This has got to take it. Breast cancer handcuffs??? Hands-behind-your-back for the cure???
In the early days of personalized genomic medicine, skeptics wondered how tailored medical care could be profitable. Who would develop a drug for just one or a few people?
Turns out they were looking in the wrong direction. The answer lies in genetic testing more than drug development. A detailed report in today’s New York Times examines how the promise of personalized or precision medicine is being “tainted” by hype. “Across the industry,” they write,
investors are pumping tens of millions of dollars into clinical laboratories that are developing and selling the genetic tests. President Obama recentlycalled on Congress to spend $215 million next year on personalized medicine, calling it “one of the greatest opportunities for new medical breakthroughs that we have ever seen.” A major use of the federal funds would be to create a research group of a million volunteers that would provide scientists with an enormous collection of data.
Doctors and their patients, finding it hard to resist the promise, are being swept up in the excitement. The number of tests has almost doubled in the last few years, creating a $6 billion industry.
While acknowledging that some genetic tests are proving highly valuable–particularly in diagnosing different forms of cancer, which can respond highly specifically to certain drugs depending on the mutation–they note that many genetic tests are doing more to fatten corporate wallets than they are to improve patient care. The tests often run to $1000 or more.
WIth so much at stake, federal regulators are growing concerned about fraud. Turns out some doctors are ordering and charging for tests that people don’t need!
An internal chart reviewed by The New York Times suggests the company was not shy about pointing out that doctors could amass a substantial income by participating. If a doctor enrolled five patients per day and took 110 swabs per month, that physician could earn as much as $125,400 in compensation from the study over a year.
Shock and awe!
[Edit: I’ve had many positive comments on this post but one negative one keeps coming up, so I want to address it. A few people have felt it makes those who give to ALS feel stupid or duped. Not my intention at all. I’ve had it with ice buckets, not ice-bucket donors. My criticism is of a system, not individual people. I’ve added a line to the disclaimers to address the ALS donors, who obviously are acting with good intentions.]
I’ve had it with ice buckets.
Amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) is the disease of the moment. Not because it’s the most important medical problem today, but because it’s got a clever bit of marketing that got lucky and went viral. Kudos to the ALS Association’s ad campaign person. The ice-bucket gimmick has nothing to do with ALS—you could ice-bucket rectal cancer just as logically. Maybe more so, in fact, given most people’s physiological response to a couple gallons of ice-water. But hey, for whatever reasons, it has worked brilliantly. But I’m not dumping water on my head and I’m not writing the ALS Association a check. Giving money to biomedical research is like loaning Bill Gates busfare.
There’s a long list of people who could be pissed off at that position, so before I make my case, a few disclaimers:
First, I have great empathy for patients with ALS and their families and loved ones. It’s an awful disease and I hope a cure or at least an effective treatment is found. Soon. I am all for curing ALS. Also, the ALS Association is a fine charity. According to Charity Navigator, they have a high degree of transparency and use only a small percentage of their money for administrative costs. Also, I don’t mean to make those who have already given to ALS feel bad or misled. There’s always a benefit with an act guided by conscience. I’m just going to make the case that the charitable bang/buck is small.
Finally, I feel for scientists. I recognize that funding for the National Institutes of Health—the major federal agency for biomedical research—has been cut this year. But still, I don’t see biomedicine hurting seriously for money. I think that of all the industries that are working with tighter budget constraints, relatively speaking, science is not feeling the most pain, and offsetting its budget cutbacks is not going to have much effect on how soon a great new drug for ALS is found. I love science because it’s cool. But as charity goes, I think it is a pretty low return on investment. Here’s why.
I study biomedicine as a social enterprise. I look at it in the context of its history and in the context of contemporary society and culture. The majority of breakthroughs in basic science and almost all translations of basic science into new drugs and other therapies occur in the top university medical schools. I happen to work at one of them; the other biggies include U.C. San Francisco, Harvard Medical School and associated Boston-area hospitals, Baylor, Memorial Sloan-Kettering, Michigan, and a few others.
Science is kind of like a country club, in that it’s hard to get in and those who do have money. In order to enter an elite science building, you probably have to get past a security guard. Inside, there is wood paneling, lots of glass, gleaming chrome, polished floors. It’s like Google, only with worse food. If your building does not look like this—if it’s more than 20 years old—there is probably a fundraising campaign to replace it with something swankier.
It looks corporate because it is corporate. A lab is basically a business. Principal Investigators (PI’s, i.e. faculty lab heads) are entrepreneurs. Their principal role is development; i.e., raising money. The company staff consists of graduate students, postdocs, and technicians, and however many administrators you can afford. It’s a for-profit business, in that all or part of the PI’s salary comes from grants. Often, PI’s also literally run companies on the side; a PI without a little start-up is ever so slightly suspect, as though she’s perhaps not quite ambitious enough for the big leagues. A cut in federal funding means that competition for grants will be stiffer. But the elite schools, where most (not all, I recognize) of the most fundable grant applications come from, have “bridge funding” to help such investigators. The system can absorb some cuts.
The scientific community as a whole is rich, white, smart, and obviously highly educated. Getting one of these PI jobs takes brains, dedication, and in most cases, a good family background. Many scientists have parents who were scientists, and most come from middle- to upper-middle class backgrounds. It helps a great deal to be white. Every basic science department in my school cites diversity as one of its weaknesses. For a variety of reasons, it’s really hard to get to grad school if you’re black. I believe this to be mostly a failure of our education systems before grad school: basically, as a society we have decided to stop educating poor kids. My school makes a good effort to accept and nurture minority students. It just doesn’t get very many.
Those who do get into grad school have their schooling paid, get health insurance and a stipend of $30,000 a year or more. Postdocs make significantly more and starting salary for a beginning faculty member is north of $100,000, plus a start-up package of half a mil or more to get your lab going. Science is full of rich prizes, for best student paper, best article in a journal, best investigator under 40, best woman scientist, lifetime achievement, and so on: these can range from a few thousand to a million dollars. The prize money comes from professional societies, which run mainly on dues from scientists, and from private companies interested in developing science. In short, scientists have money to throw around.
Giving money “to ALS” feels good, but what does it actually buy you? Say a scientist has a gene or a protein and she thinks it’s the coolest thing since canned beer. But to work on it, she needs money. So she scans the grant opportunities and finds a disease she can plausibly link to. Let’s say it’s ALS. She dolls up her little geeky research project in a little black dress and stilettoes, with an up-do and some lipstick, hits “Submit” on the NIH website and sits back and waits for half a year for her funding score. The budget cuts mean that the funding cut-off moves down a few points, say from 25 to 20. Her application has to be in the top quintile to win. The ice bucket money, though, means she can apply to the ALS Association and have another chance. It effectively raises the cut-off again, back to 25 or even 30. That’s the impact of all this feel-good pop charity—a few percentage points on the funding cut-off.
The standard argument is that research needs to move forward as fast as possible: more grants=faster cure. That’s not obviously true. I’m not aware of any studies that examine that hypothesis; it’s simply taken as self-evident. If it is in fact true, the effect will probably be small. It is unlikely to bring new people into science. Most of the extra funding raised by the ice bucket challenge will go to people already working on ALS-related research. And again, as tragic as ALS is for those who live with it, it’s not the most dire medical issue facing us today.
For all these reasons, I’m interpreting the ice-bucket gimmick as a general challenge to give to a worthy charity. It’s so easy to forget to give back to the community. We’re all struggling financially in our own way, so we forget how rich we are in the bigger picture. All these ice buckets reminded me of this. I’m hardly rolling in dough, but I can find a hundred bucks. So while Sarah Palin and Patrick Stewart and everyone else is apparently writing checks to ALS, I gave $100 to the East Baltimore Community Development program of the Living Classrooms Foundation.
Baltimore, a city of 620,000, has a poverty rate of 25%. That’s about 150,000 people. Take the bottom quarter of them and you have more people in truly grinding poverty in one city than have ALS in the entire country.
And best of all, there is already a cure for poverty: money. Money well spent, of course—on education, nutrition, counseling, childcare, transportation, career guidance and training. My C-note could buy lunch for 20 kids. It could buy chalk for a hundred classrooms. It could enable a single mom to take the bus to work for a month. If transparent, responsible, effective non-profits like Living Classrooms had $40 million, they could lift an entire neighborhood out of poverty. That would mean less gun violence, fewer murders, less drug use, more economic development for my city. Maybe one of those kids will go to college, get interested in science, and apply to grad school.
So here’s my “ice-bucket” challenge: skip the bucket, let biomedical research take care of itself, and donate to an underfunded charity that will do some direct and long-term good.
Had a request for a teaser of my recent review of Nic Rasmussen’s Gene Jockeys from Nature (April 10). If you want the whole thing, log in to Nature or shoot me an email.
In 1969, the molecular biologist Gunther Stent published one of the most spectacularly inaccurate predictions in the history of modern science. In The Coming of the Golden Age: A View of the End of Progress (Natural History Press), he stated his belief that molecular genetics — which had only really been a science for 15 years — had peaked. The “golden age,” he wrote, would be one of modest discovery and waning public interest in science. That year, Jonathan Beckwith isolated the first gene. In 1970, Hamilton Smith found the first site-specific restriction enzyme, which his colleague Daniel Nathans developed into a tool for cutting and pasting DNA. Then, in 1972, Paul Berg spliced a bacterial gene into a virus. With the ability to engineer genes, molecular genetics began in earnest. Never mind the Age of Aquarius; this was the age of recombinant DNA.
In Gene Jockeys, the biologist and science historian Nicolas Rasmussen delicately unravels the tangled fibres of discovery, entrepreneurship and lab life in the first decades of genetic engineering.
Here it is, 2014, and we have “Is the will to work out genetically determined?,” by Bruce Grierson in Pacific Standard (“The Science of Society”).
The story’s protagonist is a skinny, twitchy mouse named Dean who lives in a cage in a mouse colony at UC Riverside. Dean runs on his exercise wheel incessantly—up to 31 km per night. He is the product of a breeding experiment by the biologist Ted Garland, who selected mice for the tendency to run on a wheel for 70 generations. Garland speculates that Dean is physically addicted to running—that he gets a dopamine surge that he just can’t get enough of.
Addiction theory long ago embraced the idea that behaviors such as exercise, eating, or gambling may have similar effects on the brain as dependence-forming drugs such as heroin or cocaine. I have no beef with that, beyond irritation at the tenuous link between a running captive mouse to a human junkie. What’s troubling here is the genetic determinism. My argument is about language, but it’s more than a linguistic quibble; there are significant social implications to the ways we talk and write about science. Science has the most cultural authority of any enterprise today—certainly more than the humanities or arts!. How we talk about it shapes society. Reducing a complex behavior to a single gene gives us blinders: it tends to turn social problems into molecular ones. As I’ve said before, molecular problems tend to have molecular solutions. The focus on genes and brain “wiring” tends to suggest pharmaceutical therapies.
To illustrate, Grierson writes,
File this question under “Where there’s a cause, there’s a cure.” If scientists crack the genetic code for intrinsic motivation to exercise, then its biochemical signature can, in theory, be synthesized. Why not a pill that would make us want to work out?
I have bigger genes to fry than to quibble over the misuse of “cracking the genetic code,” although it may be indicative of a naiveté about genetics that allows Grierson to swallow Garland’s suggestion about an exercise pill. Grierson continues, quoting Garland,
“One always hates to recommend yet another medication for a substantial fraction of the population,” says Garland, “but Jesus, look at how many people are already on antidepressants. Who’s to say it wouldn’t be a good thing?”
I am. First, Jesus, look at how many people are already on anti-depressants! The fact that we already over-prescribe anti-depressants, anxiolytics, ADHD drugs, statins, steroids, and antibiotics does not constitute an argument for over-prescribing yet another drug. “Bartender, another drink!” “Sir, haven’t you already had too much?” “Y’know, yer right—better make it two.”
Then, what if it doesn’t work as intended? Anatomizing our constitution into “traits” such as the desire to work out is bound to have other effects. Let’s assume Dean is just like a human as far as the presumptive workout gene is concerned. Dean is skinny and twitchy and wants to do nothing but run. Is it because he “wants to exercise” or is it because he is a neurotic mess and he takes out his anxiety on his wheel? Lots of mice in little cages run incessantly—Dean just does it more than most. His impulse to run is connected to myriad variables, genes, brain nuclei, and the reported results say nothing about mechanisms. We now know that the physiological environment influences the genes as much as the genes influence physiological environment. The reductionist logic of genetic determinism, though, promotes thinking in terms of a unidirectional flow of causation, from the “lowest” levels to the “highest.” The more we learn about gene action, the less valid that seems to become as an a priori assumption. The antiquated “master molecule” idea still permeates both science and science writing.
Further, when you try to dissect temperament into discrete behaviors this way, and design drugs that target those behaviors, side effects are sure to be massive. Jesus, look at all those anti-depressants, which decrease libido. Would this workout pill make us neurotic, anxious, jittery? Would we become depressed if we became injured or otherwise missed our workouts? Would it make us want to work out or would it make us want to take up smoking or snort heroin? In the logic of modern pharmacy, the obvious answer to side effects is…more drugs: anti-depressants, anxiolytics, anti-psychotics, etc. A workout pill, then, would mainly benefit the pharmaceutical industry. When a scientist makes a leap from a running mouse to a workout pill, he is floating a business plan, not a healthcare regimen.
And finally, what if it does work as intended? It would be a detriment to society, because, having a pill, it would remove yet another dimension of a healthy lifestyle from the realm of self-discipline, autonomy, and social well-being. It becomes another argument against rebuilding walkable neighborhoods and promoting public transportation and commuting by bicycle. A quarter-mile stroll to an exercise addict would be like a quarter-pill of codeine for a heroin junkie—unsatisfying. Not only is this putative workout pill a long, long stretch and rife with pitfalls, it is not even something worth aspiring to.
And that’s just one article. Scientific American recently ran a piece about how people who lack the “gene for underarm odor” (ABCC11) still buy deodorant (couldn’t possibly have anything to do with culture, could it?). Then there was their jaw-dropping “Jewish gene for intelligence,” which Sci Am had already taken down by the time it appeared in my Google Alert. I’d love to have heard the chewing out someone received for that bone-headed headline. Why do these articles keep appearing?
The best science writers understand and even write about how to avoid determinist language. In 2010, Ed Yong wrote an excellent analysis of how, in the 1990s, the monoamine oxidase A (MAOA) gene became mis- and oversold as “the warrior gene.” What’s wrong with a little harmless sensationalism? Plenty, says Yong. First, catchy names like “warrior gene” are bound to be misleading. They are ways of grabbing the audience, not describing the science, so they oversimplify and distort in a lazy effort to connect with a scientifically unsophisticated audience. Second, there is no such thing as a “gene for” anything interesting. Nature and nurture are inextricable. Third, slangy, catchy phrases like “warrior gene” reinforce stereotypes. The warrior gene was quickly linked to the Maori population of New Zealand. Made sense: “everyone knows” the Maoris are “war-like.” Problem was, the preliminary data didn’t hold up. In The Unnatural Nature of Science, the developmental biologist Lewis Wolpert observed that the essence of science is its ability to show how misleading “common sense” can be. Yet that is an ideal; scientists can be just as pedestrian and banal as the rest of us. Finally, Yong points out that genes do not dictate behavior. They are not mechanical switches that turn complex traits on and off. As sophisticated as modern genomics is, too many of us haven’t moved beyond the simplistic Mendelism that enabled the distinguished psychiatrist Henry H. Goddard to postulate—based on reams of data collected over many years —a single recessive gene for “feeblemindedness.” The best method in the world can’t overcome deeply entrenched preconception. As another fine science writer, David Dobbs, pithily put it in 2010, “Enough with the ‘slut gene’ already…genes ain’t traits.”
As knowledge wends from the lab bench to the public eyeball, genetic determinism seeps in at every stage. In my experience, most scientists working today have at least a reasonably sophisticated understanding of the relationship between genes and behavior. But all too often, sensationalism and increasingly greed induce them to oversell their work, boiling complex behaviors down to single genes and waving their arms about potential therapies. Then, public relations people at universities and research labs are in the business of promoting science, so when writing press releases they strive for hooks that will catch the notice of journalists. The two best hooks in biomedicine, of course, are health and wealth. The journalists, in turn, seek the largest viewership they can, which leads the less scrupulous or less talented to reach for cheap and easy metaphors. And even though many deterministic headlines cap articles that do portray the complexity of gene action, the lay reader is going to take away the message, “It’s all in my genes.”
Genetic determinism, then, is not monocausal. It has many sources, including sensationalism, ambition, poor practice, and the eternal wish for simple solutions to complex problems. Science and journalism are united by a drive toward making the complex simple. That impulse is what makes skillful practioners in either field so impressive. But in clumsier hands, the simple becomes simplistic, and I would argue that this risk is multiplied in journalism about science. Science writing is the delicate art of simplifying the complexity of efforts to simplify nature. This is where the tools of history become complementary to those of science and science journalism. Scientists and science writers strive to take the complex and make it simple. Historians take the deceptively simple and make it complicated. If science and science journalism make maps of the territory, historians are there to move back to the territory, in all its richness—to set the map back in its context.
Studying genetics and popularization over the last century or so has led me to the surprising conclusion that genetic oversell is independent of genetic knowledge. We see the same sorts of articles in 2014 as we saw in 1914. Neither gene mapping nor cloning nor high-throughput sequencing; neither cytogenetics nor pleiotropy nor DNA modification; neither the eugenics movement nor the XYY controversy nor the debacles of early gene therapy—in short, neither methods, nor concepts, nor social lessons—seem to make much of a dent in our preference for simplistic explanations and easy solutions.
Maybe we’re just wired for it.
Yesterday I and seemingly everyone else interested in genomes posted about the FDA letter ordering the genome diagnostics company 23andMe to stop marketing their saliva test. FDA treats the test as a “medical device, because “it is intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or is intended to affect the structure or function of the body.” The company first issued a bland, terse statement acknowledging the letter and then company president Anne Wojcicki signed a short post affirming the company’s commitment to providing reliable data, promising cooperation with FDA, and reasserting her faith that “genetic information can lead to better decisions and healthier lives.” (I say she “signed” it because of course we have no way of knowing whether she composed it and she’s no fool: surely the text was vetted by Legal.) In other words, the company followed up with a bland, less-terse response, carefully worded to reassure customers of the company’s ethical stance and core mission. Reactions to the FDA letter range from critics of the company singing “Hallelujah!” to defenders and happy customers are attacking FDA for denying the public the right to their own data. The 23andMe blog is abuzz and, hearteningly, a few sane souls there are trying to dispel misinformation.
I am doing history on the fly here. If journalism is the first draft of history, let’s take a moment to revise that first draft—to use the historian’s tools to clear up misconceptions and set the debate in context as best we can. The history of the present carries its own risks. My and other historians’ views on this will undoubtedly evolve, but I think it’s worth injecting historical perspective into debates such as these as soon as possible.
We must be clear that the FDA letter does not prohibit 23andMe from selling their test. It demands they stop marketing it. The difference may not amount to much in practice—how much can you sell if you don’t market your product?—but the distinction does help clarify what is actually at stake here. FDA is not attempting to instigate a referendum on the public’s access to their own DNA information. They are challenging the promises 23andMe seems to make. This is, in short, not a dispute about access, but about hype.
The company seems to promise self-knowledge. The ad copy for 23andMe promises to tell you what your genome “says about you.” “The more you know about your DNA,” they trumpet, “the more you know about yourself.” On one level, that’s perfectly, trivially true: your genome does have a lot to do with your metabolism, body structure, how you respond to disease agents, and so forth. The problem is, we as yet know very little about how it all works. The 23andMe marketing exploits a crucial slippage in the concept of “knowledge,” which FDA correctly finds misleading. In short, the marketing implies a colloquial notion of knowledge as a fixed and true fact, while the science behind the test is anything but.
Historians and other scholars of science have thought a lot about the concept of scientific knowledge. In 1934, Ludwik Fleck wrote about the “genesis and development of a scientific fact,” namely the Wasserman test for syphilis. It is a pioneering classic in a now-huge (and still growing) literature on how scientific facts are created. Science claims to gather facts about nature and integrate them into explanations of natural mechanisms. A moment’s reflection reveals that very few scientific facts last forever. Most, perhaps all, undergo revision and many are discarded, overthrown, or reversed. They are historical things, not universal truths. A surprisingly small amount of what I learned in science courses 20 and 30 years ago is still true. As that great philosopher of science John McPhee wrote, “science erases what was previously true” (Oranges, p. 75). Because scientists search for universal, timeless mechanisms, they easily slip into language suggesting that they discover universal, timeless truth. But there is uncertainty, contingency, malleability built into every scientific fact.
This goes double for genome information. The 23andMe product, like every genome test, provides probabilities of risk, not mechanisms. Probabilities are messy and hard to understand. They carry an almost irresistible tendency to be converted into hard facts. If you flip a coin 9 times and it comes up heads every time, you expect the next flip to come up tails. And if you get heads 49 times in a row, the next one has got to be tails, right? Even if you know intellectually that the odds are still 50:50, just like on every previous flip. You can know you have a particular gene variant, but in most cases, neither you nor anyone else knows exactly what that means. Despite the language of probability that dots the 23andMe literature, their overall message—and the one clearly picked up by many of their clientele—is one of knowledge in the colloquial sense. And that is oversell.
Human genetics has always been characterized by overstatement and hype. In the early 1900s, the rediscovery of Mendel’s laws persuaded many that they now understood how heredity works. Although every scientist acknowledged there was still much to learn, prominent students of human heredity believed they knew enough to begin eliminating human defects through marriage and sterilization laws. We now view such eugenic legislation as almost unbelievably naive. Combine that naivete with race, gender, and class prejudice and you obtain a tragically cruel and oppressive eugenics movement that resulted in the coerced sterilization of many thousands, in the US and abroad—including, of course, the Nazi sterilization law of 1933, based on the American “model sterilization law,” which culminated not only in racist forced sterilization but euthanasia.
Human-genetic hype hardly ended with the eugenics movement. In 1960s, as human diseases were finally being mapped to chromosomes, it seemed transparent that if a chromosomal error that produces an individual with an XXY constitution feminizes that individual (which it does), then an extra Y chromosome (XYY) must masculinize. Such “super-males,” data seemed to suggest, were not only taller and hairier than average, but also more aggressive and violent. It was, for a while, a fact that XYY males were prone to violent crime.
The molecular revolution in genetics produced even more hype. When recombinant DNA and gene cloning techniques made it possible to try replacing or augmenting disease genes with healthy ones, DNA cowboys hyped gene therapy far beyond existing knowledge, promising the end of genetic disease. The 1995 Orkin-Motulsky report acknowledged the promise of gene therapy but noted,
Overselling of the results of laboratory and clinical studies by investigators and their sponsors…has led to the mistaken and widespread perception that gene therapy is further developed and more successful than it actually is.
Soon after this report was published, Jesse Gelsinger died unexpectedly in a gene-therapy trial, patients in a French gene-therapy trial for adenosine deaminase (ADA) deficiency unexpectedly developed leukemia, and the gene-therapy pioneer W. French Anderson was arrested, tried, and convicted on charges of child molesting—in other words, abusing and overestimating his power over the children whose health was entrusted to him. The risks of failing to heed warnings about genetic oversell are high.
Like gene therapy, genome profiling has great promise, but the FDA letter to 23andMe is a stern reprimand to an industry that, like gene therapy and the entire history of human genetics, blurs the line between promise and genuine results.
The current controversy over commercial genome profiling has two qualities that distinguish it as particularly serious. First, unlike previous examples of overselling human genetics, it is profit-driven. The “oversell” is more literal than it has ever been. Although 23andMe presents as a concerned company dedicated to the health of their clientele, they are also—and arguably primarily—dedicated to their stockholders. In a for-profit industry, oversell is a huge temptation and that risk needs to be made transparent to consumers.
Second, the 23andMe test is being sold directly to individuals who may not have any knowledge of genetics. The tendency to convert risks into certainty is higher than ever. The knowledge they sell is a set of probabilities, and further, those probabilities are not stable. The consumer may not—indeed probably doesn’t—appreciate how much we know, how much we don’t know, and how much we don’t even know we don’t know. The company claims to be selling knowledge but in fact they are selling uncertainty.
In a characteristically insightful and clarifying post, the geneticist (and 23andMe board member) Michael Eisen doubts whether the 23andMe test will ever meet FDA’s definition of a “medical device.” It is not an MRI machine or a Wasserman test. It’s something new. Adequate regulation of products such as the 23andMe genome profile will require rethinking of what exactly the company is marketing.
Putting this controversy in context, then, illustrates another critical risk: the risk of failing to acknowledge the uncertainty underlying the science. In some sense, the more we learn, the less we know.
 Orkin, S. H., and A. Motulsky. Report and Recommendations of the Panel to Assess the NIH Investment in Research on Gene Therapy. Bethesda, MD: National Institutes of Health, 1995.
Thoughtful blog post over at Nature recently by Erika Check, on a $25M set of 4 studies that will sequence the exomes of 1500 neonates, whether ill or not. Called the Genomic Sequencing and Newborn Screening Disorders program, it is essentially a pilot study for universal newborn genome sequencing. One could see such a study coming down the pike. But if this is a direction in which medicine is heading, we should be moving like a wary cat, not like a bounding puppy.
The dominant rhetoric for whole-genome screening sketches a benevolent world of preventive care and healthier lifestyles. “One can imagine a day when every newborn will have their genome sequenced at birth,” said Alan Guttmacher, director of NICHD, which co-sponsors the program with the genome Institute. In his genotopian vision, a baby’s sequence “would become a part of the electronic health record that could be used throughout the rest of the child’s life both to think about better prevention but also to be more alert to early clinical manifestations of a disease.”
But deeper in her article, Check responsibly quotes a skeptic, Stephen Kingsmore of Children’s Mercy Hospital and Clinics in Kansas City, who estimates that the program is likely to find 20 false positives for every true positive. In other words, only around 5% of what will loosely be called “disease genes” will in fact lead to disease. One of the reasons for that low rate of true positives is that many of the disease alleles we can screen for concern diseases of old people: Alzheimer’s, various cancers, and so on. Life experience plays a large and still imperfectly understood role in such diseases. Sure, we can test at birth or even before for the SNPs we know correlate with those diseases, but, Check asks, what does that really tell us?
In Guttmacher’s sunny scenario about early prevention, the parents and later the child could be regularly reminded of this individual’s elevated risk. This itself has not only direct health risks but potentially a significant inadvertent impact on the patient’s social life. Everything from the child’s temperament (is she anxious by nature?) to family situation (ill siblings? Alcoholic parent? Suicide?) to many other factors could profoundly modulate how this genetic knowledge would affect the child. Social context matters.
But such an individualized, lifelong health-maintenance program is unlikely ever to be accessible beyond medicine’s most elite customers. Personalized medicine has been around since the ancient Greeks, and, logically enough, it’s expensive. Only the rich have ever been able to afford truly individualized care. “Personalized medicine” seems to have almost as many meanings as people who use the term, but if what you mean by personalized medicine is a physician who knows you as an individual and tracks your healthcare over a significant part of your lifetime, you’re talking about elite medicine.
Medicine for the middle and lower classes tends to be much more anonymous and impersonal. Throughout medical history, the headcount–if they can afford a doctor at all–get more routinized, generalized care. Even many in that fortunate segment of the population today who have health insurance attend clinics where they do not see the same doctor every time. In any given visit, their doctor is likely to know them only by their chart. No one asks, “Has your family situation settled down yet? Are you sleeping better? How’s your new exercise program going?” What you get is a 15-minute appointment, a quick diagnosis, and, usually, a prescription. Genomic technology is unlikely to change this situation. If anything, it will enhance it.
For the hoi polloi, then, personalized medicine will likely mean personalized pharmacology. Some of those most excited about personalized medicine are biotech and pharma companies and their investors, because some of the most promising results from genomic medicine have been new drugs and tests. Should neonatal genome screening become part of routine medical care, middle and lower-class parents would likely be given a report of their child’s genome, the associated disease risks, and a recommended prophylactic drug regimen. Given an elevated risk of high cholesterol or other heart disease, for example, you might be put on statins at an early age. A SNP associated with bipolar disease or schizophrenia might prompt preventive anti-depressants or anti-psychotics. And so forth.
Such a program would be driven first by the principles of conservative medical practice. Medicine plays it safe. If there’s a risk, we minimize it. If you go to the ER with a bad gash, you’ll be put on a course of antibiotics, not because you have an infection but to prevent one. Second, it would be driven by economics. Drug companies obviously want to sell drugs. So they will use direct-to-consumer marketing and whatever other tools they have to do so. That’s their right, and in a comparatively unregulated market, arguably their duty.
But now recall Kingmore’s figure of 20 false positives for every true positive. This may sound high, but again, medical practice is conservative: we’d rather warn you of a disease you won’t get than fail to notify you of a disease you will get. False positives, in other words, are preferable to false negatives. Add to that the scanty state of our knowledge of gene-environment interactions. We are rapidly accumulating mountains of data on associations between SNPs and diseases, but we still know little about how to interpret the risks. We needn’t invoke any paranoid conspiracy theory: that kind of data is devilishly hard to acquire. Science is the art of the soluble.
If Kingmore is even in the ballpark, then, the more neonatal genome screening reaches into the population, the more unnecessary drugs people will be taking. Unnecessary medication of course can have negative effects, especially over the long term. Indeed, the long-term and developmental effects of many medications–especially psychiatric medications–are unknown.
The Genomic Sequencing and Newborn Screening Disorders program is purely an investigative study. Parents in this study won’t even be given their children’s genome reports. But the study is obviously designed to investigate the impact of widespread neonatal whole-genome screening. Currently, all 50 states administer genetic screening for phenylketonuria and other common diseases. The historian Diane Paul has written a superb history of PKU screening. It’s not hard to imagine a similar scenario playing out, with one state leading the way with a bold new program of universal newborn exome screening and, in a decade or two, all other states following its lead.
“Personalized medicine” is a term that’s used increasingly loosely. It covers a multitude of both sins and virtues, from old-fashioned preventive regimens to corporate profiteering. From here, widespread neonatal genome screening looks like an idea that will benefit shareholders more than patients.