Thursday, April 18, 2024

Genes, in more context: a reply to a review of How Life Works


SFSU biologist Michael Goldman has written a generous and thoughtful review of How Life Works in Science. He raises some issues that I will respond to here.


I figured it was always likely, indeed inevitable, that some would respond to my book by saying it creates straw men of one kind of another. (Goldman doesn’t exactly say this; although his comments could be read that way, he phrases them more kindly.) After all, given that what I’m saying reflects rather than challenges what molecular and cell biology has been revealing over the past few decades, obviously all of it will to some degree or another be “known” to some practising biologists. What I am arguing is that, in the light of this work, it is time to reconsider some of the narratives about “how life works” that are passed on to the public.


In this regard, then, when Goldman says “We already knew this” (for example, “the edifice Ball builds up and deftly tears down, if it ever existed at all, had not been a major factor in genetics or evolutionary biology for decades before [the Human Genome Project]”), I suspect he is referring to things recognized by many professional biologists, but not by plenty of lay people. In particular, they have often been given lazy, outdated and misleading narratives about genes that are now causing problems for public understanding of genomic technologies, medicines, and genealogies. In the light of my own experience, I suspect Goldman might be a little horrified to discover what misconceptions or over-simplifications some – even other scientists – still believe about biology, and especially about genetics.


Goldman affirms that genes play a “central role” in biology. This, in my view, is beyond question. Of course they do, and I would not want anyone to think my book suggests otherwise. Insofar as I talk about genes (and only one of ten chapters addresses them directly, though this seems to be what quite a few reviewers have latched onto – which tells a tale in itself!), I want rather to examine exactly what that role is. I suggest that it is not a “blueprint” role, nor an “instruction book” role. It is harder to summarize than that, but it is precisely because of research over the past few decades that we can now begin to find better metaphors.


Among the things we didn’t know before the completion of the Human Genome Project, and which I explore in the book and which I believe have significant consequences for our notions of how life works, are these:


- The real extent of regulatory machinery, including masses of non-coding RNA. There were almost no noncoding genes recognized before the HGP began; now many estimates suggest they outnumber coding genes. It would be bizarre to suppose that this alone does not significantly revise our narrative of the human genome.


- How gene regulation in humans really works, which is not in general how it works in prokaryotes.


- The extent to which genomic linkages for many traits and diseases lie outside the coding part of the genome.


- The vital importance of protein disorder, particularly in helping to explain biomolecular promiscuity and the kinds of linkages between signalling or regulatory pathways that promote pleiotropy. (Incidentally, yes of course it is true that pleiotropy has been long known – for over a century, in fact. But for a long time it was simply a word to describe a puzzling phenomenon. We have known for some time how isolated cases arise, but only relatively recently have we understood how polygenic most traits are. And only even more recently have we started to be able to say why.)


- The widespread occurrence of liquid-liquid phase separation as a mechanism for creating organization in the cell – an issue that itself is closely bound up with the recognition of the roles of disordered proteins, RNA-binding proteins, and noncoding RNA.


- The possibility of reprogramming cell states, à la Yamanaka. This is of course an immensely big issue for our understanding of cell fate determination as well as biomedically.


- The complexity and diversity of transcriptional landscapes, revealed for example by single-cell RNA sequencing.


The argument I lay out in the book is that it is developments like these that constitute a “new biology”, insofar as they enable us to tell new stories about how life works that go beyond, and in fact often undermine, earlier, simplistic ideas about “gene action”.


Goldman seems to imply that the notion of agency is invoked as  “the idea that there is a gap between what we can explain mechanistically and what we observe” – an idea that he says “has gained traction in philosophy of science circles but has been resisted by mainstream science.”


I am not sure what he means by this. There is lots in biology that we currently can’t explain mechanistically (especially in neuroscience), but I see no reason why explanations won’t be found eventually, if they are addressing the right level. Agency is not about that! It is not some mysterious property that goes where mechanism cannot. Rather, it speaks to a more top-down view of life: rather than trying to reduce life’s mechanisms to principles that are no different to those that operate in inorganic matter, it starts by considering what truly differentiates the living from the non-living.


To imagine that agency is a kind of resurgent vitalism seems a little like scientists pre-Boltzmann complaining that thermodynamics invokes this mysterious entity called “entropy” rather than sticking to a strictly Newtonian view of matter as billiard-ball atoms. Or perhaps an even better analogy: it’s like supposing that the concepts psychologists use to talk about the properties of mind are suspect and a bit woo because they don’t start from action potentials.


I am not sure how Goldman could have got this impression about efforts to develop theories of agency, except to say that this seems to confirm my sense that many biologists struggle even to recognize what agency – the central property of all living things – can mean. As I say in the book, this is an extraordinary lacuna in biology.


I hope this won’t sound like grouchiness. I truly appreciate Goldman’s comments, and am delighted that he find the book offers “a great chance to review and admire the beauty and complexity of life” – that was indeed a key objective. And if he sometimes seems to miss the message I wanted to convey, that’s a reason for me to think carefully about whether I conveyed it clearly enough. But I hope these remarks help a little to clarify what I’m aiming to do in this book.