Bursting the Genome Bubble

Early this year, UCLA held a daylong conference billed as “The Storefront Genome.” The premise was that gene testing would soon become cheap and convenient, offering consumers unprecedented insights into their medical futures, as well as revealing unprecedented threats.

“Imagine being able to go to a shopping mall and pick up your own genetic profile for roughly the same price you’d pay for a high-end pair of running shoes,” said the conference literature. “It may seem like science fiction but could soon be a reality . . . . Recent developments in the area of genetics have increased the likelihood that, in about five years, an individual will be able to obtain a comprehensive genetic profile for approximately $100.”

The pitch was seductive. A “genetic profile” consists of a battery of tests for specific genes that may be linked to specific diseases. The diseases of interest aren’t the rare genetic conditions that arise soon after birth, such as cystic fibrosis or Tay-Sachs disease, because the genes for those conditions have been known for a while and tests for them are well established. Rather, the allure is the relationship of genes to the common maladies of middle age and beyond: heart disease, hypertension, diabetes, cancer and Alzheimer’s. A comprehensive genetic profile would give your doctor a head start on treatment years in advance.

“In less than 10 years we will have identified hundreds of genes that predispose to virtually all of the common, late-onset diseases,” said Leroy Hood, one of the pioneers of gene-sequencing technology. “What we will be able to do is take from each of you a blood sample and write out a probabilistic health history of what is likely to happen to you. And once we have your predicted health history, we can say, ‘Here is a course of action which, if you follow it, will delay, if not prevent, the onset of the predicted disease and extend your life span.’”

No doubt many in the audience would have signed up for a genetic profile right then, had one been offered. Others would have held back, worried that their test results, if they got out, might endanger their privacy, their jobs or their access to health insurance. Conference speakers explored those concerns too.

One listener was skeptical of both prospects, however. He was Wayne Grody, a professor of pathology, pediatrics and human genetics at the UCLA School of Medicine, and also the director of the university’s DNA diagnostic lab. “I was thinking, my lab is not gearing up for it,” says Grody. “I thought, based on our experience with cystic fibrosis, establishing the national screening program, that all of this is going to take a long time to ramp up.”

Grody, 51, has labored in the trenches of medical genetics for 20 years. His resume--he’s embarrassed that it’s almost 50 pages long--lists not only dozens of reseach papers but also more than 80 “national and regional appointments” and professional memberships. He is a believer in gene testing and has butted heads with those who would restrict it. But he is not one of the drum-beaters for the DNA revolution. He has always taken a cautious view of what the technology can and cannot deliver. That’s why he was in the audience at “The Storefront Genome” and not on stage. If you organize a conference to talk up the brave new world of the gene, with all its promise and peril, you don’t want your conscience on stage, letting air out of the balloon.

April marked the 50th anniversary of James Watson and Francis Crick’s breakthrough description of DNA (deoxyribonucleic acid). The scientists showed that the DNA molecule, the raw material of genes, was a double helix. The structure was a spiral whose long strands unwind and come together again when cells divide and genes are passed along.

The National Institutes of Health used the anniversary to declare that the sequencing of the human genome was complete. Winding up a long-running project, scientists said that they had resolved the order of all 3.2 billion chemical “letters” within our store of DNA. Most letters in the sequence are repetitive and apparently without function, but scattered among them are about 30,000 “words.” These words are the genes that define our species and drive our cells.

The NIH grandly compared the success of its Human Genome Project to splitting the atom or going to the moon. It made Grody a bit uncomfortable. “My field has become the sexy field in medicine,” he allows. “I don’t mind that the public is captivated by genetics. I do love the double helix, but I try to demystify it in lectures. I try to bring it down to earth. If we doctors put genetics up on a pedestal, things could go too far. Just accept it as one of the new things in medicine.”

The DNA lettering of the genome has been transcribed, but the significance of the wording remains largely a mystery. As Grody notes, completion of the human sequence “hasn’t revealed any disease genes that we didn’t already know about.” Those were uncovered separately, by other techniques. What the Human Genome Project delivered was a “parts list,” Grody says. “One of my colleagues puts it this way: If it takes 100,000 parts to make a Boeing jetliner, and if you had all those parts in front of you, could you make a plane that flies?”

What is a disease gene anyway? Briefly stated, it is a normal gene that has gone awry. A gene may be hundreds or thousands of letters long, and if a mutation--a change in chemical lettering--alters some part of the sequence, then a disease may ensue.

Take the gene for cystic fibrosis, a lung disease of children that is often fatal. Genes come in pairs. In cystic fibrosis, both copies of the child’s CF gene are flawed. A protein that is the normal product of the gene is either defective or missing from the child’s cells.

The disease is the most common genetic disorder of white Americans, affecting one person in 3,000. But many more people than that are healthy carriers of a misspelled CF gene. Only if two carriers of the gene come together, and if their baby happens to inherit the two bad copies--one from each parent--does the child get cystic fibrosis.

Grody is an expert on the permutations of the CF gene. “It’s where I’m most known.” His lab offers testing both for diagnosing the disease in children and for telling prospective parents if they may be carriers. Grody helped to establish national standards for a voluntary program of CF screening for couples who want children. Launched in 2001, the program is slowly expanding, with the aim of reducing or even eliminating cystic fibrosis. But there has been some confusion in the interpretation of test results, leading a few parents to have invasive prenatal testing that runs the risk of inducing an abortion.

The overwhelming majority of the 1,400 disease genes identified to date behave like the CF gene, in which a single small failure triggers a severe illness, or even death in the womb. Most of the rest of the genes in our DNA aren’t so harmful when they are misspelled. Most function just fine with alternate spellings. What’s more, the common diseases of Americans, such as heart disease, diabetes and cancer, involve subtle variations and interactions among many genes. These diseases also involve environmental factors, such as the effects of diet and lifestyle. So figuring out the genetic bases of these ailments is to assemble the plane and make it fly.

Each Monday the UCLA Medical Center holds a clinic for patients with genetic and metabolic disorders. Usually the patients are children. They are sad cases for the most part, their faces pinched and their frames deformed. A few are in wheelchairs, pushed bravely down the hall by their mothers. For these children with broken genes, treatments are few and the damage is usually irreversible. “It’s the biggest frustration of genetics,” says Grody. “A lot of the patients we see, there’s not a lot we can do.”

Indeed, after medical school, Grody chose to specialize in pathology initially because genetics, in the early 1980s, seemed open-and-shut. “It was a small specialty,” he says, seemingly cut off from the rest of medicine. By contrast, pathologists ran laboratories, conducted tests and helped other doctors make diagnoses. Today Grody’s dual training enables him to track an inherited disease from a broad family pedigree (genetics) to the very heart of the patient’s cells (pathology).

On a recent Monday at the clinic, a woman from Ventura came to him to discuss having a genetic test for breast cancer. The most important advance in genetics in the last decade may be the identification of cancer genes that run in families. Two genetic clues for breast cancer have been isolated and DNA tests devised for them, which permit the women who test positive to take action ahead of the disease. The genes connected to breast cancer are called BRCA1 and BRCA2. Unfortunately they account for only 10% of all cases of breast cancer in the U.S.

Complicating matters further, the chances that a woman who tests positive for a BRCA mutation will actually contract a breast cancer are between 50% and 85%. So a positive test does not guarantee that the patient will ever fall ill. Or she may not get the disease until late in life.

Those odds make it hard for the patient to decide what to do. Should she have a mastectomy because of the test result? Should she start taking tamoxifen, a new drug that has shown promise against the disease? Should she tell her relatives about their own possible risks, putting the rest of the family into the same limbo?

“If I sent you to Las Vegas with those [50-85%] odds, what would you do?” asks Grody. “Would you gamble a lot of money?” He shakes his head over the uncertainty. Yet the BRCA genes represent the coming order of disease genes, because by themselves they will not decisively determine if a person will get sick. They aren’t either red or black, like the gene for CF. Still, every American who undertakes a genetic profile will become a health gambler, as he or she weighs the risks and probabilities of the results.”

Grody speaks with more flair than he appears to possess. He’s not tall, and his features are unassuming. He’s got dark, youthfully thick hair that he tries to smooth out and plaster down--unsuccessfully. He holds himself at the elbows when he talks, or somewhat nervously strokes his hands in front of him, like a praying mantis who is utterly benign. He smiles frequently and tends to agree with most everything his interviewer says, as he’s unfailingly courteous and self-effacing. It amounts to a great bedside manner.

The woman from Ventura, whose first name is Kristi, has agreed to participate in this article and to release her medical information. Before she arrives at the clinic, Grody sketches the details of her case, so far as he knows. A 46-year-old mother of three, Kristi contracted breast cancer at age 42. If she’s had breast cancer already, why would she still want a BRCA test?

“There is still reason to have the test because of the risk for cancer in the other breast, and for recurrence in the area of the original breast, and for ovarian cancer,” Grody says. It turns out that the BRCA disease genes elevate a woman’s risk for ovarian cancer as well. Significantly, Kristi’s mother died of ovarian cancer at age 62.

In the examining room, Kristi is slim, tanned, composed: a breast cancer survivor but not yet out of the woods. Her arms are folded in front of her chest. She and the doctor sit in undersized chairs with a low table between them as he takes her family history and explains the BRCA test.

“For the majority of women with breast cancer, this test is useless, because 90% of breast cancer is not inherited,” he cautions. “It’s ‘sporadic,’ ” meaning that the cancers crop up without a discernible pattern.

Whether Kristi inherited hers is not known, Grody continues. He tells her that the two cancers, breast and ovarian, occurring in two generations of her family--along with her relative youth when the disease struck--make Kristi a candidate for gene testing. “Still, I bet you’re going to test negative,” he says.

Grody doesn’t want Kristi to bank too much on the test. As he said on another occasion, “This is not a general screening test, like the test for cystic fibrosis carriers. You can’t just start offering this to millions and millions of women, because breast cancer is too common a disease. You have to have some prior indication of risk.”

The genetic analysis of the patient’s blood sample is performed by a company in Salt Lake City called Myriad, which owns the patents for the BRCA disease genes. It seems wrong to many people that a piece of nature can be patented, but since 1980 the courts have upheld the principle, not so much on the ownership of genes as on the technology for extracting and using them. Thousands of patent applications have been filed after discoveries of other genes. And patent holders could certainly drive up the cost of genetic profiles, such as those quickie versions touted at the UCLA conference. “I’m pretty much against [patents], but the precedent has been set,” says Grody.

When Myriad scientists won the race to identify the BRCA genes, the company received the commercial rights to test for them, and has conducted advertising campaigns in Atlanta and Denver to promote the testing. Some experts think that the ads, which ran last fall on local TV and in magazines, preyed on the fears of women who were unlikely to test positive.

Grody finds Myriad’s direct marketing of the test acceptable because the women were referred to their doctors, who could advise whether the test was necessary. Myriad officials believe “they’re doing it as a public service, to raise awareness, and maybe they are, but they’re also doing it to make money,” Grody says.

The cost of the test, he informs Kristi, is $2,800. (UCLA gets no part of that.) She says that her insurance company has agreed to cover it, so a big hurdle is out of the way.

“Genes come in pairs,” Grody says next. “If you’re tested and it comes back positive, there’s a 50-50 chance that your children would have it too.”

Having anticipated the possibility, Kristi says that she’s ready to have her daughter tested. “No, wait,” says Grody. “Not now. She’s not going to get breast cancer at 13, and you’re not going to conduct a mastectomy on her. So wait until she’s 18, at least.”

Then he brings up something that Kristi hadn’t given any weight to: the risk of breast cancer in her sons. The disease is very rare in males, to be sure, but they are more susceptible if they carry the BRCA2 misspelling.

“Your oldest son is 19,” he says, looking at his notes. “But we wouldn’t test him unless he’s ready to have children and unless you have one of the BRCA mutations.”

Kristi has two sisters, which raises more issues about testing. Grody assures her, “We’d never go to your sister--say if you’re estranged--and tell her the outcome of your test.” A positive result may prompt family tension, he advises, especially if another sibling takes the test and it’s negative. “Why did my sister get it and not me?” might be the guilt felt by the latter sibling. So the ripples of Kristi’s decision spread outward from the coils of her DNA.

The doctor points out another drawback. “There are theoretical risks of insurance discrimination,” he says. He’s about to add that the risks in his opinion are low when Kristi interjects with a laugh, “I’m already an insurance risk.”

Then she asks, “If my sisters take the test, are they obligated to tell their insurance companies?” Grody’s view is that honesty is always the best policy. “Some women don’t want the companies to know if they’re positive, but I think that’s silly, because they’ll have to tell later if they need surgery. And a negative result will be welcomed by the insurance company.”

The session speeds up. They discuss whether she should have her ovaries removed, a step that might make sense if she receives a positive result. Kristi says “OK” to each of Grody’s points. “I am waiting to hear something I am not familiar with,” she says. Relaxed, her mind made up, she drops her hands to her lap.

“The chemo knocked me into menopause,” she says, allowing Grody a glimpse of her ordeal three years ago. Because Kristi’s husband had to travel for work, sometimes her son had to drive her to the chemotherapy appointments. Day after day the teenager watched his mother’s hair fall out and the weight slip from her body.

“Oh,” says Grody, wincing. “Oh, that’s terrible.”

Myriad, among the most respectable of the new breed of gene laboratories, has a host of low-budget competitors, who advertise mainly on the Internet. For example, a North Carolina company called Genovations asks consumers if they would like to have their DNA (and Alzheimer’s risk) analyzed through a simple mouthwash sample.

Stephen Barrie, founder of the laboratory that created Genovations, says, “We offer Cardio, Osteo, Immuno and Detoxi profiles. We launched these in March of 2002, and by now they have been taken by tens of thousands of people.” Ordered through a physician, the four profiles cost the consumer about $1,500. The campaign is similar to the one mounted by Myriad for its BRCA testing, except that the disease genes analyzed by Genovations have not been validated by scientific studies of large groups of patients.

Concerned by what he believes is misleading advertising, Grody co-chairs a committee of the American College of Medical Genetics that is looking into the claims of the consumer test outfits. In a recent review paper, he summarized the problem: For the diseases that most people are concerned about, such as heart disease and most cancers, DNA screening is not yet ready. To start such testing now “would risk imparting incomplete or even erroneous information to the patient and doing more harm than good.” He thinks the technology to deliver the information responsibly is at least 20 years away.

He is against hype not just from the boosters of gene testing but also from its critics. The Human Genome Project was unique among scientific undertakings in that it helped to fund its own critics. Over the course of 13 years, NIH and its governmental partners spent some $3 billion to sequence the lettering of DNA, while at the same time spending $135 million to examine the “ethical, legal and social implications” of the work. The reviews by NIH consultants of what could go wrong in medical genetics, such as discrimination against those with disease genes, were important. Some of the warnings found their way into books and the news media, where they helped to stir up fears that scientists like Grody are trying to tamp down.

In 1995, Grody uncharacteristically got into hot water by challenging the ethical overseers, one of whose committees was known as the Working Group. In an editorial in a medical journal, he wrote: “There are some who feel that the Working Group’s deliberations have been too heavily weighted toward the ethicists and lawyers at the expense of the view of working geneticists. Indeed, it sometimes seems as though modern genetics has created countless new careers for ethicists, who have seized on this discipline as their own special domain.”

Grody asked why genetics, in particular, was being singled out for scrutiny. He thought that it had to do with the “sense that molecular genetics . . . has an aura of evil hanging over it . . . . The science of human genetics must remain forever humbled and apologetic for the abuses of Lysenko, Nazi Germany and the earlier eugenics policies of our own country.” Later in the editorial he wondered if people might be advised to sign medical consent forms before having their hair cut, lest the clippings be taken and the DNA analyzed without their knowledge.

To wheel out haircuts, Hitler and a crackpot Communist geneticist was strong stuff. Although Grody is uncomfortable, even chagrined, over the flap he caused, he has not changed his position. “There have been a few cases of genetic discrimination,” he says, “but I would say, on the medical side, that the threat has been exaggerated. This whole idea that we can’t be trusted, when we’re entrusted with all other aspects of patients’ care . . . . It’s putting speed-bumps into progress.”

In Grody’s view, there’s more danger in making too many promises on the benefits of the double helix than in undermining people’s rights.

It’s the end of another 14-hour day. The doctor is ready to go home. He stands up from his desk in his small office in the warren of the UCLA Medical Center. If he had a secretary, that person would have long since left. That he doesn’t have a secretary doesn’t bother Grody, who hates to delegate chores. For a guy who works with complicated technology, Grody is something of a Luddite. He likes e-mail but won’t carry a cell phone, complaining that the rudeness of those who do annoys him. “I don’t want to be part of that culture,” he says. As a result, when he travels, which is often, he’s constantly on the lookout for a working pay phone. He’s constantly disappointed.

This evening he carefully puts the plastic dust covers over his Dell computer and keyboard--5-year-old equipment that you couldn’t give away. “I still do my writing with WordPerfect 5.0,” he says sheepishly, “which is in DOS, not Windows, and doesn’t use the mouse.” PowerPoint presentations? Forget it. Grody uses slides and yellowing overheads when he lectures.

He goes to the garage and gets into a low-slung, bulky-doored 1987 Toyota Supra with a “John Kerry” sticker on the rear window. It’s only the second vehicle he’s owned in his life. Swinging onto the street, he checks the movies playing in Westwood. He’ll stop if it’s near Oscar time and he hasn’t seen one of the nominated pictures.

This being L.A., Wayne Grody is not only a movie buff but also a TV scriptwriter and Hollywood consultant. Lately he’s been too busy to work in that line, but in the past he consulted for “The Nutty Professor” movies and the “Life Goes On” and “Chicago Hope” TV series. Grody wrote up an idea for how Mandy Patinkin, who played a doctor on “Chicago Hope,” could leave the show. The character would have a rare genetic disorder that predisposed him to heart attacks. Another doctor would find out about the genetic time bomb by examining a sample of Mandy’s blood without his knowledge. “But they didn’t use it,” says Grody.

“If I have a career goal, it’s not in medicine but in the arts,” he says solemnly. “Really, if anything, my goal is to write a movie screenplay.”

He did complete a screenplay 20 years ago, registering it with the Writers Guild. The theme of the movie wasn’t medical, but international espionage, a Cold War thriller. He was inspired by Robert Redford’s character in “Three Days of the Condor.” Grody’s hero was “this nerdy, studious character” who becomes entangled in a spying affair. The screenplay didn’t sell.

Tonight the doctor passes up the movies and heads home to his wife and young son. His wife, a writer, has prepared a meal for Wayne to heat up. It’s 11:30 p.m. Everyone’s asleep. He knows he shouldn’t eat right before bed because he’s got chronic heartburn and inflammation of the esophagus. A hectic day followed by rich food will make his reflux disorder worse, but he usually eats anyway.

He takes a pill for his stomach and another pill for his higher-than-it-should-be cholesterol. His doctor tells him “there must be something genetic” about his cholesterol. Grody shrugs. Like most Americans, he would rather deal with a pill than a regimen of running on the treadmill and overhauling his diet.

In a few hours he’ll get up and start over. He hasn’t missed a day of work in 20 years. “Even when I had mononucleosis, I went in,” he admits. “My colleagues would just as soon I stayed home when I was infectious. But I didn’t want to break my record.”

Postscript: Grody’s patient Kristi tested negative for the BRCA genes.