Philip Ball - How Life Works Interview

Philip Ball is one of the most versatile science writers operating today, covering topics from colour and music to modern myths and the new biology. He is also a broadcaster, and was an editor at Nature for more than twenty years. He writes regularly in the scientific and popular media and has written many books on the interactions of the sciences, the arts, and wider culture, including Bright Earth: The Invention of Colour, The Music Instinct, and Curiosity: How Science Became Interested in Everything. His book Critical Mass won the 2005 Aventis Prize for Science Books. Ball is also a presenter of Science Stories, the BBC Radio 4 series on the history of science. He trained as a chemist at the University of Oxford and as a physicist at the University of Bristol. He is also the author of The Modern Myths. He lives in London. His latest title is How Life Works.

Your book is about the ’new biology’ - how new is ’new’?

Great question – because there might be some dispute about that! Many of the issues I discuss have been around for a long time. For example, I give plenty of attention to the notion of “canalization”, the channelling of complex biological phenomena such as development into just a few possible outcomes, that Conrad Waddington wrote about in the 1940s. I highlight the importance of gene regulation, which we knew about at least since the work of Jacques Monod and François Jacob in the early 1960s. When I talk about the importance of noncoding RNA – RNA molecules encoded in the genome that do not themselves encode protein structures – we need to recognize that some of these, specifically those involved in protein production by the ribosome, such as rRNA and tRNA, have been recognized for a long time too. Even noncoding RNA that performs gene regulatory functions – both long RNAs and very short (micro-)RNA – has been known since the 1990s.

But the argument I am presenting is that the knowledge that has been gained about such things over the past two decades or so is now enabling us to see these things not merely as miscellaneous elements in a perplexing puzzle – the puzzle of how life works – but as central components of a kind of logic of life that is quite different from the one long thought to be the case. There’s an emerging coherence to this picture. Quite frankly, I could not see that when I began writing the book – I wrote it not to explain this new picture, but in an attempt to understand it myself. It’s perhaps not ideal to start writing a book before you know what it is going to say. But this isn’t the first time I have done that (I worked this way, for example, with my book on quantum mechanics), and I figure that sometimes it is the only hope I have for getting any kind of deeper understanding of my material. As is often said, the best way to discover what you do and don’t understand is to write or talk about it.

• In saying this is new, what is it replacing or amending?

This is the crucial issue for explaining why I think it is genuinely new. It is one thing, for example, to say “Oh, we knew about noncoding RNA 30 years ago”. It is quite another to acknowledge that we now recognize more noncoding genes than protein-coding genes in the human genome (and those of other metazoans, at least). There is absolutely no question that, when the Human Genome Project began in the early 1990s, it was generally accepted that genes were all about making proteins – one can adduce any number of comments from eminent biologists to that effect. This has turned out to be wrong, and to suggest that the error changes nothing substantial about how (our) life works is bizarre – like saying that the discovery of dark matter and dark energy changes nothing about cosmology.

Similarly, it was the general assumption that gene regulation – the central issue for how our cells actually make use of the genome to grow and maintain us – works in much the same way in humans as it does in the bacteria that Monod and Jacob studied. And this too has proved to be wrong: the fundamental logic of metazoan gene regulation is different. I tell a story in the book of how an expert in gene regulation (who I have decorously left anonymous) who studied it in bacteria poured scorn on the new picture that seemed to be implied by the discovery of the involvement of lots of noncoding RNA in the early 2010s. His objections made perfect sense if we assumed that eukaryotic gene regulation was like that in prokaryotes. But it evidently never occurred to him that this assumption might be invalid.

Another old “certainty” that has been rewritten in the new biology revolves around the issue of protein structure. Or rather, this discovery that many metazoan proteins, including those involved in gene regulation (transcription factors) and those that represent key “hubs” in protein interaction networks, don’t actually have as much structure as we’d supposed: they are said to be intrinsically disordered, their polypeptide chains left loose and floppy rather than precisely folded. This means that they tend to bind targets less discriminately than ordered proteins: they are promiscuous. Such promiscuity in biomolecular interactions is very common in our cells – we see it too in our regulatory microRNAs. This was a revelation to me, as it blows apart the idea that everything is kept on track by the precision and selectivity of biomolecular interactions. This promiscuity is evidently by design, because we see far less of it in bacteria. There is something about it that is useful, even necessary, in our own molecular biology. I talk a little about what that might be.

All these changes to the view of how life works (for us) point towards one common theme: information is not simply coded in genes and fed upwards like a precise unfolding program or algorithm. That’s why I argue it makes no sense to think of the genome as a kind of blueprint for us. It’s long been said that biology is hierarchical, with processes happening on many scales. But what we can now see is that none of these scales is any more fundamental than any other, not least because what happens at one level might not depend on the fine details of what goes on in the level below. And that too is by “design” (to use a dangerous word!), because it creates robustness in complex organisms like us. 

• Why do you think that we have had such a focus on genes up to now?

The key reason, I think, is that we look for simple stories. And this one indeed looked so simple and appealing, once it became clear from the work of Crick, Watson, Franklin, Wilkins and others how DNA can encode heritable information: that information must be the program that makes us, encoded much as digital information was then being encoded on magnetic tape. This picture fitted too with Erwin Schrödinger’s influential notion of a “code-script” that prevented living things from disintegrating due to the Second Law of Thermodynamics. Once this genetic view became aligned with Neodarwinism, not least through the popular and intuitive idea of “selfish genes”, it seemed as though we had the complete story, apart from the details that the Human Genome Project would unravel. I suggest in the book that the irony is that the HGP itself helped to expose why in fact that story won’t work.

But the other reason why the focus has been so relentlessly genetic is sociological. The Human Genome Project was predicated on this picture, and so there were vested interests in preserving it. It might have been perceived as embarrassing to say “Well we thought things worked this way, but it turns out that they don’t!” Which is a shame, because there is absolutely no shame in that – it is simply how science works, right? But so many promises were made, about how the HGP was going to revolutionize medicine and lead to all these new cures and transform our understanding of human biology, that it became hard to backtrack. What has happened instead is that parts of the biology community have said, “Oh, well it seems actually we need all this other data too”, and so we have all these expensive further -omes beyond the genome – the proteome, metabolome, transcriptome, connectome. Each of them undoubtedly generates lots of useful information, but they tend to become exercises in mere data collection, lacking in any hypotheses to guide them and with a blind hope that somehow understanding will fall out from it all, which it rarely if ever does in science. Yet we go on collecting data because it is what we know how to do.

At root, part of the problem is that the gene eclipsed the cell – that biology’s centre of gravity became genetics rather than developmental biology. Yet the cell is the proper starting place to understand life, as it is the smallest thing that is actually alive. I point out in the book that genes have ended up being ascribed a spurious agency they don’t possess, because the gene-centred view has nowhere else to put it. And this neglect of developmental biology has been lamented by developmental biologists since Waddington. Happily, there are now some influential voices calling for the cell to be reinstated at the centre of biology.  

• Does this change how we look at evolution?

I’m sure it does, but I have tried to be very circumspect about that in the book, confining my comments largely to a section of boxed text right at the end. One reason for that is that I am aware how subtle evolution is and how poorly I understand it, and so I did not feel confident making bold pronouncements about it. I’m actually fairly conservative about it. While some are calling for a complete overhaul of Neodarwinism, for example in an Extended Evolutionary Synthesis, I would advocate a cautious approach that begins from the assumption that the central concepts of Neodarwinism are probably fine. But the second reason for my circumspection is that I think we simply don’t yet know how these new ideas in biology are going to impact evolutionary theory. 

One key issue here is that of agency, which I say is a notion that biology needs to take more seriously: to recognize that living organisms, from cells to metazoans, have an autonomous agency and are not simply passive vehicles directed and controlled by genes. It’s then a question whether, if the whole organism possesses this self-directed capacity for action governed by goals, this changes the way in which evolutionary change relates to genotypic change. I don’t know the answer, and I don’t think anyone does – but the question seems valid. 

• Are the layers of complexity you describe complete, or could there be more we still don’t acknowledge?

Well, there’s one thing in our favour: I think we can be confident that there are no hidden layers of complexity below the scale of the molecule, or above that of the organism (although of course the environment and ecosystem matter)! But that said, it would be a bit silly to imagine that we have now identified all the elements and modules of the system. We are, for example, still discovering new families of microRNAs with key functions. One big question remains about the way that the supramolecular structure of chromatin is governed, and how that affects gene regulation. We are also constantly discovering more about how cell fates are determined – what makes a cell one type rather than another – and indeed how many different cell fates there are in organisms like us, and how they change over time and during development. So there will certainly be more layers to discover, which is what makes biology still so exciting.

In fact, I really hope that this book, rather than being a list of what biology has got wrong and has needed to revise, will be seen as a celebration of the amazing advances in understanding over the past two decades or so, and of why biology is for that reason in such a vibrant and thriving phase. I am immensely excited by it myself.

Interview by Brian Clegg - See all of Brian's online articles or subscribe to a digest free here