Against Medical Nihilism!

 A couple of years ago I reviewed the book Medical Nihilism by Jacob Stegenga. Broadly speaking, Stegenga's narrative is that medical interventions are mostly ineffective. There are some obvious exceptions. Emergency medicine really does stabilize trauma victims and save their lives, or less dramatically, fixes broken bones in place so they'll knit properly. Prenatal care, lifestyle interventions, sanitary water supply, and vaccines can be highly effective. But generally speaking, pharmaceutical interventions don't work all that well. Huge clinical trials using very large samples often find only trivial differences between the control group and the treatment group, casting doubt on whether the treatment truly has a significant effect on the disease. Even when a study finds a "statistically significant" difference, it can be an illusion or a fluke or a result of p-hacking. And "statistical" significance does not imply clinical significance; the effect of the medication on a disease can be so small that the cost-benefit analysis is overwhelmed by side effects. We like to think we live in an age of science and enlightenment. We'd love to believe that basic research has brought us to a mature understanding of how our bodies work, and we can simply engineer new treatments based on our first principles understanding of our own biology. The reality is that we can't engineer cancer cures or cholesterol medications from first principles. We discover empirically, that, say, a blood pressure medication treats erectile disfunction, or a cancer drug turns out to be effective at treating Alzheimer's (maybe). It reminds me of the saying, "Thermodynamics owes more to the steam engine than the steam engine to thermodynamics." In other words, practical discovery comes first and scientific theorizing follows, rather than the other way around. Our bumbling, plodding research into new pharmaceuticals occasionally yields an effective treatment by chance, after which we might be able to back-fit a biological mechanism. The narrative of our conquering nature with scientific theories is mostly wrong. I won't rehash his entire argument here; please read my prior post for that, or pick up Stegenga's excellent book. 

I wanted to check in to say, "To hell with all that!" Stegenga's story is true enough for certain classes of medicine, but we have all just witnessed a massive counter-example. See this piece by David Henderson and Charles Hooper, particularly the timeline:

The Moderna lab in Massachusetts took all of one weekend to formulate the vaccine, which was ready on Monday, January 13. David Wallace-Wells of New York magazine writes, “It was completed before China had even acknowledged that the disease could be transmitted from human to human, more than a week before the first confirmed coronavirus case in the United States.” 

Here’s the timeline:

January 13, the mRNA-1273 vaccine is formulated

February 7, the first clinical batch is produced

February 24, Moderna ships the first batch to the NIH for a Phase 1 clinical trial

March 4, the FDA gives permission to conduct a Phase 1 clinical trial (safety only)

March 16, the first human subject is given a dose

March 23, Moderna begins scaling up for commercial production

March 27, another Phase 1 clinical trial begins

April 27, Moderna ask the FDA for permission to run a Phase 2 clinical trial (safety and efficacy in a limited number of test subjects)

May 1, Moderna and Lonza announce a plan to manufacture a billion doses a year

May 12, the FDA gives Moderna Fast Track designation for mRNA-1273

May 18, Moderna announces positive Phase 1 clinical results

May 29, the first test subjects are dosed in a Phase 2 clinical trial

July 14, Phase 1 results are published

July 27, a Phase 3 clinical trial begins (safety and efficacy in a large number of test subjects)

July 28, non-human primate study results are published

November 16, Phase 3 results show the vaccine is 94.5% effective at preventing infections

November 30, the FDA announces that it will convene an advisory committee meeting on December 17

December 2, the U.K. approves a similar vaccine from Pfizer and BioNTech

December 11, the FDA gives the Pfizer/BioNTech vaccine an emergency use authorization

In other words, scientists developed a 95% effective vaccine on their first try using basic first principles. The vaccine was designed over the course of a weekend. It doesn't seem to be a fluke, either. There are two vaccines authorized for emergency use in the US and several more promising ones under development. The two that have been authorized are both mRNA vaccines, something that didn't really exist before the pandemic, except as a scientific curiosity. If I'm getting this right, the vaccine is a shot of mRNA that gets into your cells and tells them to make proteins specific to the SARS-Cov-2 virus. Your immune system learns to spot these proteins and develops antibodies to them. So you get immunity without the need to fend off the live virus. I find this very cool. The mechanism of action is something one could imagine with only a high school level understanding of biology. The exact engineering feats required to turn that idea into a working vaccine are no doubt more complicated, but then again scientists at a lab got it right basically on the first shot. And this was in January, before anyone was talking about lockdowns or freaking out about the coronavirus. This happened before there was any massive mobilization of resources to come up with a vaccine. 

In my previous post on Medical Nihilism, I invited the reader to think about the trajectory from present day to a Star Trek future with unimaginable treatments for all known diseases. It matters a great deal to our descendants' well-being whether that future is a mere 100 years off or a full 200 years off, so we should do what we can to speed up the transition. I basically accepted Stegenga's thesis that most new medicines are ineffective, but I argued that we'd need to do a lot of slow, plodding experimentation and tolerate a lot of false promises to find truly useful treatments. That's likely true for many types of medical problems, but I should probably update my priors. Maybe SARS-Cov-2 was a uniquely easy puzzle to solve, but the speed of development, the multiple early successes, and stunning effectiveness makes me think there are more opportunities for "first principles medicine" lurking in the background. I'm going to double down on my observation that Stegenga got the policy implications exactly backwards. He suggested that the low effectiveness of medicines implied that the FDA should be stricter about the approval process. I think he didn't appreciate that this could be a self-fulfilling prophecy: strict approval guidelines means we see less experimentation, slower progress, and fewer breakthrough medicines. New treatments are being held back by stifling regulations. Let's give drug developers the right to innovate and give patients sovereignty over their bodies so they can try these new medicines. 

I don't want to over-apply this lesson. Maybe the example really is very specific to vaccines, or even specific to coronavirus vaccines. That's still huge. If we can have a vaccine ready to go within weeks of discovering a new virus, we have the tools to stop the next pandemic before it gets going. Even if that only happens once a century it's a big deal. (There have been flu seasons comparable to 2020 in terms of mortality, so "once a century" is likely an underestimate for the frequency of deadly pandemics.) Even if this truly is just a one-off, even if all it does is shorten a single global pandemic by a few months and save a hundred thousand lives, it still stands as an impressive (and high-impact) counter-example to a narrative that I mostly bought into before. 

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I remember Tyler Cowen quoting someone back in June or July regarding the slowness of vaccine development, in a blog post that I couldn't find now if I tried. The quote was something like: Isn't it funny that it takes months or years for the world's best scientific minds working in concert to develop a vaccine, but our body just does it in a week or two? This was back when people were saying a vaccine might be two years off, with some even saying we might never have one. Turns out we had one in mid-January. Some clever scientists know precisely what your immune system is trying to do, and they figured out how to trigger it without making you sick.