The Wall Street Journal,
March 10, 2012Link
I talk to scientists for a living, and one of my most memorable conversations took place a couple of years ago with an engineer who put electrodes in bird brains. The electrodes were implanted into the song-generating region of the brain, and he could control them with a wireless remote. When he pressed a button, a bird singing in a cage across the lab would fall silent. Press again, and it would resume its song.
I could instantly see a future in which this technology brought happiness to millions of people. Imagine a girl blind from birth. You could implant a future version of these wireless electrodes in the back of her brain and then feed it images from a video camera.
As a journalist, I tried to get the engineer to explore what seemed to me to be the inevitable benefits of his research. To his great credit, he wouldn't. He wasn't even sure his design would ever see the inside of a human skull. There were just too many ways for it to go wrong. He wanted to be very sure that I understood that and that I wouldn't claim otherwise. "False hope," he warned me, "is a sinful thing."
Over the past two centuries, medical research has yielded some awesome treatments: smallpox wiped out with vaccines, deadly bacteria thwarted by antibiotics, face transplants. But when we look back across history, we forget the many years of failure and struggle behind each of these advances.
This foreshortened view distorts our expectations for research taking place today. We want to believe that every successful experiment means that another grand victory is weeks away. Big stories appear in the press about the next big thing. And then, as the years pass, the next big thing often fails to materialize. We are left with false hope, and the next big thing gets a reputation as the next big lie.
In 1995, a business analyst named Jackie Fenn captured this intellectual whiplash in a simple graph. Again and again, she had seen new advances burst on the scene and generate ridiculous excitement. Eventually they would reach what she dubbed the Peak of Inflated Expectations. Unable to satisfy their promise fast enough, many of them plunged into the Trough of Disillusionment. Their fall didn't necessarily mean that these technologies were failures. The successful ones slowly emerged again and climbed the Slope of Enlightenment.
When Ms. Fenn drew the Hype Cycle, she had in mind dot-com-bubble technologies like cellphones and broadband. Yet it's a good model for medical advances too. I could point to many examples of the medical hype cycle, but it's hard to think of a better one than the subject of Ricki Lewis's well-researched new book, "The Forever Fix": gene therapy.
The concept of gene therapy is beguilingly simple. Many devastating disorders are the result of mutant genes. The disease phenylketonuria, for example, is caused by a mutation to a gene involved in breaking down a molecule called phenylalanine. The phenylalanine builds up in the bloodstream, causing brain damage. One solution is to eat a low-phenylalanine diet for your entire life. A much more appealing alternative would be to somehow fix the broken gene, restoring a person's metabolism to normal.
In "The Forever Fix," Ms. Lewis chronicles gene therapy's climb toward the Peak of Inflated Expectations over the course of the 1990s. A geneticist and the author of a widely used textbook, she demonstrates a mastery of the history, even if her narrative sometimes meanders and becomes burdened by cliches. She explains how scientists learned how to identify the particular genes behind genetic disorders. They figured out how to load genes into viruses and then to use those viruses to insert the genes into human cells.
By 1999, scientists had enjoyed some promising successes treating people--removing white blood cells from leukemia patients, for example, inserting working genes, and then returning the cells to their bodies. Gene therapy seemed as if it was on the verge of becoming standard medical practice. "Within the next decade, there will be an exponential increase in the use of gene therapy," Helen M. Blau, the then-director of the gene-therapy technology program at Stanford University, told BusinessWeek.
Within a few weeks of Ms. Blau's promise, however, gene therapy started falling straight into the Trough. An 18-year-old man named Jesse Gelsinger who suffered from a metabolic disorder had enrolled in a gene-therapy trial. University of Pennsylvania scientists loaded a virus with a working version of an enzyme he needed and injected it into his body. The virus triggered an overwhelming reaction from his immune system and within four days Gelsinger was dead.
Gene therapy nearly came to a halt after his death. An investigation revealed errors and oversights in the design of Gelsinger's trial. The breathless articles disappeared. Fortunately, research did not stop altogether. Scientists developed new ways of delivering genes without triggering fatal side effects. And they directed their efforts at one part of the body in particular: the eye. The eye is so delicate that inflammation could destroy it. As a result, it has evolved physical barriers that keep the body's regular immune cells out, as well as a separate battalion of immune cells that are more cautious in their handling of infection.
It occurred to a number of gene-therapy researchers that they could try to treat genetic vision disorders with a very low risk of triggering horrendous side effects of the sort that had claimed Gelsinger's life. If they injected genes into the eye, they would be unlikely to produce a devastating immune reaction, and any harmful effects would not be able to spread to the rest of the body.
Their hunch paid off. In 2009 scientists reported their first success with gene therapy for a congenital disorder. They treated a rare form of blindness known as Leber's congenital amaurosis. Children who were once blind can now see.
As "The Forever Fix" shows, gene therapy is now starting its climb up the Slope of Enlightenment. Hundreds of clinical trials are under way to see if gene therapy can treat other diseases, both in and beyond the eye. It still costs a million dollars a patient, but that cost is likely to fall. It's not yet clear how many other diseases gene therapy will help or how much it will help them, but it is clearly not a false hope.
Gene therapy produced so much excitement because it appealed to the popular idea that genes are software for our bodies. The metaphor only goes so far, though. DNA does not float in isolation. It is intricately wound around spool-like proteins called histones. It is studded with caps made of carbon, hydrogen and oxygen atoms, known as methyl groups. This coiling and capping of DNA allows individual genes to be turned on and off during our lifetimes.
The study of this extra layer of control on our genes is known as epigenetics. In "The Epigenetics Revolution," molecular biologist Nessa Carey offers an enlightening introduction to what scientists have learned in the past decade about those caps and coils. While she delves into a fair amount of biological detail, she writes clearly and compellingly. As Ms. Carey explains, we depend for our very existence as functioning humans on epigenetics. We begin life as blobs of undifferentiated cells, but epigenetic changes allow some cells to become neurons, others muscle cells and so on.
Epigenetics also plays an important role in many diseases. In cancer cells, genes that are normally only active in embryos can reawaken after decades of slumber. A number of brain disorders, such as autism and schizophrenia, appear to involve the faulty epigenetic programming of genes in neurons.
Scientists got their first inklings about epigenetics decades ago, but in the past few years the field has become hot. In 2008 the National Institutes of Health pledged $190 million to map the epigenetic "marks" on the human genome. New biotech start-ups are trying to carry epigenetic discoveries into the doctor's office. The FDA has approved cancer drugs that alter the pattern of caps on tumor-cell DNA. Some studies on mice hint that it may be possible to treat depression by taking a pill that adjusts the coils of DNA in neurons.
People seem to be getting giddy about the power of epigenetics in the same way they got giddy about gene therapy in the 1990s. No longer is our destiny written in our DNA: It can be completely overwritten with epigenetics. The excitement is moving far ahead of what the science warrants--or can ever deliver. Last June, an article on the Huffington Post eagerly seized on epigenetics, woefully mangling two biological facts: one, that experiences can alter the epigenetic patterns in the brain; and two, that sometimes epigenetic patterns can be passed down from parents to offspring. The article made a ridiculous leap to claim that we can use meditation to change our own brains and the brains of our children--and thereby alter the course of evolution: "We can jump-start evolution and leverage it on our own terms. We can literally rewire our brains toward greater compassion and cooperation." You couldn't ask for a better sign that epigenetics is climbing the Peak of Inflated Expectations at top speed.
The title "The Epigenetics Revolution" unfortunately adds to this unmoored excitement, but in Ms. Carey's defense, the book itself is careful and measured. Still, epigenetics will probably be plunging soon into the Trough of Disillusionment. It will take years to see whether we can really improve our health with epigenetics or whether this hope will prove to be a false one.
Copyright 2012 Carl Zimmer