23andMe, FDA, and the history of hype

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.

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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.[1]

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.

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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.

 


[1] 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.

DNA Ink

We’ve been pretty serious for a while, which always makes me a little edgy. And “tattoos” or some version thereof continues to be one of the biggest search terms for this blog. So, to raise the font size of “tattoos” in the tag cloud, I’ve put together a gallery of eye candy.

In their 1994 book, The DNA Mystique, Susan Lindee and Dorothy Nelkin write that “habitual images and familiar metaphors…provide the cultural forms that make ideas communicable.” The double helix is the scientific icon of our age—much like the Bohr atom was during the Cold War. Putting it on your body identifies you with science, with biotechnology, with life. It is also just a stone beautiful image, which works in a line, say down your spine, wrapped around a biceps or ankle, or curving sinuously just about anywhere. The best collection of science-themed tattoos of course is Carl Zimmer’s “Science Tattoo Emporium.” Many of these were borrowed from his archive, so a big hat-tip (tat-hip?) to him. I have the hardcover version Science Ink prominently displayed on my coffee table. Others drawn from elsewhere around the web. Click the picture to open the original url.

tree-dna
A DNA riff on the Darwinian image of the “tree of life.” But it of course also reminds me of the eugenics tree…

eugenics-tree

Foot tattoos are hard. Here's a cute rendition of unwinding DNA that flows nicely with the anatomy.
Foot tattoos are hard. Here’s a cute rendition of unwinding DNA that flows nicely with the anatomy.
Not the best execution of the image (no major and minor grooves), but a neat black-light effect that reminds me of fluorescent labeling.
Not the best execution of the image (no major and minor grooves), but a neat black-light effect that reminds me of fluorescent labeling.
Just. Wow.
Just. Wow.
All right, I admit I'm wondering whether this represents bacterial DNA (and is therefore circular).
All right, I admit I’m wondering whether this represents bacterial DNA (and is therefore circular).
An interesting “biomechanical” visual effect.
Here artist Jason Stomber has woven the double helix into a full sleeve.
Here artist Jason Stomber has woven the double helix into a full sleeve.
Clever use of the DNA icon by a pair of twin sisters. Of course, when they line them up, they become prokaryotes.
Clever use of the DNA icon by a pair of twin sisters. Of course, when they line them up, they become prokaryotes.

 

 

23andMe, myself, and I

Here is the new ad from 23andMe that will begin airing shortly on cable TV*:

Genomics is going mainstream and the best news is first that it’s real simple and second that it’s all about me.

Let’s take the most obvious first: the “me” meme. Of course this relates to the company name, but the ad takes me to a new level. It makes “you” your DNA. I give them points for a couple of qualifiers — it “helps” make me who I am, one character says. But the overall message is that you are your genes.

It also exploits the meme of egocentrism. Nearly everything today seems to be all about me. Memoirs are the hottest genre of nonfiction. We have a magazine called “Self.” One of the most common themes on commercial websites is to have a “My [company name]” area, which usually just means they have your personal information to use to sell you more stuff. There’s even a “.me” internet domain, which they advertise “is all about you.” Who isn’t curious about himself? I’m the most interesting topic in the world! And 23andMe will tell me about my true inner nature for just $99.

One element of personalized medicine, then, is narcissism. Another, more noble, element is individuality. No one is more committed to his individuality than I am—but I’m also wary of its dark side: selfishness. I am struck by the single reference to future generations (“what I will pass on to my kids”). Again, this is a two-sided coin. In the Progressive era, the literature on genetic medicine emphasized family and community. There isn’t a hint of that here. On the one hand, then, the ad is free of the eugenic message of controlling human evolution. On the other, it’s relentlessly selfish. Most likely, the reason for staying away from issues such as family, community, and responsibility is that it enables them to steer way wide of abortion. This ad is about me, not my kids and not the future. That’s actually a new and rather radical development in genetics. 

A persistent theme in popular literature from the 19th century to the 21st, is that hereditary information provides certainty. This despite the fact that one of the signal insights from genomics is how uncertain its results are. Genetic medicine today is all about probabilities, and to make informed decisions based on our genetics we have to understand how probability works. The ad works against this principle, promising certainty where there is only chance. “Now, I know” says one woman. No, you don’t. Now, you have a sense of risk—not certainty. This is a dangerous over-simplification.

double helix
Simplified double helix from Watson and Crick’s 1953 paper.

This sense of simplicity is also carried in the graphics. Note how there’s hardly a double helix in it. “Your” DNA is reduced to circles, dots, and lines. They move and whirl entertainingly and there’s just enough suggestion of complexity to carry the message that you can’t understand “you” without them‚ 23andMe. If DNA becomes as central to identity as companies such as 23andMe want to make it, this ad suggests that its iconic image may fade. Even the stripped-down ribbons and bars version is simply too complex for TV.

karyotypedowns
An early karyogram (of Down syndrome) from the 1960s.
A comprehensive chromosome map from UCSF.
Screen shot from 23andMe commercial. Her “DNA” is those two colorful cylinders by her ear.

Most of the genetic “knowledge” promised is simple enough to be carried in the one- and two-syllable words that dominate mass-market media. Genetic medicine, stuffed as it is with Latinate and Greek words, is a tough sell in that market, but the ad pulls it off. At 0:21 we hear the longest word in the ad: “hemochromatosis.” The speaker pauses after the second syllable, to suggest empathy with viewers who get hung up on such terms. According to the Mayo Clinic website, hemochromatosis is indeed usually inherited, is rarely serious, is most common in men, and is the most common genetic disease in Caucasians. The ad script gives this word to a black man. Thus, one of the ad’s subtle messages is to erase racial differences—even differences supported by scientific evidence. It’s a commonplace in TV ads nowadays to feature men and women of many hues, but the 23andMe ad takes it a step further.

Another theme of the commercial is the way it suggests communities based around biological identities of health and disease. Once, our primary identities were with those who lived near us, or shared our work or hobbies or politics. But politics has become personal, our communities are digital, and our identities center around health. The sociologist Nikolas Rose calls this “biological citizenship.” The 23andMe website features forums where members who share particular mutations or risks can discuss diets, lifestyle habits, child-bearing decisions–or their pets, if they wish. They are communities based around health. The ad sends the message that race, class, and gender are no longer our defining social themes: what matters now is health and disability.

We hear so much about the importance of educating the public about their biology as a key component of contemporary personalized medicine, but in this ad that biology is reduced to bumper-sticker-like phrases about this circle “saying” I will have blue eyes and that line segment “saying” I have a risk of this or that disease. Learning about me will be fun, easy, and inexpensive. Thank goodness I can mail off a C-note, spit in a cup, and in a few weeks get a report that simplifies it all in language I can understand. The ad ends with a rainbow of people chanting “Me. Me. Me.” It’s the “Om” of the 21st century.

 

*h/t to Bob Resta for sending the link to the ad, and to Shirley Wu (@shwu) for a tweet that showed me that the hemochromatosis passage was too terse in yesterday’s version. I’d been wanting to add something about biological citizenship and Shirley’s comment suggested a way to do it.

 

 

 

DNA spoofing

Okay, there could not be a more apt title for a Genotopia post. This conceptual art piece is scientifically silly, almost frivolous, but it makes a serious point (I know!): the prospect of genetic surveillance is creepy. I love the notion of “genetic ambiguity.”

http://ahprojects.com/projects/dna-spoofing

Sexuagenerian Double Helix

It’s not “DNA day.” That’s in April–fittingly, the date of publication. Today is double helix day.
On this date in 1953, Watson and Crick solved the structure of DNA. What better day to lay to rest a few myths about it?

Watson and Crick
Another, more candid shot from Barrington Brown’s roll.

1) It sparked a scientific revolution.
The double helix caused a stir in the scientific fields closest to Watson and Crick’s work: X-ray crystallography and bacteriophage genetics. But it took several years for the structure and it’s most important implication–the copying of the genetic material–to be confirmed. True, Time Magazine sent a photographer to Cambridge to shoot for a possible feature. From it came Barrington Brown’s famous photo of the duo before a mock-up of the structure, with Crick brandishing of all things a slide rule at it and smirking at the silliness, and Watson gazing, baffled, up at his hero. But they pulled the story. The double helix didn’t become world-famous until after the Nobel Prize, in 1962. the revolution did come, then, but it reverberated from the fusillade of discoveries from molecular biology of the fifties and early sixties: the double helix, the Meselson-Stahl experiment, the operon, and, perhaps most importantly, the genetic code.

Photograph 512. Watson stole Photograph 51.
The beautiful photograph of the diffraction pattern of b-form DNA taken by Rosalind Franklin and Raymond Gosling famously provided crucial evidence that enabled Watson and Crick to solve the structure. Watson obtained the image without Franklin’s knowledge. But the image was given by Gosling to Maurice Wilkins, who gave it to Watson. As correspondence recently published in The Annotated and Illustrated Double Helix makes clear, the administrative relationship between Wilkins and Franklin was murky. Franklin reasonably assumed she was independent of Wilkins; yet he apparently was technically if not in practice her supervisor. Watson may well have exploited these ambiguities; he was intensely competitive for that time. But theft is such an ugly word.

3. Watson and Crick were racing against Linus Pauling.
Pauling seems to have been genuinely surprised to learn that he was racing for the double helix against the oddball duo from Cambridge. Watson probably felt a sense of competition with the great pioneer of structural chemistry, but it takes two to race. Watson thought he was racing against everyone, with the possible exception of Crick. The real competition was with the group at King’s College London–Wilkins and Franklin.

4. The Double Helix is a history of the double helix.
Watson’s best-selling book is a literary-historical memoir. It is an important source for historians, but it must be read with care. The book was shaped by personal goals, politics, and literary strategies as much as by historical events. It is naive to treat it as a literal account of what “really happened.”

In the past sixty years, DNA has become the foundation of biomedicine, an emblem of innateness, the most famous molecule in history. It promises more revolutions to come, in healthcare and in our sense of identity. Let us celebrate it by demystifying it. History, too, can be salutary.

Read On

Comfort, Nathaniel. “‘Novel Features of Considerable Interest’.” Science 339, no. 6120 (2013): 648-48. doi:10.1126/science.1233356.

Gingras, Yves. “Revisiting the “Quiet Debut” of the Double Helix: A Bibliometric and Methodological Note on the “Impact” of Scientific Publications.” J Hist Biol 43, no. 1 (2010 2010): 159-81.

Creager, Angela N. H., and G. J. Morgan. “After the Double Helix: Rosalind Franklin’s Research on Tobacco Mosaic Virus.” Isis 99, no. 2 (2008 2008): 239-72.

de Chadarevian, Soraya. “Portrait of a Discovery : Watson, Crick, and the Double Helix.” Isis 94 (2003 2003): 90-105.

The biology of good and evil

In today’s New York Times, columnist David Brooks writes about the innate capacities for good and evil. Criticizing what he considers the prevailing worldview today, he writes that we believe that nature is fundamentally good, and hence, so we believe, are people. The Hitlers, the Idi Amins of this world are fundamentally warped. “This worldview,” he writes, “gives us an easy conscience, because we don’t have to contemplate the evil in ourselves. But when somebody who seems mostly good does something completely awful”–such as Robert Bales‘s recent massacre of 16 Afghan civilians, including children–“we’re rendered mute or confused.”

Brooks prefers an older view, in which humans are believed to be a mixture of good and evil. Thus, everyone possesses in some measure the capacity for atrocity. We should be concerned and shocked when such actions are committed, but not surprised. So far, I’m with him. I agree about the “easy conscience” that comes with the lack of hard introspection.

But Brooks then makes his argument biological. He cites the University of Texas evolutionary psychologist David Buss in support of his view. Buss studies human behavior such as jealousy, violence, and mating strategies in the context of Darwinism and especially sex differences. He is thus part of a long tradition of psychologists who seek to explain sexual and antisocial behavior in naturalistic terms, stretching back through Edward O. Wilson‘s sociobiology in the 1970s (here is the famous “Chapter 27” from his textbook, which defined the field) and 1980s, to Progressive-era researchers such as the feeblemindedness expert Henry Goddard, the founder of eugenics Francis Galton, and the Italian criminologist Cesare Lombroso. Such work inevitably sparks controversy because it claims that antisocial behavior is innate and therefore genetic.

Genetic determinism is often associated with a conservative and punitive worldview. If violent tendencies are inborn, there is little we can do about them. Those who display them must be locked up, so that the law-abiding can get on with their lives. Genetic determinism tends to ignore the environmental causes of violence, such as poverty and oppression. Historically, it has tended to align with the preference for criminalization over medicalization of antisocial behavior. That, however, may be changing. Perhaps it is possible to “cure” such behavior by tweaking our genes.

In “The Murderer Next Door: Why the Mind is Designed to Kill,” Buss argues that murderous tendencies have been selected for in evolution. By definition, that which can be selected for has not only a basis in our physical bodies, but therefore a basis in our genes. A necessary implication of this view, then, is that there are certain forms of certain genes that predispose us to violence. Buss’s work is the evil twin of works such as Matt Ridley’s The Origins of Virtue. Although the eugenics of the 1910s–1930s is easily mocked for its simplistic biologically determinist analyses of complex behaviors, now we have more complex biologically determinist analyses of complex behaviors. The problems raised by both are essentially the same.

If there are genes for good and evil, then we can find them. Genome-wide association studies are certainly capable of finding correlations between murder and certain passages in our DNA text. I believe they can find correlations between DNA and almost anything. It is only a matter of time before the “genes for” heinous acts such as Bales’s are found.

I believe those genes exist. There is no rational reason to doubt it. The problem is that the finding may well be meaningless. Something like criminal behavior is so complex that it will turn out to be influenced by hundreds if not thousands of genes. Those genes will interact in complex ways, both with each other and with the environment—and those interactions will themselves depend on other genes and other environmental factors. Finding genes associated with violence would be like finding a handful of sand and claiming that a cause of surfing has been discovered. Well yes, but so what?

Historically, finding that violence is “in the genes” has reinforced punitive models of behavior modification. “Innate” has equaled “immutable.” But biomedical research is moving rapidly toward being able to change the genes. In principle, the controlled environment of the laboratory is much more conducive to engineering than the messy world of populations, culture, and economics. Someday, we may wish for a trait to be found to be strongly heritable, for then it will be easy to alter–the way infectious diseases such as tuberculosis, which once were a death sentence, are now in the age of antibiotics easily treatable. In such a world, the ultimate arbiter of social behavior shifts from the justice system to the biomedical system.

Such a biomedical Brave New World would have enormous implications. I don’t see that we have begun to address the consequences of such a shift.

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