Curiosity Doesn't Defend Itself - An Interview with Dr. Rob Phillips
Photo from Caltech
Dr. Rob Phillips is the Fred and Nancy Morris Professor of Biophysics, Biology, and Physics at the California Institute of Technology (Caltech). Dr. Phillips has an unconventional background, as he didn’t initially intend to go to college. After spending seven years traveling, self-studying, and working as an electrician, Dr. Phillips earned his bachelor's degree by mail at the University of Minnesota in 1986. In 1989, he earned his PhD in condensed matter physics at Washington University in St. Louis. Before joining Caltech in 2000, Dr. Phillips was a professor at Brown University. His research currently focuses on developing quantitative, theoretical models to describe biological phenomena, and spans areas such as gene regulation and energy flow in biological systems. Dr. Phillips was the recipient of the Richard P. Feynman Prize for Excellence in Teaching, Caltech’s highest teaching prize, in 2021. Dr. Phillips is a co-author of the widely used biophysics textbook Physical Biology of the Cell. He has authored and co-authored many other books, such as Crystals, Defects, and Microstructures: Modeling Across Scales, Cell Biology by the Numbers, and The Molecular Switch: Signalling and Allostery. Dr. Phillips is an avid reader and enjoys surfing in his free time.
My conversation with Dr. Phillips covered a wide range of topics, from his love of surfing to his cutting-edge research on gene regulation. In speaking with Dr. Phillips, I learned a lot about the importance of estimation and quantitative thinking as important tools for understanding complex systems. Curiosity drives science. The natural world is thrumming with a myriad of wild and wonderful phenomena, many of which have yet to be discovered or explained. Some may never be fully understood, and others may have the potential to completely overturn our knowledge of the world. As Dr. Phillips mentions multiple times in our interview, ‘curiosity doesn’t defend itself’: there are questions to be asked everywhere and anywhere, but it’s on us to pursue them.
Vivek: Could you give me and my audience a sense of your background, your education, and your journey to becoming interested in science?
Dr. Phillips: To summarize simply, I had two parents who were extremely supportive of questioning everything, being highly creative, and doing your best—those kinds of things. I never felt that school suited me. It never did, even when I was young. I was in all the honors classes, and then we moved to San Diego, where I was put in public schools. I became a surfer, and somehow that felt more natural than being an honors student. But it also felt a little off because some of the guys were interested in drugs and other things.
I had zero interest in science and not particularly any deep interest in math. But there was one day—April 30, 1977—when I went to a friend's house. His dad spent hours explaining all sorts of fascinating things to us, from how Eratosthenes measured the radius of the Earth to Kepler’s work, Tycho Brahe's naked-eye astronomy of Mars, what Galileo had done, and what Newton had done. I was deeply impressed by the idea that a single individual human being could have a question, work hard enough, and actually learn something universal. I was deeply moved by that, and very quickly after, I embarked on a seven-year-long course of self-study in math and physics. I loved it. I wouldn’t trade it for anything.
I’m poorly educated in a way—I missed a lot of things—but I had passion, and that’s what drove me. There was no concern about grades, no worry about peers judging me as better or worse. It was purely about how fun it was to learn about quantum mechanics and how amazing it was that Maxwell figured out there were waves traveling through space at the speed of light. I thought it was incredible. I went on a six-month sailboat trip, a six-month van trip by myself, and a four-month trip to Europe. I didn’t go to college. I ended up going to grad school in physics after spending a couple of years at WashU in St. Louis. I got my undergraduate degree by mail from the University of Minnesota. And, to be a bit provocative—if only to challenge you and your audience—I’m pretty suspicious of the whole educational enterprise. I think it’s too focused on questions of performance. I don't have a structured version of physics, mathematics, and biology—all these subjects that are my main métier. They are all weirdly tangled up with each other, in a way, because I didn't go through some curriculum. Instead, I was like, ‘Yeah, I'm curious about that thing,’ you know, like climbing plants that circle around a vine. Like, that's just cool. And do I need to call that biology, or do I need to call that physics or mathematics? I don't care. And actually, Nature doesn't care either. I had a dad who was super insistent about the uniqueness of outlook, and I'm such a believer in that. My background was based on the following notion: curiosity never defends itself. That's just not the structure of going to high school or college. There are courses, and there are credits, and there are grades. And all those priorities are completely different than me telling you, ‘Hey, Vivek, you want to go through the Galapagos? We're going to go there for a week, and, yeah, we're going to swim with penguins at the equator.’Just the exploration of the fact that penguins at the equator exist could keep us busy for a week, probably more. No tests, no credits, no anything other than, ‘That's cool.’
Vivek: A significant part of your research centers on gene regulation. Could you describe your research and what you hope to discover?
Dr. Phillips: So the research directions we pursue are pretty broad, but on the subject of genes and their regulation, I think it's something that's really interesting. For your generation, which has been imbued right from the start with the use of computers and software, I think you'll appreciate the following. Maybe it's a metaphor or an analogy—I’m not sure which word fits best.
If you look in the mirror, [we] each have hundreds of different cell types. In our brains, we have neurons; we have blood cells that wander around chasing bacteria; we have muscle cells; we have bone cells that create bone, and so on. There are all these different cell types, and they're very different. For example, if you look at a neuron, like in your eyes, you have photoreceptors. These are gorgeous, weird cells, and they are very different from a red blood cell, which looks like a donut without the hole cut out.
Here’s the point: all of these cells have the same DNA message inside them. Using a computer science analogy, it’s like handing the same computer code to a bunch of different computers, and each computer spits out a different result. So, how is it that all the genes conspire in space and time? For instance, right now, I’m looking at you, and above your nose, you have these two objects called eyes. Those eyes are full of photoreceptors. You also have a beating heart, made up of these weird cells that are essentially oscillators. The way cells end up adopting these different fates is because only certain collections of genes are turned on at specific places and times. When I say ‘turned on,’ I want you to think of it as an analogy of a switch. A gene can be ‘off’ or ‘on,’ and you have about 20,000 different genes. This creates a very high-dimensional space—two to the 20,000th power dimensions if you think about it. And it’s even more complex because genes are not simply on or off. But let’s go with that for now. Somehow, cells have to decide their fate, and that decision might depend on where they are within the body or other factors. The simple question is: how do we take a sequence of letters—A’s, C’s, G’s, and T’s—and attribute meaning to them? When I say ‘meaning,’ maybe you’ve learned in a biology class about the central dogma, where DNA leads to proteins. But some proteins have a special job: they land on the DNA and either, like a bouncer at a nightclub, shut the door or open it, depending on whether you're the right ‘person’ or not. These proteins control whether a gene is ‘open for business’ or not.
The research we’re doing, stated simply, is trying to tackle the genomic dark matter of the modern world. We don’t really know how most genes are controlled—how they’re turned on and off. You’d think we’d have a good grasp on this by now, but we just don’t. That’s a simple summary of what we’re up to.
Vivek: How do you go about figuring out how genes are controlled?
Dr. Phillips: One way we pursue this research, which I think you might find amusing, relates to the opening sentence of Tolstoy's Anna Karenina. The sentence says: ‘All happy families are alike; each unhappy family is unhappy in its own way.’
Now, let’s say I were to change 10% of the letters in that sentence. Take the word happy: if I change the P to an L, you’re still going to recognize that the word is happy. But consider the word way in the sentence: 'Each unhappy family is unhappy in its own way.' If I change the A to an H, it completely changes the meaning of the word from way to why. That means there’s more information content in the letter A in the word way than there is in the P in the word happy.
What we do in our research is similar. We go to the genome and mess it up—we mutate it—and then we ask the cell: ‘Hey, did you care? Did you care that we messed with this particular base, like in the sentence?’ For example, if I change the A in the word way to H, I’ve completely altered the meaning, so that letter matters a lot. On the other hand, if I spell out H, A, P, blank, Y, there’s not really much ambiguity—the missing letter is almost certainly P, so that letter is less informative.
In essence, we mutagenize the DNA and then ask the cell: ‘Do you care?’ That’s how we start to figure out which parts of the genome are critical.
Dr. Phillips’ research laboratory at Caltech is focused on applying and creating quantitative models to describe biological phenomena. He emphasizes the importance of thinking about biology quantitatively and is the co-author of Cell Biology by the Numbers. I asked Dr. Phillips to expound on what it means to think quantitatively and what approaching biology from a quantitative perspective has allowed him to do.
Dr. Phillips: There’s a beautiful thing that is true for some people in physics, like Enrico Fermi. If you look up Fermi problems, you’ll see that he could basically get a numerical estimate for any problem within 15 minutes. It’s about answering the question: What sets the scale of X?
For example, what sets the height of the highest mountains on Earth? One way to think of it is to take a column of rock and make it so tall that it crushes the rock at the bottom. That’s it. Using that idea, you can figure out the height of mountains on Mars, where gravity is weaker, so the weight is less, and you can make a taller mountain before reaching the crushing stress of the rock. Using this logic, you can calculate that mountains are roughly 10 kilometers tall.
Whether it’s something like how many people are at a presidential inauguration, how much fuel it takes to fly from New York to Paris, or how much it costs to build a railroad, the question is always: What sets the scale?
In biology, this way of thinking opens up fascinating insights. For instance, consider the front of a jet engine. When you’re taxiing, you might notice a little white spiral slowly rotating. But when you’re on the runway at full throttle, the engine is rotating at 6,000 RPM—100 rotations per second. That is the same speed at which the molecular factories in your body that make ATP are rotating. That comparison is mind-blowing.
Another example is the accuracy of DNA replication. This analogy was thought of by Tanya Baker at MIT. Imagine scaling DNA so that it has a one-meter diameter. At that scale, the machinery copying the DNA would be the size of a FedEx truck, traveling at the speed of a jet airplane, making deliveries on both sides of the street every 10 centimeters. It would finish its work in 40 minutes, and it would make one mistake only once every three years. That’s how accurate the DNA copying machinery is.
I’m telling you this because putting numbers on these things makes you think about and understand them in a completely different way. Another important point is that we have to find ways to approximately represent the world around us. You can’t make a map the size of an empire—it’s useless. When we conceive of the world, we have to intentionally simplify, so we don’t lose sight of what matters. Quantitative thinking is the fine art of approximating the world.
Vivek: Is there any advice that you have for young students and scientists?
Dr. Phillips: Yeah, I don’t like giving advice very much because I don’t really know what I’m doing. I like the story about Abraham Lincoln, I think it’s apocryphal, but he had a debate with his cabinet, and at the end, he said, ‘Let’s take a vote. Everybody in favor, say yes. Everybody against, say no.’ He counted 12 no’s and one yes, and then said, ‘The yes wins.’
What’s the meaning of that? It means you listen to other people, but then you make your own call. I like advice in that sense—somebody tells you, ‘Here’s what I’ve observed,’ but ultimately, you’re going to have your own journey.
I think there’s way too much emphasis on performing for others. I think authenticity is really spectacular. It’s one of my favorite things in life—meeting people who have the courage to go at things in their own way. I think it’s important to figure out what means something to you. It’s your one and only life, as far as I know. Be careful about falling into the trap of letting others tell you they know better than you. I’m super skeptical of that—even when it comes to your parents.
Of course, there are times when others do know better, like if you’re a little kid running into the street and your parent pulls you out. But for things like falling in love, it’s not very helpful for someone else to say, ‘I know best.’ That’s not how it works—you can’t just tell the heart what to do.
Let me try to put this into some pithy statements:
Science is a craft. Like shooting three-pointers, it needs to be practiced and respected. If you respect the craft, it will respect you.
Pay attention to detail. There’s beauty in that.
Curiosity doesn’t defend itself. Nobody is allowed to tell you that something isn’t interesting. They can say, ‘I don’t find it interesting,’ but that’s different. Don’t let them dictate what you pursue. That’s just off-limits.
Learn widely. Never stop learning.
Ask questions. Take yourself seriously. If you have a question and you address it rigorously, you’ll learn something. Often, you’ll discover something, but at the very least, you’ll learn.
Mastery is a beautiful thing, but it’s hard. It takes hard work and dedication.
Those are just a few thoughts. But again, I don’t really know what I’m talking about. All I know is, I’ll wake up tomorrow morning and try the craft again. That’s all you can do—just wake up and try again.
