Nobel Laureate, Paul Nurse, on the Future of Biology

Philip Ball in Conversation with Francis Crick Institute Director, Paul Nurse

Joseph Decker, Ripening Pears (1884) | The National Gallery

Introduction

Marginalia Review of Books' Institute for the Meanings of Science is honored to host a conversation between Sir Paul Nurse, Nobel Laureate and Director of the Francis Crick Institute in London, and Dr. Philip Ball, longtime editor at Nature, author of over 25 books, most recently, How Life Works: A User's Guide to the New Biology (Chicago University Press).

This conversation is the first in a series of interviews for The Meanings of Life Project: The New Biology, led by Institute Director, Samuel Loncar, and Lead Researcher, Philip Ball. The project brings together a working group of leading scientists, scholars, and industry leaders coming together to advance the new scientific vision of life revealed by modern biology, and synthesized in Ball’s book.

The project convenes around this major synthesis, and aims to identify a new narrative for this field through a multi-disciplinary integrative approach that seeks to unite fundamental research at the level of genes, molecules and cells to notions of agency, purpose, and meaning in living entities. The purpose of the project is to seek ways of understanding and communicating how living organisms function at many different scales, look for the new conceptual and metaphorical frameworks that do justice to the richness of “post-genomic biology,” help to inform medical and health sciences, and reveal the special and wondrous nature of living organisms.

This inaugural project conversation between Ball and Nurse begins with a discussion of Nurse's beautiful book, What is Life? Five Great Ideas in Biology (David Fickling Books) and then dives into Nurse's Nobel winning work on the wonder of the cell, why words like purpose and meaning are often taboo in biology, and how a modest definition of agency leads us to a deeper understanding of what life is.

Join Marginalia in advancing the new scientific vision of life revealed by modern biology: change the narrative and contribute today to The New Biology.

What is life?

Philip Ball

Paul, I want to start with your book, What is Life? What struck me about this book, first of all, is that you begin with the cell.

So, we’re asking the question: what is life?

And you say, the cell is where we need to start. You call the cell “biology's atom.” What I understand from that is that you recognize the cell as being the smallest entity that we know of that is actually alive. We can, and in fact we must, go down to a lower level to understand what's going on to look at the molecules – but once we do, then we're not looking at something that is itself a living entity.

I've even heard it said that right now we're in an era where biology is rediscovering the cell after decades of focusing on genetics. The notion of the cell being what we need an understanding of is coming back in. So, I wondered if you could start by saying something about that business of going between molecules—which you've looked at, and your work looks at, very closely—and the whole organism or the whole cell. What do we lose and what do we gain by going between those levels?

Sir Paul Nurse

Well, it's a very important question, Phil. I do think the cell unlocks the secret of life. Let's call it the secret of life, because the cell is the smallest entity, I would say, where there's no doubt that it's alive. We can argue about viruses and so on, but I think everybody would agree a cell is alive.

Biology is complicated, and one reason I focused on thinking about the cell is that it has the attributes of life in its simplest form. And given the complexity of life— to make you or me, we’re made up of billions and billions of cells, all of which have to do different things to keep us alive (work the nervous system, work the stomach, work the muscles, etc.)—these all get in the way, to be honest with you, when thinking about the basic principles of life.

Now, why am I so excited about the cell and the basic principles? Well, life is organized in space and time. By this I mean, life is something that is able to self-assemble into a whole, behaving object. And that's what a cell is, too. I want to emphasize that, because we don't often think of it like that. A cell can organize itself in space and time. It has purpose, the purpose of the whole—to grow, reproduce, maintain itself. All the things that you or I would do, but in a much simpler state.

So, I think of the cell as the atom, as life’s atom, perhaps for two reasons. The first is that it's the simplest entity. The second is that we may have a chance of beginning to understand it because we stripped away all the other things that I mentioned earlier about multicellular organisms. So we have an opportunity, in my view at least, to focus on what matters: to produce organized form in space and time, working with a purpose.

Philip Ball

Right, okay. Now, you called your book, What is Life? And that's obviously a conscious reference to at least a couple of other books that have that title, one of which—

Sir Paul Nurse

Oh, I just copied them. I just copied them.

Philip Ball

Well, I had no doubt! In particular, the one that people tend to know about is What is Life by the physicist Erwin Schrödinger, published in 1944. But there was also J. B. S. Haldane, the British biologist, who published an essay called What is Life…

Sir Paul Nurse

Yes, only a few years after Schrödinger.

Philip Ball

I like the way Haldane started his essay on this. He said, “What is life? I'm not going to answer that question. In fact, I doubt if it will ever be possible to give a full answer.”

But he then went on to focus on chemical aspects of life, on enzymes, on biochemistry, which was a big focus at that time. Schrödinger looked at, I think, what became a key focus of biology in the rest of the century, which is genetic information. And famously, he came up with this idea that seemed to foreshadow the discovery of DNA and how DNA encodes that information.

You, in your book, look at both of those issues, but you also bring in other aspects. You look at the cell, you look at evolution. But you introduce two words in particular, and you've just used one of them again, a word that one doesn't tend to see or hear in biology. And in fact, sometimes you get the impression that they are taboo words: purpose and meaning. So, what do you understand those two words to imply in biology?

Why are Purpose and Meaning Taboo Words in Biology?

Sir Paul Nurse

I do deliberately use the word purpose to be a bit provocative. Because you're right, we don't hear it. But that's because we're shy about using the word because some people think it's to do with being a human and having purpose.

My use of it is, I think, accurate, but more modest. The word purpose is really to, in a short form, describe that something is acting as a whole to deliver something for the whole organism—in this case, the cell. I briefly alluded to those sorts of things. A cell has to grow and it has to organize all this complex chemistry you were talking about; it is immensely complicated, but immensely complicated chemistry, which does things like grows the cell and grows the cell with all sorts of structures, is behaving in a way which is delivering purpose, which is growth.

Not only that, and this is what I actually research on—it leads to the reproduction of the cell from one to two, which involves the ability to replicate all the components that are needed and then segregate them into two newly divided objects, which is also a purpose of reproduction. And without reproduction, of course, ultimately, you can't have evolution by natural selection, and so on. So, it's also fundamental.

So, these words. Purpose, particularly, is the one that I use. You had another one that you added to purpose.

Philip Ball

Well, one that I’d add is agency. Let’s talk about agency in biology.

Sir Paul Nurse

Agency, well, I would put agency in the same category—agency and purpose. So, how is it that these chemical reactions have agency and can deliver purpose?

You mentioned information in your earlier question, and too often when information is used, people only think of genes and the storage of information in genes. Now, that's absolutely critical, and it’s actually sort of rather wonderful what it does. I use it in this book, and what I believe is that information is a more generic quality of life. For example, there are all of these different chemical reactions that are going on inside a cell, many thousands of them going on in a tiny little space of, say, 10 micrometers cubed. Or in the yeast I work on, which is even smaller. These chemical reactions are all going on, yet they all have to be somewhat separated, because the chemistries are all a little bit different. But if they were all separated, it would be complete anarchy. Nothing could possibly happen. So, somehow all of these chemical reactions have to be connected, and then we get into the realm of information. Because connections imply talking from one part to another, connecting those different parts, and coordinating behaviors. And all of that is to do with management of information. This does not have to do with genes, particularly, but it has to do with the interaction of these components.

So, I think of life in terms of extraordinary chemistry—and physics, of course, because some part of it is physical, though most we interpret in terms of chemistry —but combined with the management of information.

Philip Ball

So flows of information within the cell, including the information that's in the genome, but not restricted to that alone?

Sir Paul Nurse

Correct. Yes.

Philip Ball

Meaning is an even more contentious term. There's a theory of information, and it was developed at the same time Schrödinger was writing his book, and physicists use it, and it's to do with how many different arrangements of things there can be. And that theory explicitly excluded the notion of meaning, of what the information means.

But it seems in biology, we can't do that. We have to think about meaning because evaluation is involved: cells evaluating the signals they get, evaluating their environment, evaluating other organisms. In other words, there is construction of meaning from that information: a sifting of what is meaningful to the cell or to the organism from what isn't.

Is that the way you understand this word, meaning?

Sir Paul Nurse

It is. And as we were just discussing earlier, one of the problems with these words is that we immediately interpret them in terms of human behavior. And this is the reason why it becomes contentious.

When people think about the question what does life mean, then you begin to verge into religion and philosophies of existence. Whereas, how you describe it, which is in a more modest way, is expressing meaning. But the reasons why scientists often shy away from words like purpose and meaning is because of the anthropomorphic use of things. When, in fact, both of these words are very useful combined with agency, as you've said, and overlap to some extent when we look at the simple cell.

Philip Ball

It’s really interesting that you say that, because I've certainly encountered some pushback, including actually from some other Nobel laureates, when one starts to talk about things like agency and meaning.

Sir Paul Nurse

Nobel laureates can have strong opinions, and they shouldn’t always be listened to.

Philip Ball

But the scepticism is precisely for that reason: that it sounds like you're getting into something anthropomorphic. It’s the same with the idea of agency: we think about human agency, about our conscious decisions to do things. But it seems to me that, as much as anything else, if we believe that there is a Darwinian continuity in biology, then it wasn't as though all of these attributes suddenly popped out of nowhere when humans began. We can see the beginnings of the attribution of meaning, and even value, in simpler living systems. Because it seems to me that's how they have to been able to do that, to survive. They have to be evaluating, in some sense, what is out there, what they're encountering, whether it's useful or whether it's something to ignore, or whether it's something to flee from. This is something that's pretty universal in biology.

So, would you think that actually we've got to help people get over their antipathy or their worry about these things? Is it actually an important for how to do science to get scientists to worry less about these connotations and to embrace these ideas?

Sir Paul Nurse

Before I answer that question, I want to make one comment because you mentioned Darwinian continuity in biology—you were mentioning cell reproduction. There is something quite extraordinary about cell reproduction. If you think about it, we are all connected by this chain of cell divisions that goes back into deep time. I mean, if you can go back and back and back to the beginning of life, three and a half billion years ago, we're connected to it. It's not just an abstract concept. We're connected in reality. If we believe in Darwinian evolution, which, in fact, I do, then we are connected in that extraordinary chain that has never stopped. It never stopped, and we are physically connected across three and a half billion years. I mean, until I wrote that book, I didn't even think about how incredible that is, but it's true.

But I know you weren't asking that. You were asking about the weaknesses, really, when human beings talk about purpose, meaning, or agency, and only think about human beings. They are not usually thinking about the other objects, living objects in the universe, which may not have the attributes that we describe in the way that you did, because it's associated with brain behavior, but actually are still meaningful in the concept of a cell. The cell is, for sure, acting with purpose, with agency, and we can capture those terms, and we shouldn't be embarrassed of them.

The Wonder of Cells and What They Teach Us about Life

Philip Ball

Right. So I want to pick up on what you were saying about information flows in the cell, and complexity, the chemical complexity of the cells.

I wonder if this is a good time to come to your Nobel-winning work in biology. That work, it seems to me, is a fantastic example of how we think about those notions of information flows, but also an example of many of the new findings that I've talked about in my book that seem to me to be creating a slightly different narrative from the traditional one we've had. You were looking at the cell cycle, at this process by which cells replicate, and it turns out to be an extraordinary, complex process. But in particular, you found that there were these types of proteins that you called CDCs, CDC-2 in particular, that in some sense control or orchestrate that process. Can you say a little bit about what that was all about? And whether we might be able to explore in some detail what's going on and why there's a new narrative there.

Sir Paul Nurse

I'm a geneticist, actually a geneticist and cell biologist, and therefore I use genetic techniques to try and analyze what's going on. One thing that I like to emphasize is that often geneticists are tarred with the brush that is ultra-reductionist, but this isn't really true, not good geneticists anyway. You interfere with genes, but you only try to understand it in the context of the whole of the cell or the organism, at least in my case. If you only focus on what the gene makes and the chemistry there, then you lose the point of what you're doing.

I started working on this problem when I was a graduate student over fifty years ago. And it really came about because I was doing research that was so damned difficult because a person failed all the time. If you're in discovery, I thought, you've at least got to try and work on something that is interesting. And I thought, well, what's interesting? And I began thinking about the basic properties of life, and one of them is reproduction and the ability to self-order. And we see that with the cell cycle, where a cell is reproducing itself. So I thought, well, this is perhaps worth a shot at trying to understand.

But, as you quite rightly pointed out, you can't study all the found objects inside a cell. But what would be critical is how it's all controlled. I didn't quite know what I meant by the word control, but I had this notion it's what regulates the temporal order and progression through the events of the cell cycle. I decided to take a genetic

approach of looking for altered genes that would change the rate at which a cell could reproduce itself, using the metaphor of, say, an accelerator or the throttle in the car, which can make the car go faster or slower by changing the accelerator. I thought that if we could make cells divide faster, that we would be likely to identify rate-limiting controlling steps.

I did that work in Edinburgh. I isolated mutants that divided faster than they could grow, and it actually unlocked this secret, because there's five thousand genes. I work on yeast—five thousand genes. Since then, we've deleted every gene and done things I won’t explain here. So we know about five hundred of those. Five thousand are involved in the reproductive process, but probably a handful of ten or less control it using very simple thinking.

Now, shall I describe how that works, or is that too much?

Philip Ball

Well, if you could say a little bit about these particular proteins.

Sir Paul Nurse

So, the genes which we identified—and of course, it is a we, because there is a collaborative effort in my lab, and then subsequently other labs who are interested—encoded an enzyme called cyclin-dependent kinase, CDK. What these proteins do is they add a phosphate onto other proteins, which is called phosphorylation. Now, that's a very efficient way of changing the activity and function of another protein. Often we think about transcription, translation, the making of a protein, but that is actually very energy-demanding. If you change the behavior of an enzyme by putting on a single molecule, a small molecule, and then you can take it off again, you can switch things on and off, so it's much more efficient. And the CDK, cyclin-dependent kinase, phosphorylates probably three or four hundred different proteins in the cell, many of which, not all, but many of which are required for the reproductive process.

So what you now have is a molecule that is catalytic and puts phosphates on other molecules. The simplicity of it is extraordinary, because, though we like to talk about complexity, it just goes like this. It starts the cell cycle with a very low activity and can only phosphorylate certain substrates that are sensitive. So it only phosphorylates certain proteins, which are particularly sensitive to the kinase, and those are the proteins that need to be activated or inactivated, depending upon what the phosphorylation does early on in the cell cycle. Early on in the process we copied the DNA, and it controls, ultimately, whether that occurs or not. Then, as you go through the cell cycle, it simply increases in activity and fires off phosphorylation of different proteins that gives you the temporal order of progression through the cell cycle until you get to mitosis [cell splitting]. Then, there's a sudden burst of mitosis. It's a bit of a complicated process, more so than DNA replication. Mitosis is the process that divides the nucleus of the cell, and at the end of the cell cycle, there's a lot of activity, and it activates all these different proteins that are needed for that process. So it means the control couldn't be simpler. It's just increasing one particular activity that does something at low level and something else at high level, and then it's killed, because one of the protein components of the cyclin-dependent kinase is destroyed. That was discovered by my colleague, Tim Hunt, who also received the Nobel Prize. It’s destroyed, so the activity goes down to zero, and it starts again.

So, despite all the complexity that we have, this is extraordinarily simple. However, it's regulated in a complicated way, particularly in your cells and my cells, because these molecules, these CDKs, have to be controlled by all sorts of other signals that have to do with making a tissue, making an organ, responding to damage, and so on, all of which is a bit distracting if you want to understand the principle of reproduction, because you're layering on top of it the complexities of a normal multicellular organism.

So the reason we could work it out in yeast, is because it's all yeast does. Reproduction is all that yeast does. And so that simplicity—the low numbers of genes, our ability to genetically manipulate it with fine precision—all meant it was easier for us to work out exactly how it works. And it really is simple.

Philip Ball

That's exactly the kind of simple story that I have confidence in, you know, that it's possible for us to start telling people about these processes. But when we dig into it, it gets very complex, and it gets particularly complex in a complex organism like humans that have many tissues. There are several things that pop out at me from that.

First of all, what you essentially seem to be saying is that the process isn't a deterministic one that is going to happen regardless. That actually, if you like, the kinases themselves have to be sensitive to their context. In different tissues, they'll be doing different things. So there is information coming from the higher levels of the organism controlling them.

Sir Paul Nurse

Absolutely. Now, there's information coming from within the cell itself because if you try and segregate chromosomes before you've replicated them, but the cell is dead, it can't do that. So, there have to be connections. So, something has to know it's completed its DNA replication, the copying of its genes, before it tries to separate them. That is why there's a whole series of controls layered on top of the cyclin-dependent-kinases that ensure that DNA replication occurring in the S-phase is completed before you undergo mitosis. The same if you have a lot of DNA damage. You want to actually repair that before you try and separate.

Also, and very interestingly for me, cells of the similar type growing in similar conditions divide at a particular size, and we have no idea how a cell measures its own size. Now, I've been interested in this for five decades. Occasionally, I’ve thought I've solved it. I still haven't. I'm just hoping death won't intervene before I manage to sort it out.

Philip Ball

Well, that's fantastic. There's another aspect to this as well that intrigues me—so you have this kinase, a CDK, that is controlling all these different proteins in the cell cycle, and it does so for different proteins at different times.

That all sounds straightforward, except—how does that happen? We're often told this idea that a particular protein has a particular job, and it does that job because it has a shape that it can recognize and it ignores everything else. So why doesn't the cell just make lots of different kinases, each one of which has a specific protein that it switches?

You can certainly imagine using just one kinase is a more efficient way of doing it, but the promiscuity that this enzyme has needs to be enabled by something. As I understand it, part of that is to do with the fact that the protein, these proteins don't – or their substrates don't – necessarily have a fixed shape that this one recognizes and fits into. They're a bit floppy, that they have this sort of disorder, and that, in fact, with phosphorylation in particular, disorder seems to be crucial, that you have this promiscuity, this sort of fuzziness of interactions. That seems to be an essential part of how this whole process works if you're going to avoid a kind of clockwork way or mechanistic way, where you have one thing to do each particular task.

That seems to be one of the newer ideas that's come out in the past twenty years or so, the fact that you have this fuzziness, this looseness of shape in these crucial proteins that are central to their role. Is that a kind of narrative you've seen develop?

Sir Paul Nurse

Well, it's certainly talked about. It's not something I knew myself, because it tends to be a more biochemical and structural biology thing, and I'm certainly not one of those types of people. But there's no question that the molecule is fluid and interfering with the protein by putting on a phosphate, which is quite a bulky negative charge, will change and modify that fluidity and change shape in the way that you say it.

But to go back one step, I've described it as if it's simply rising CDK activity. But we also have another set of enzymes called phosphatases that take the phosphate off. So, and there's a number of those, and actually it's net phosphorylation that matters here because there are two things going on. This is why it starts getting more complicated when you go into it. One is putting the phosphate on, but you can fine-tune differences by having different phosphatases that take off the phosphate from different molecules at different rates. What that does is provide a much finer temporal ordering than if you have a continual increase. Now, this level here in different proteins can have different impacts depending on how strong the phosphatase is, either moving things forward in that phosphorylation in the cycle, or delayed. So even the overall regulation is more complicated than I described.

But the main point, you wanted to say, I take it, is the consequence of the phosphorylation is to change the overall structure. And that is quite difficult to describe, but I think we may do it through computational methods. DeepMind and AlphaFold, for example, might help contribute in being able to describe those changes without having to do such a lot of molecular structural determination.

Philip Ball

Right, and so, it seems to me that a lot of the complexity that's coming in here, and again, particularly for multi-tissued organisms like us, has to do with the fact that there needs to be feedback and responsiveness of that system. It must not actually be a simple unfolding of a program in an algorithmic way. There has to be sensitivity to the context.

Sir Paul Nurse

Yes. We're in the same place.

So, the whole thing is to do with management of information….

Part Two forthcoming

Paul Nurse is a geneticist and cell biologist whose discoveries have helped to explain how the cell controls its cycle of growth and division. Working in fission yeast, he showed that the cdc2 gene encodes a protein kinase, which ensures the cell is ready to copy its DNA and divide. His contributions to cell biology and cancer research were recognized with a knighthood in 1999, and his endeavors relating to the discovery of cell cycle regulatory molecules saw him jointly awarded the Nobel Prize for Physiology or Medicine in 2001. Over the last thirty years, he has held many senior research leadership roles. In 2010, he was elected as President of the Royal Society for a five-year term and since 2011, he has been the Director and Chief Executive of the Francis Crick Institute.

Philip Ball is a scientist, writer, and a former editor at the journal Nature. He has won numerous awards and has published more than twenty-five books, most recently How Life Works: A User’s Guide to the New Biology; The Book of Minds: How to Understand Ourselves and Other Beings, From Animals to Aliens; and The Modern Myths: Adventures in the Machinery of the Popular Imagination. He writes on science for many magazines and journals internationally and is the Marginalia Review of Books' Editor for Science. Follow @philipcball.bsky.social

Samuel Loncar, Ph.D. (Yale) is the Editor-in-Chief of the Marginalia Review of Books, the Director of the Institute for the Meanings of Science, the creator of the Becoming Human Project, and the founder of Olurin Consulting. His speaking and consulting clients include the United Nations, Red Bull Arts, Oliver Wyman, and Flagship Pioneering. His work focuses on integrating separated spaces, including philosophy and poetry, science and spirituality, and the academic-public divide. His book, Becoming Human: Philosophy as Science and Religion from Plato to Posthumanism, is forthcoming from Columbia University Press. Learn more at www.samuelloncar.com X@samuelloncar