature of our understanding," Stillman says.

Do You Really Want To Know?
The day is approaching when getting one's genome sequenced will cost only a few thousand dollars. Already, Glenn Close, Henry Louis Gates Jr., and a poodle named Shadow have had theirs done. Collins says this will be a crucial part of everyone's medical record, allowing us to see what dangers lurk in our genes. But Dr. David Goldstein, director of Duke University's Center for Human Genome Variation, says, "Right now we know very, very little of the genetics of the diseases that most people will get."

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Science blogger Daniel MacArthur has written that although we can peer into our DNA, that doesn't mean we can make much sense of it: "[E]ach of us have genomes littered with genetic variants that look like nasty mutations but have little or no effect on health. … [S]equencing technology is still moving far faster than our ability to interpret the resulting data."

The state of our ignorance is illustrated by the recent sequencing of the genome of Bishop Desmond Tutu and four Bushmen. Three of the Bushmen had a gene mutation associated with a liver disease that kills people while young. But the Bushmen are all over 80—which means either the variation doesn't actually cause the disease, or there are other factors protecting the Bushmen.

Parkinson's expert William Langston says that when the human genome was sequenced a decade ago, "people thought all key diseases were fundamentally genetic. Once we got the genes, it would all fall into place." But in the years since, there has been a growing realization that environmental influences can be just as important. While our genome is finite, environmental influences on our gene expression—the food we eat, the infections we contract, the stress we're under—are infinite.

We know we can acquire genetic damage through our behavior—ask a smoker with lung cancer. But there is a developing school of research, the study of epigenomics, that seeks to help explain how the interaction of our genes and environment causes disease. Epigenomics studies the chemical tags that lie just outside our genes and direct whether particular genes switch on or off. One thing that distinguished our epigenome from our genome is its flexibility, the way it changes in response to environmental forces. For example, a mother rat that grooms her pups sets off epigenetic changes that result in her pups growing up to be calm adults. Neglected pups grow up anxious and have more diabetes and heart disease—the stress of neglect causes changes to the chemical tags of the epigenome, which then results in the silencing or expression of certain genes. Amazingly, some of these nongenetic changes can be passed to the next generation: Unlicked pups grow up to be unlicking mothers, who beget more unlicked pups.

So the long, expensive process of mapping the epigenome hasbegun, a massive undertaking that, the NIH notes with supreme understatement, will "require the development of better technologies."

A recent study illustrates that sometimes even our most sophisticated tools only get us deeper into the mystery of our biology. Researchers at the University of California-San Francisco's Multiple Sclerosis Research Group conducted one of the most comprehensive examinations to date of the genome, and even part of the epigenome, of a set of identical twins, only one of whom had been stricken with MS. Scientists are sure MS is caused by some combination of genetic susceptibility and external trigger. Finding the differences between the twins, it was hoped, could help identify why one fell ill. But the disease hunters failed to turn up any illuminating disparities.

The Sales Pitch
If you follow the news, you might have recently gotten the impression that breast cancer is about to be eliminated by a simple vaccination. That's what the lead researcher of a study of a breast cancer vaccine in mice would like you to think. "We believe that this vaccine will someday be used to prevent breast cancer in adult women in the same way that vaccines prevent polio and measles in children," said Dr. Vincent Tuohy in a press release from the Cleveland Clinic.

Then there was the experiment that cured mice of the eye disease retinitis pigmentosa using nanotechnology. The editor of the journal that published the study, Dr. Gerald Weissmann, said, "As we have expanded our understanding of evolution, genetics, and nanotechnology, chances are that 'miraculous' cures will become as commonplace as those claimed by faith-healers past and present."

This is the kind of talk that makes the public wonder why their own doctors aren't dispensing miracles. There are forces, both external and internal, on scientists that almost require them to oversell. Without money, there's no science. Researchers must constantly convince administrators who control tax dollars, investors, and individual donors that the work they are doing will make a difference. Nancy Wexler says that in order to get funding, "You have to promise cures, that you'll meet certain milestones within a certain time frame."

The infomercial-level hype for both gene therapy and stem cells is not just because scientists are trying to convince funders, but because they want to believe. Dr. Theodore Friedmann, professor of pediatrics at the University of California-San Diego Medical Center and the former president of the American Society of Gene and Cell Therapy, was a gene therapy pioneer. He says the nature of science is that what seem like sudden breakthroughs are usually preceded by years of persistent failure and incremental victory. For example, successful organ transplantation took decades to achieve. Before doctors came up with a drug regime to get around the deadly problem of organ rejection, surgeons tried such unsuccessful interventions as destroying patients' immune systems through massive doses of radiation and even transplanting a kidney encased in a plastic bag.

But he acknowledges his profession forgot these lessons when gene therapy first appeared: "Well-meaning scientists got carried away by their own enthusiasm and expressed this to patients desperately looking for help."

The cure for this—for both scientists and the public—is simple but not very appealing: humility and patience. Friedmann says discouragement or disappointment in the pace of gene therapy, for example, is misplaced. "It hasn't been a long time. In comparison to the ways in which advances in medicine come, it's been a short time," he says. He says interfering with fundamental biological processes inevitably causes unforeseen difficulties.

Still Optimistic
So, that's it? The medicine of the future is always going to be out of reach? Some people say it's slowly arriving. There are researchers who stuck with gene therapy and are starting to see results. For instance, a rare type of inherited blindness has been successfully treated in a small study. The eye may be a particularly receptive place for gene therapy because it is a relatively contained space that does not mount a large immune response. Dismissing such caveats, Theodore Friedmann says restoring vision to blind patients is quite enough proof that gene therapy works. "If that's not a new era in medicine, I don't know what is!"

Even William Langston says he is feeling renewed optimism about the prospects for Parkinson's. Maybe there won't be a cure, or even a reversal once major damage is done, but the possibility remains that if the disease could be identified much earlier, when its effects are still minor, drugs now in the testing phase might be able to halt the disease's progression. Those are big "ifs" and "mights," but Langston says one study, called ADAGIO, has shown promise with newly diagnosed patients.

He also thinks that stem cells have the potential to illuminate the still-unknown disease process of Parkinson's. If cells from Parkinson's patients can be returned to their undifferentiated state, coaxed in the laboratory to become dopamine cells that then develop characteristics of the disease, he says, "we will have Parkinson's in a dish." That would be a technological breakthrough both for understanding how the disease starts and for testing potential therapeutics without endangering patients.

If scientists weren't optimists, science would be almost impossible to do. Medical research is too frustrating, demanding, and grueling to think that all the years of devotion won't pay off. As Nancy Wexler says, "If I didn't feel what our foundation is doing was going to make a difference, it would just be too unbearable. But you still have the question, Am I doing the right thing?"

Correction, Aug. 26, 2010: This article originally misidentified Bruce Stillman as the director of the Cold Spring Harbor Laboratory. He is its president. (Return  to the corrected sentence.)

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