Why Genetic Medicine Never Arrived

DNA: more complicated than we thought

The direct-to-consumer genetic testing company 23andMe just announced that it will close the drug-development arm of its business, roughly twenty years after the completion of the Human Genome Project (in which scientists sequenced the full human genome). This closure has symbolic importance for the promise of genetic medicine, and I want to try to explain why. 

I signed up for 23andMe not long after Time magazine named it “Invention of the Year” in 2008. I was interested in genetics, and was soon to start writing a book about genetics and athleticism, so wanted to understand what was available. I collected my saliva in a tube, sent it to the company, and pretty soon I could log in and see how likely I was to have curly hair (pretty easy to figure out even without genetic testing), to metabolize caffeine easily, or to be allergic to gluten. 

The marketing focused on helping consumers learn about their traits and health proclivities. But it was fairly obvious that the long game was to collect user information for drug development. I didn’t get very far into my research for The Sports Gene before I decided that this would probably be a failure of a business model, thanks to the inherent complexity of genetics — not to mention all the other things that impact human health, like environment, and behavior. Here is a passage from that book, published in 2013:

“A decade ago, when the sequencing of the human genome was heralded as the beginning of an age of personalized medicine, scientists hoped for a simple biological system in which a single gene or a small number of genes would define a single characteristic. Now, it is maddeningly obvious that most traits are far more complex.” 

Let me give you a simple example of this complexity, one that came out of a tragedy in my own life. 

As some of my long-time readers know, I got interested in science writing after one of my track-and-field training partners — one of the top 800-meter runners in the country in his age group — dropped dead a few steps after a mile race. I was devastated, and curious how that could happen to a guy who was an apparent picture of health. His family signed a waiver allowing me to gather his medical records, to see what I could learn. Long story short, we eventually found out that he had an undiagnosed condition called hypertrophic cardiomyopathy, or HCM, which led to the electrical signals in his heart going haywire. It’s the most common cause of young athletes dropping dead. 

I was eager to learn more about HCM, and then to write about it in the hope that others might be spared. One of the first things I learned was that the disease is caused by a single genetic mutation. That’s roughly like a single typo in one word of one book in an entire indie bookstore. 

On the one hand, I found it infuriating that such a minuscule error led to such a devastating result, as if somehow that meant it should have been caught by the genome copy-editing team. On the other hand, I found it encouraging: with such a simple genetic origin, it should be easy to understand the disease. 

In the 1990s, researchers had discovered a mutation that caused HCM. But then they discovered another mutation that also caused HCM. And then another one. And another, and another. By the time I was writing my book on genetics, there were something like 1,400 known mutations, any one of which could cause HCM. Some of those were fairly common. But when I visited a lab at Harvard that searched for new mutations, I learned that they mostly found “private” mutations. That is: mutations specific to a single individual or family. So you can have a bunch of people who all have the same disease that is caused by a single gene mutation, and yet none of them have the same genomic typo. Suddenly, a disease that appeared to be the model of simplicity looks a lot more complex. 

Still, HCM is close to the easiest possible case in terms of understanding the genetics of disease. Vanishingly few illnesses or traits stem from a single gene. When I started learning about genetics, there were scientists who hoped that a handful of genes would determine nearly all of the difference in height between adults. Now we know that there are at least thousands of spots along the genome that play a part; it’s possible that every gene (as well as non-gene parts of DNA) may be involved, each one contributing some tiny influence.¹ We know that genes influence height, but the largest study of height genetics involved 5.4 million people, and found 12,000 different gene variants that each played a tiny role, and even all of those together accounted for less than half of the height difference between adults. That’s not even to mention the impact of environment. 

Twenty years ago, there was hype that, within a decade, we would all carry a microchip with our genome around in our pocket and present it when we needed personalized healthcare. But pretty quickly it became obvious that a project like what 23andMe tried — looking for lots of individual genetic variations associated with common diseases — would not be revolutionary, and might be completely useless. 

That’s not to say that there haven’t been medical leaps from genetic research, but they have tended to come from what my friend Mike Joyner, a Mayo Clinic physiologist, calls “experiment-of-nature” patients.² For example, scientists have found individuals with mutations on a gene called PCSK9, some of whom have extraordinarily high cholesterol, and others who have extraordinarily low cholesterol. Research on those individuals has led to drugs that regulate cholesterol. (I was actually involved in one other experiment-of-nature case that ended up as medical research — in which an Olympic medalist sprinter turned out to have a mutation that causes fat loss and muscle growth.) 

For the most part, though, wishful thinking about genetic simplicity has given way to such enormous complexity that a lot of genetic research has no hope of making an impact. Grapes have more genes than humans (and don’t even get me started on rice or onions), but the human genome involves incredibly complex interactions of many bits of DNA, each usually having only a tiny impact that may be difficult or essentially impossible to discern — again, not even to mention the influence of environment. I find all this fascinating because I’ve been interested in genetics since my training partner died. But I also think there’s a cautionary tale about certain forms of technological hype, particularly the kind that give us indirect (and less accurate) ways to do or measure things we can already do or measure directly. What we really care about is not the genotype, but the phenotype, the actual observable characteristic of a person, which is the manifestation of both their genetics and environment. It seems to me that the hype of the former, at times, gets in the way of research on the latter. 

Back when I was writing The Sports Gene, companies were offering tests for ACTN3, known as the “sprint gene” because it appears to have a tiny influence on speed. But as Carl Foster, who had co-authored several ACTN3 studies told me back then: “If you want to know if your kid is going to be fast, the best genetic test right now is a stopwatch.” That’s still true. (And 80% of the world has the “sprint gene” anyway.) A lot of genetic testing, to me, is like measuring a man’s height by dropping a ball from a roof and using the time it takes to hit him in the head to determine how tall he is. Why not just use a tape measure? 

Thanks, as always, for reading. If you’re genetically predisposed to finding this post interesting, please share it:

And if you’re new here, please subscribe:

Until next time…

David

1. Genes, the portions of DNA that contain specific instructions for building proteins, comprise only a small part of your genome.

2. Another example of a medical success story that involved genetic research.