When I was in college, I got really excited about Michael Behe’s book “Darwin’s Black Box”. A lot of people did. It had just been published, and it was generating lots of discussions on college campuses and in the general reading public. The book is intended to be a challenge to the theory of evolution, and the challenge is based on Behe’s concept of “irreducible complexity”. The notion is pretty straightforward. The living systems that populate the Earth are noggin-poppingly complex. We think of evolution as working by way of some features of living systems being favored and improved over time, and other features being disfavored and weeded out over time. But, according to Behe, evolution working this way simply would not have had enough time over the entire history of the Earth to start with basic molecules bonking into one another and end up at the eyeball or human cognition. To arrive at what we know as Earth’s living systems, evolution must have started from something much more complex than basic molecules, and the only way that could happen is intelligent design.
At the time, I found the book to be provocative, insightful, and unsettling. It was exciting to think about the rigorous application of science leading to a conclusion that resembled God in many important respects. I was a science major, so obviously I was also a sci-fi geek and knew that it generally doesn’t go well in fictional universes when scientists invent God. But I was also shaken by the idea that science might have such explanatory power that it could lead inexorably to the conclusion of a divine or intelligent origin of life on Earth (again, sci-fi geek, so I was open to the possibility that it was aliens and not God).
What can I say? Undergrad is a heady time.
For me, undergrad was especially heady in the mid-1990s, when neither Google nor Wikipedia nor PubMed as you probably know it existed yet. I couldn’t just google “irreducible complexity” and go to the Wikipedia page to read all about its historical underpinnings and known logical and scientific holes going back to the 17th century and possibly even to Cicero circa 45 BCE. But what I *could* do was stay excited about science and the pursuit of rigorous understanding of complexity. That’s exactly what fired me up when I learned about Stanley Miller and the Miller-Urey experiment. In 1953, Miller and Urey wanted to rigorously test the idea that a “primordial soup” environment might somehow be a first step on the path to life. They simulated conditions that were believed to exist on Earth before life showed up – water (both liquid and steam), ammonia, methane, and hydrogen. They kept it mixing and zapped it a bunch of times with electricity over about a week (simulating lightning and miraculously not blowing the whole damn thing up in the process) until this dark sludgy stuff formed. In that dark sludgy stuff they found amino acids, some of the very building blocks of living systems.
The experiment and subsequent ones conducted by Miller and his colleagues created the new field of exobiology. More importantly, this work showed in a rigorous and reproducible way that complex pieces of the recipe of life could emerge from conditions that had nothing to do with aliens or gods, and that a few billion years might very well be enough time to allow mechanistic evolution to produce eyeballs and blood clots and the brains that came up with Cool Ranch Doritos. Over the years, exobiologists have produced lots more of the basic chemical building blocks of life from conditions that likely existed on Earth before life arrived. Evolutionary biologists and exobiologist have also shown that evolution likely works through processes much more efficient and much less linear than had been previously imagined, using things that already exist to accomplish new tasks. For example, the first job that RNA had was probably to catalyze reactions, including making copies of itself. Now, proteins do a lot of that kind of work, and RNA is more in the business of conveying orders though it still does some enzymatic consulting work.
Behe’s arguments were compelling to a lot of people. The arguments hinged on the idea of irreducible complexity, which somewhat ironically is an idea simple enough to grasp fairly readily – too complicated to explain with science, so must be God/intelligent design. The simplicity itself is appealing, and the argument is even more believable because it’s coming from a card-carrying scientist. The problem, of course, is that we now know that “too complicated to explain with science” isn’t correct. Science and scientists have wrestled with the complexity very capably. I don’t necessarily fault Dr. Behe for this error or oversight when writing his book. I *do* fault him as a scientist for sticking to his guns as an expert witness for the defense in Kitzmiller v. Dover Area School District. Despite a decade of discussion and data-informed critique of his arguments, Behe testified that intelligent design is a legitimate scientific theory. Federal Judge John E. Jones III disagreed in a very well-reasoned decision, finding in favor of the plaintiffs and recommending to the U.S. Attorney’s office that some of the defendants (including Behe) be investigated for perjury.
Perjury or not, I think Behe’s big mistake as a scientist is oversimplification. He didn’t appreciate and wrestle with the complexity of living systems, instead relegating that beautiful complexity to an undefined and unfalsifiable (thus unscientific) intelligence. Such complexity is daunting. It can be impenetrable to any one person or group for a long time, sometimes longer than a career. But dismissing it, ignoring it, or otherwise failing to reckon with it doesn’t make it go away. Most of the time, it just makes you wrong.
If The Music’s Too Loud (or The Science Too Simple), You’re Too Old
I think when one is knocking on the door of 50 years old, it’s probably pretty normal to be sensitive to any signs of impending curmudgeonly oldness. I think this might be especially true for Gen Xers who were really plugged into the punk rock vibe in our younger days and still feel it in our hearts now. Ever since we first felt the energy and the community and the power of the youth collective in a mosh pit at a garage/backyard show, we’ve tried hard not to betray that.
So it made me worry a whole lot when I recently found myself in two different situations remembering undergrad and Behe and thinking the same thing: “There needs to be more gray hair in this room.”
In both cases, young scientists and thinkers were putting forth ideas intended to challenge the status quo, challenge calcified notions of how things are done, and push open the aperture of what’s possible. In both cases, the stated goals were noble ones. In both cases, the young scientists and thinkers had the ear of powerful people ready to act on what these visionaries said they could see that older establishment people simply can’t or won’t.
And in both cases, I found myself worrying very much about the damage that their naivete could do. The ideas that were being discussed, put forward, and in some cases put into motion were intriguing. But as one of the other folks with as much gray as me put it, “This is like 101 stuff.” The ideas were appealing in their simplicity, which was also the main problem. They were too simple. Many of the ideas being considered had to do with the foundations of how we do science, especially science involving people as participants – stuff like clinical trials and first-in-human studies. These young visionaries were right that making changes at foundational levels can have big impact. I think they were wrong about how easy it might be, and I definitely think they didn’t appreciate the full range of possible outcomes.
As examples of the kinds of ideas and issues that we’re talking about here, consider the following:
· Clinical trials are incredibly expensive, especially in the U.S.
· The possibilities for human-machine interface devices like cybernetic implants are very exciting
· Regulatory requirements can be opaque and confusing and onerous in ways that slow down research progress
· There are immense opportunities for discovery in real-world data
· Moving early drug development into testing in non-animal models could make the process faster and cheaper
These are all basically true statements. Indeed, there are often numbers attached to them (e.g., the average clinical trial in the U.S. costs $50M, a price tag that is several fold higher than 10-20 years ago). For each of these, though, there is often a second part that I think falls flat because of a lack of appreciation for important complexities that are more apparent to people who have more experience. It’s not really age per se. It’s experience, or lack thereof.
It would be wonderful if the above issues had relatively simple solutions that just required new eyes to see them and new energy to implement them. Clinical trials too slow and expensive, with cumbersome regulatory processes? Just make first-in-human trials easier and reduce IRB oversight requirements, like other countries have done. Drugs can’t be accessed by the people who need them because the drugs are expensive? Just use some real-world databases and shift to non-animal models, and drugs will get cheaper.
I’ve had an unofficial rule for a long time – the word “just” used as an adverb is a red flag that should make you wonder if the person who said it fully understands the situation. “You just have to do XYZ” or “If we just changed PQR and S” are appealing in their simplicity, and they’re almost always wrong in some important aspect. It’s not that streamlining Phase 1 clinical trials is a bad idea that won’t help anything. But because of the complexities of the clinical trials ecosystem, it’s entirely possible that streamlining Phase 1 clinical trials might not meaningfully change any of the issues that so frustrate people, especially if the second order and third order and nth order effects aren’t considered because they aren’t appreciated or accounted for. There are absolutely tremendous opportunities for discovery in real-world data. But there *must* be reasons for why we haven’t realized the full impact of those opportunities. And yes, it turns out there are *lots* of reasons, only a subset of which are addressed by any one proposed solution. Smart people have been working on these issues for a long time and have been frustrated by them for a long time. That’s not because there isn’t a desire to solve them, but it’s because these are really complicated, thorny, nuanced problems. These issues are new to all of us at some point, but they’re not new to the field.
Hey! Ho! Let’s Go!
At this point I should also say that nothing irritates me more than when someone is presented with an idea or proposal to change something for the better and has a knee-jerk response of, “Oh, XYZ was done ABC years ago” or “So-and-so worked on that a decade ago” or something like that. As though whatever those previous efforts were addressed the issue sufficiently, and we should move along. I always want to immediately pop off with, “And yet, here we [expletive] are so I guess they didn’t really [expletive] do it, did they??!!!” I generally don’t, as it’s not a way to make friends. But offhandedly dismissing the entire question or issue or proposal reads like calcification and a lack of curiosity, neither of which are a good look for a serious scientist.
So, to both the young folks and the older folks, I urge you/all of us to fall in love with the complexity of the issues. Young folks, loving the complexities will help keep you from oversimplifying in ways that don’t stand the test of time and that don’t let you actually improve anything. Older folks, loving the complexities will keep you curious and will help stave off calcification of ideas and insights. Once we’ve all fallen in love with the complexities, we need to seek each other out. The older folks will help the young folks avoid reinventing wheels and avoid doing things that seem to make sense but are bad ideas. The young folks will help the older folks stay engaged with and excited about the most important challenges of the moment, will bring fresh perspective, and will help ensure that solutions fit the present moment.
It might look chaotic to the uninformed, but it’s about all of us loving the same thing and coming together to do something impactful that we couldn’t do alone. Kinda like a mosh pit, and that’s pretty punk rock.
Gabba gabba hey!
