Rob Phillips is a Professor at Caltech in Pasadena working at the intersection of physics and biology. Over the past12 years he has evolved from being a condensed matter physicist to now concentrating on biophysics. He wants to understand how we can use mathematics and physics to understand biological systems and is co-author of the book ‘Physical Biology of the Cell’ which came out in 2008. He began by describing why he thinks scientific disciplines should work together.
Rob Phillips: Somehow the new ideas come from unexpected places. I think the history of science is replete with examples. Just to give you an example in the other direction; the first law of thermodynamics, the idea that energy is conserved, was discovered by a German doctor who happened to go to the tropics and noticed the color of blood was different; Julius Robert Meyer was his name. So in that sense I would say, writ large, that I think there are philosophical reasons to expect that getting new people to think about these kinds of problems, that maybe they’ll have new ways of viewing things. The other thing is that there are lots of different pieces of the puzzle where physical bisection, using techniques, quantitation, and trying to understand them from a physics perspective may shed light. I can give you examples you want.
Pauline Davies: Please do.
Rob Philips: Okay, so one is that people make a lot of noise about the role of mechanical force and what the decisions are that cells will make. So, if you talk about the role of force than you need to be able to measure force, just as an example. Once you’ve measured it, then you like to think about what are the consequences of that force and so on. That's one example. Another one is that cells make decisions. And when I say they make decisions, there are commitments that are made in genetic programs and it's interesting to try and dissect those. How do they depend on all the external parameters that control those decisions?
Pauline Davies: So physicists can delve into what's going on in the cell and look at the way they move and as you say, their mechanics. And you somehow you think that's what will enable us to understand what's going on and eventually if we can understand what cells do then and maybe even understand what cancer cells do.
Rob Phillips: That’s the kind of thinking. And I guess, again I don't want to overstep my boundaries in terms of cancer because I think it's incredibly complicated system and people been working on it forever, and I don’t want to come in and say I know what's going on, but I'm a real believer in infrastructure. And what I mean by that is that there are tons and tons of examples where some unexpected discovery in one area ends up being very important to some other area. There are many different ways I think that that physics can contribute.
Pauline Davies: And now you are involved in the PS-OC. Tell me about that.
Rob Phillips: So I’m part of the Northwestern PS-OC and there are many pieces to that overall puzzle. One of the ideas that people are thinking about is the fact that DNA is a mechanical object; and what that means is that you just as you have a wire attached to this microphone and you can bend it, it costs a certain energy to bend the microphone. So, DNA is all wrapped up; in each of our cells we have a meter or more of DNA. It's in a nucleus that's like 1/10 the width of a human hair. So it’s a super tiny region that this is packed in. The DNA is wrapped around these proteins called histones and people are trying to figure out the rules of what makes the DNA get packed, how do the histones, these proteins, decide where to go, how many of them are there? And one of the hypotheses has to do with the mechanical bendability of DNA. It’s a very controversial topic and the PS-OC at Northwestern has been exploring that idea.
Pauline Davies: And that’s what your friend Jon Widom was doing, wasn’t he?
Rob Phillips: Yes, so Jon had a really very unique perspective and he came at things from the physical/chemical side. And his thinking, I talked to him about this often, was start with the simplest thing and try to see where it fails. So he had a hypothesis, I wouldn't say that he was particularly wedded to it in the deepest sense of the word - it became somewhat controversial, but he was interested in pursuing ‘What are the rules?’ And so he would start in vitro. He would take some chicken histones, if I remember correctly, some DNA maybe from yeast, he asked the question how does it get wound up? People in the meantime, for example there's a group at Penn State, they did a really beautiful experiment where they showed how if you add extra proteins it tightens up the distribution of these nucleosomes. I think it's crystal clear that trying to understand the organization of this one meter of DNA in a eukaryotic cell is really very interesting; it’s clearly important. With each passing year we learn more and more about that the ….there’s a classic sort of old-school view of cell as a bag of enzymes and it is a bit of a strawman. But what we're learning in every regard is that things are ordered in all of these exquisite ways, it raises very deep questions about what drives this organization, who's in control of it, and what are the rules? And that’s the kinds of thing that people are trying to figure out. Maybe if one figures out what those rules are, then perhaps we can understand how they go wrong.
Pauline Davies: So now you’ve seen the PS-OC at work, and you’re involved in it, how do you think it’s working?
Rob Phillips: So I guess again I’ll maybe take a 30,000 foot view to comment on that. Maybe I'll do it by virtue of appealing to a really interesting paper written by Paul Nurse, who is a very famous guy in biology who won the Nobel Prize for his work on the cell cycle. He wrote a paper called The Great Ideas of Biology, and in it he talks about what he thinks are the five or so most important things in biology: cell theory, the unity of biochemistry, evolution and what I wanted to say, that I think goes back to something you asked earlier, which is why would people interested in physics be interested in cancer? Cancer is a part of biology that exhibits all of the great ideas of biology; cancer is at a fascinating problem. You know how physicists are and I think they’re very interested and curious about the way stuff works and so as I come and listen to the talks, I’m fascinated by the diversity of perspective. I see all sorts of experiments and my metric in a way, is I like to think about how I’m going to feel sitting on an airplane after a trip. Am I going to say to myself, “Wow, that was so cool, I wish I working on it!!” I can just tell you that having been at this meeting there's a couple of things that I heard that really caught my eye and will for sure continue to inspire my own thinking. It's really quite intriguing.
Pauline Davies: And you gave a talk yourself after that meeting, didn’t you?
Rob Phillips: Yeah, so I give a talk in a session that was part of the tutorial epigenetics. Stuart Lindsay and Steve Henikoff were before me and they talked about some of the absolutely beautiful and amazing experiments of people are doing genome wide to be able to understand what's going on with some of the topics we talked about earlier, having to do with DNA packing. My talk was a little bizarre, it was kind of an attempt to use statistical mechanics, which is a theory from physics, to try and understand molecules that switch back and forth between different states. Just to give you an example, I’m going to take a deep breath (inhales), so I just breathed and I saturated the hemoglobin molecules in my lungs with oxygen. And in doing so, I switched the molecules from one state to another by saturating them with oxygen. So my talk was trying to link what we know about hemoglobin, and what we know about ion channels, to what we know about chromatin. So basically, trying to use mathematics to dissect how certain classes of molecules work. I thought it was fun.
Pauline Davies: Well I heard some great feedback about that.
Rob Phillips: Well thanks, that’s nice.