Monday, May 27, 2024

Thoughts on a podcast about How Life Works


The podcast run by the computer company Oxide has hosted a discussion of my book How life Works. It’s deeply thoughtful, engaged, and also fun, and I’m very grateful for it. I’d recommend it to anyone as a fascinating listen for its own sake.


I’m also particularly grateful to the biologist on the panel, Greg Cost, for such a considered appraisal. Greg doesn’t agree with everything in the book (and he’s a Dawkins fan, after all!), but he is generous and measured in all that he says. 


I have some comments on some of that. One small issue: while it is of course true that cancer is mostly linked to genetic “breakdowns” of some sort, this is not invariably so.


What strikes me most about Greg’s comments – given that he is someone who is evidently very knowledgeable, thoughtful, and receptive – is his pessimism about figuring life out, at least until we have pinned down every last detail. I was pleased and relieved to hear that he recognizes the significance of the various new aspects that I cover, such as the importance of RNA, protein disorder, condensates etc. But it seems that for him this just makes the matter all the more complicated – even though I suggest in the book ways in which we can start to integrate these considerations into a synoptic view that does after all seem to have general principles (just not the ones we once believed!).


It's not that Greg seems to think the general considerations I identify are wrong or misplaced. He simply doesn’t remark on them at all, as if they were not there. I’m struck by this because it’s rather similar to one or two other reviews of the book I’ve had from thoughtful and receptive biologists: they say yes, yes to all the details, but are simply silent about – as if blind to – efforts to draw broader insights from them.


Thence Greg’s view that made what we’ll need is Sydney Brenner’s approach of exhaustive simulations down to the last molecule. That, to me, is the strategy of desperation: “We’ve run out of ideas so we just have to be literal about it and include everything”. What I want the book to suggest is that, not only is this not necessary but it is not helpful. It gives no real insight, but also it denies the fact that no highly complex system can work if every detail matters. What the “new biology” is telling us is precisely that not all the details do or can matter – and what principles might be needed that allow a system to transcend its microscopic details.


Greg, for example, says that his heart sank when we started to realise that the formation of condensates/phase-separated blobs by proteins and RNAs is a common process in our cells. It seems that to him this merely drives another nail into the coffin of the old picture of all things happening in aqueous solution. But I have been immensely excited and stimulated by it. As I suggest in the book, what we’re surely seeing here is a general principle whereby cells create structure and marshal many molecules into a shared location where they can work collectively. Perhaps it’s simply that this is a “condensed matter” way of thinking that is (as I have discovered) wholly unfamiliar to biologists. But I can’t help but suspect too that all biologists tend to see is a further receding of long-cherished ideas. I was struck by Greg’s apparent longing to retain the “DNA blueprint” picture, seemingly by means of saying that there is after all still a blueprint but also lots of “noise” between it and the phenotype. To my mind, that “noise” is metaphorical, perhaps even psychological: it implies “details we don’t and may never understand, but which can be invoked to explain away anything that doesn’t fit a blueprint picture”. The story in the podcast about the building of household steps was telling: in the end it amounted to “Well, the steps were made according to a blueprint, even though the blueprint was ignored”. The actual construction, the application of a real joiner’s skill in seeing how to do the job, then became the “noise” that accounted for the difference between the alleged blueprint and the reality. In other words, “noise” here is the gap between how we see life work, and how we would like it to work.


This attitude becomes particularly evident in Greg’s comment about theoretical biologist David Penny’s remark from the book that he’d have been proud to be on the committee that designed the E. coli genome, but not the human genome. Greg takes this to imply that the genomes of bacteria/prokaryotes are somehow “more evolved” and thus better designed, as though the 3.5(?) bn year evolutionary history of prokaryotes has perfected their genomes.


I’m very curious about this, because it is so obviously wrong (as well as missing the point) that, coming from a very smart guy, it seems to suggest that something else is going on.


The implication seems to be that prokaryotic genomes were once as seemingly messy and confusing as ours, but have been cleaned up and streamlined by their longer evolution. But that’s simply not so. After all, no genome was produced de novo since life began. Rather, we obviously evolved from prokaryotes, and so our genomes have acquired their alleged messiness out of the simplicity of theirs. Indeed, molecular phylogenetics allows us to effectively watch this happen. 


So the puzzling complexity and seeming messiness of our genome is absolutely not something that, given time, evolution could and would simplify. Rather, this difference seems to have been *necessary* to make complex metazoans possible.


So it rather feels as though Greg is desperately eager to find a way of making biology “make sense” – which E. coli seems to promise with its more transparent logic. This then becomes how biology “should be”, while we are a messy aberration. That is reinformed by the fact that, when one of the panellists raises my point that it is evidently now known that what is true for E. coli is not necessarily true for the elephant, Greg immediately and only talks about the ways in which we are the same.


As I say in the book, Penny’s remark reveals how far the answer of “how life works” for us humans is from our intuitions based on machine-like technologies. The fact that we look at it and think “Good God, what?!” is not an indication that nature has done a terrible job, but that we need to rethink our preconceptions. And that’s what this book is about.


Oh, and guys, guys: yes, you’re computer scientists so you know all about Alan Turing. But I’m not sure you know how much he was (and perhaps still is) not known beyond your field. And yes, as history The Imitation Game was pretty terrible - but that doesn’t mean it didn’t help to put Turing on the radar of lots more people. Just as it may be inconceivable to you that plenty of people don’t know about Turing, so it is not easy for me to accept that some people who know a lot about Turing did not know at all about his morphogenesis paper. We’re all constrained by our priors!


But in any event, thank you chaps for a nice discussion.

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.

Thursday, March 28, 2024

How our cells cope with oxygen stress: a paradigm of life's fuzzy, distributed control


My nephew Andrew, a chemistry postdoc at Oxford, has just published a paper in JACS on developing inhibitors of the protein HIF (hypoxia inhibitory factor) 1A. Hurrah for him! And this got me curious enough to delve into what this molecule does. Andrew had told me before that it’s a transcription factor, which naturally led me to guess it has a fair degree of intrinsic disorder – as is indeed the case (see the floppy bits of polypeptide chain here):


Why? Because most eukaryotic TFs do, as they tend to operate in conjunction with a host of other molecules such as cofactors and seem to benefit from having a degree of promiscuity in their interactions.


That’s just one way in which I suspected a protein like this might exemplify the ways in which our molecular mechanisms operate. And indeed, this turns out to be the case. At face value, how HIF1A (sometimes written as HIF1[alpha]) does what it does looks ever more perplexingly, indeed impossibly, complicated the harder you look. But in every respect I found those details confirming the kind of picture I have tried to sketch in my book How Life Works – and I’d hope that the book might help a non-specialist see how there are actually some generic principles operating in a case like this that can bring some sense of order and logic to what otherwise appears utterly confusing. So if you’re ready for the ride, strap in.


HIF1A is a member of a family of HIF proteins, in mammals encoded by the genes HIF1A, HIF2A and HIF3A. The proteins enable cells to cope with oxygen-depleted circumstances, in general by activating or inhibiting the expression of certain genes. For example, HIF1A can upregulate expression of vascular endothelial growth factor (VEGF), a key gene involved in angiogenesis (the formation of new blood vessels), so as to encourage the formation of new sources of oxygenation. For this reason, HIFs are not merely activated in unusual conditions of oxygen stress but are a crucial part of normal development, and are associated with disorders of blood circulation, such as atherosclerosis, hypertension and aneurysms. The 2019 Nobel Prize in physiology or medicine was awarded to William Kaelin, Peter Radcliffe and Gregg Semenza for their work in discovering the HIF proteins and how they regulate the cell’s response to hypoxia.


HIF1A has also become a focus of interest for cancer treatments, because if it can be inhibited specifically in cancer cells, this could enable the tumour to be slowed or even killed by oxygen depletion. That’s what Andrew and his colleagues are working on.


The basic mode of action is interesting, but also a major saga in itself. HIF1A is produced even when the cells have plenty of oxygen – but is then targeted by enzymes that stick ubiquityl groups onto it so as to label it for destruction by proteases. Those ubiquitylating enzymes are oxygen-sensitive, and if lack of oxygen stops them working, HIF1A is no longer degraded but is free to do its regulatory work as it accumulates in the cell nucleus. (This bit of the story, like all the others, is actually rather more complicated, as HIF1A degradation is also sensitive to factors other than oxygenation, such as nutrient levels – there is evidently a fair amount of context dependence and integration of various input signals determining HIF stability. What HIF1A does, and indeed how stable it is, is also influenced by having other chemical groups appended to it: phosphorylation, SUMOylation and acetylation.)


In the nucleus, HIF1A dimerizes with another member of the family, HIF1B [or beta] (which has two subunits, encoded by the genes ARNT1 and ARNT2) to form a complex that can bind to DNA and regulate genes. Those genes it regulates have promoter groups denoted hypoxia-response elements (HREs) that the HIF1A/1B complex recognizes. These are generally close to the target genes themselves, but not always; some are distal.


OK, so far it seems like classic switch-like regulation (albeit fiendishly complicated!). But here’s where things get complicated. For one thing, there are many more genomic loci carrying the 5-base-pair HRE recognition sequence than there are actual HRE binding sites. In fact, less than 1% of the potential HRE sites are bound by HIFs in response to hypoxia. How come HIF1A/1B isn’t sticking to all those others too? No one really knows. But it seems that some of the selectivity depends on sequences flanking the HREs, in a manner as yet unclear. This reminds me of the work I wrote about recently by Polly Fordyce at Stanford and colleagues, who showed that repetitive sequences flanking regulatory sites, previously dismissed as “junk”, might act as a sort of attractive well that accumulates and holds onto the regulatory molecules like TFs, via weak and fairly non-specific interactions that nevertheless somehow cumulatively impart the right selectivity. These so-called short tandem repeats act as a kind of “lobby” where the molecules can hang around so that they are ready when needed. I’ve no idea if anything like that is happening here, but it shows that we should not be too ready to dismiss parts of the genome that seem literally peripheral and “probably” useless. However, it seems likely that factors other than the DNA sequences are also influencing HIF binding to HREs.


What’s more, HIF1A doesn’t do its job alone. Eukaryotic TFs hardly ever do. There is a whole host of other molecules involved in regulating those genes, as evident in this diagram from one article:


When I see something like this, I now know not to take it too literally. It may well be that these molecules aren’t getting together in well defined and stoichiometric complexes, but are more probably associating in looser and fuzzier ways – perhaps involving what some call transcriptional hubs or condensates, blobs with liquid-like behaviour that constitute a distinct phase from the rest of the nucleoplasm. I haven’t been able to find any indication that this is what goes on for the HIF proteins, but it wouldn’t surprise me, given how such structures seem to be involved in other regulatory processes. One review of this topic simply says that “HIF1A may stimulate transcription either by means of cooperative DNA binding or cooperative recruitment of coactivators.” (That word “recruitment” is always a giveaway, since obviously the protein is not literally summoning its coactivators from afar – “recruitment” tends to mean “these molecules somehow gather and act together in a way we don’t understand.”)

And get this: “HIF1A has been shown to contribute to transcriptional control independently of its DNA binding activity, working instead in partnership with other DNA binding proteins to affect other cellular pathways.” In other words, there seems to be another (at least one other?) mechanism by which HIF1A does its regulatory work. How is a protein designed to do a job in two totally different ways? The answer is surely that it is modular. But how do these different channels depend on one another, if at all? When does one happen, and when the other? At what level is that decision made?

So in short: what the hell? How can we start to make any sense of this process, beyond the morass of details? Well, here’s the key thing: it seems that this fuzziness and multiplicity of actors enables the regulatory process to be sensitive to higher-level information – so that exactly which genes the HIF complex regulates is tissue- or cell-state-specific. That, after all, is what we’d expect: what’s needed to survive hypoxia will vary between tissues, so the response has to be attuned to that. This is an illustration of why we mustn’t imagine that Crick’s Central Dogma gives any kind of indication of the overall information flow in cells: it is not simply from DNA to RNA to protein (even if that applies to sequence information). What a protein does will be sensitive to higher-level information too.


And in fact, even what a protein is is sensitive to that too. We have known about alternative splicing – the creation of different mRNAs, and thus proteins, from the same primary transcript – since the 1970s, of course. But I am not convinced, despite protestations to the contrary, that the implications of that have really filtered through to the public consciousness, not least in terms of how it undermines the notion of a genetically encoded “program”. Contextual information from the surroundings literally changes the output of the Central Dogma. And the HIF family offer a great illustration of this, as you’ll see.


The other two alpha units of the HIF family, HIF2A and HIF3A, also bind to HIF1B. HIF2A has its own set of target genes. But weirdly, its DNA binding domain is very similar to that of HIF1A, and so the sequences HIF1A and HIF2A bind are essentially identical. Yet they do target different genes. How on earth does that happen? Well, it seems that for one thing they have differently spliced varieties (isoforms), meaning that the proteins are stitched together differently by the spliceosome during translation. Still, it’s hard to figure out how, or if, this is the key factor in their target specificity. One review says:

Although several studies have attempted to define the isoform-specific transcriptional programs, few common themes have emerged from these investigations, thus highlighting the complex nature of this cellular response. Variables such as cell type, severity, duration and variety of stimulation, the presence of functional VHL, and even culture conditions reportedly influence the transcriptional output mediated by HIF1A versus HIF2A. Furthermore, many of these studies have only examined either HIF1A or HIF2A, and untangling HIF-dependent from HIF-independent hypoxia-induced responses has proved challenging.

Again, what the hell? And again: it’s clear that a whole bunch of higher-level information is involved in determining the outcomes. For example, a part of the cell-type specificity seems to relate to the state that the chromatin is in: how it is packaged.


HIF3A, meanwhile, seems a little different from HIF1A and HIF2A, both in terms of sequence and functionally.  There are several – around six – alternative splicing variants with different regulatory functions. Some of these seem to have a negative regulatory action – for example, one isoform of HIF3A inhibits HIF1A. HIF3A seems to be a classic example of a protein with very tissue-specific alternative splicing: one form, called HIF3A4, for example, is expressed only in the corneal lens epithelium and controls vascularization there in response to hypoxia.


There’s more. How does HIF binding actually alter gene expression? Well, it’s sure not in the way the classic regulatory paradigm, the lac operon of E. coli, does it: by simply blocking RNA polymerase from attaching and transcribing the adjacent gene. Or perhaps we should say that yes, ultimately it’s a matter of hindering transcription, but in a manner that is far more complicated. In essence, HIF does this by initiating a change in the way the chromatin in that region is packed, for example by making the packing denser so that the DNA there is inaccessible to transcription.


And this too is subtle. One thing HIF binding does is to trigger enzymes that stick methyl groups onto the histone proteins around which DNA is wound in chromatin. Such changes are known to affect chromatin packing, but the details aren’t well understood. Certainly it’s not as simple as saying that methylation makes the histones bulkier and less well packed; sometimes that process will enhance transcription, and sometimes inhibit it. We don’t know what the “rules” are. But they aren’t, I think, going to be governed by any sort of simple, digital code – not least because they involve issues of three-dimensional molecular structure and solvation, and appear again to have a context dependence.


Nor should we imagine that the hypoxia response is merely a matter of the HIF proteins. Several others are involved too. At this point you might want to despair of making any sense of it all. But the point is that this process resembles nothing more than what goes on in the brain, where information from many sources is integrated and contextualized in the process of generating some appropriate output. That process involves several different scales – it is not simply a matter of this molecule speaking to that one in linear chains of communication. In this case, a more useful framework for thinking about the problem is one that is cognitive and analogue, not mechanical and digital.


Oh, there are yet more wrinkles, but I’m going to spare you those. The bottom line is that there are perils in taking the tempting line of explaining how HIF1A works by saying something along the lines of “It is a master regulator that switches genes on or off when the cell gets hypoxic.” That is true in a sense, but risks giving a false impression of understanding. In the end it implies that proteins (or their genes) just “do” things, as if by magic, and so suggests that they are in control. In reality, the way it works bears little resemblance to those pictures of blobby molecules sticking together and working via magical arrows. The information flow is much more omnidirectional, and the logic is fuzzy and combinatorial, and also poorly understood in many respects, and only makes sense if we take into account the system as a whole. When we do, it becomes clear that there is no basis for saying that genes like HIF1A dictate the hypoxia response; we can with more justification say that cells “decide” how to use their genetic resources to mount a response that is appropriate to their particular state and circumstances.


This is nothing that molecular biologists don’t know (and it is phenomenally impressive that they have got as far as they have). But I believe we need better ways to tell the story, which do justice to the real ingenuity, versatility, and contextuality of life.

Friday, September 15, 2023

The new Climategate that wasn't


Climate-change denialists got all excited last week by an alleged revelation that the top science journals are bullying climate scientists into presenting the most alarmist versions of their research, and suppressing anything that doesn’t fit with a “climate catastrophe” narrative. The problem (this story went) has been exposed by a whistleblower named Patrick Brown, formerly an academic scientist who now works for a privately funded environmental research centre.


Sounds bad? Is this another Climategate? But it takes very little digging at all before a very different, and extremely strange, story emerges.


Let’s start this tale with Matt Ridley. In his column in The Telegraph, he tells us this:

Patrick Brown, the co-director of climate and energy at the Breakthrough Institute in California, has blown the whistle on an open secret about climate science: it’s biased in favour of alarmism. He published a paper in Nature magazine on the effect of climate change on wildfires. In it he told the truth: there was an effect. But not the whole truth: other factors play a big role in fires too. On Maui, the failure of the electric utility to manage vegetation along power lines was a probable cause of the devastating recent fires, but climate change proved a convenient excuse.


OK, wait – what? So Brown knowingly suppressed facts relevant to the conclusion his paper reported? Was this some kind of “gotcha” stunt to show that you can get any old nonsense through peer review, even at a major journal? Oh no, not at all. In his blog about the issue, Brown tells us this:

I knew not to try to quantify key aspects other than climate change in my research because it would dilute the story that prestigious journals like Nature and its rival, Science, want to tell. 

This matters because it is critically important for scientists to be published in high-profile journals; in many ways, they are the gatekeepers for career success in academia. And the editors of these journals have made it abundantly clear, both by what they publish and what they reject, that they want climate papers that support certain preapproved narratives—even when those narratives come at the expense of broader knowledge for society. 

To put it bluntly, climate science has become less about understanding the complexities of the world and more about serving as a kind of Cassandra, urgently warning the public about the dangers of climate change. However understandable this instinct may be, it distorts a great deal of climate science research, misinforms the public, and most importantly, makes practical solutions more difficult to achieve. 

Oh, people really don’t know any longer about the myth of Cassandra, do they? Cassandra’s prophecies were true, but she was fated not to be believed. Anyway, Brown goes on to say:


I wanted the research to be published in the highest profile venue possible. When I began the research for this paper in 2020, I was a new assistant professor needing to maximize my prospects for a successful career.


So he is telling us that he wanted to get a paper in Nature to advance his career and he figured that telling this partial, distorted story was the best way to achieve this aim.


Kinda weird, right? And not exactly the exposé story Matt Ridley implied. Rather, Brown seems to be admitting to having committed the unethical practice of keeping certain facts hidden, or simply unexamined, in order to get on in the academic world.


Well OK – but can you blame him if that’s the only way to succeed? I mean, it is still weird for him to come out and admit it, but you can understand the motive, at least – right?


Except… is he correct about this? His charge – “the editors of these journals have made it abundantly clear, both by what they publish and what they reject, that they want climate papers that support certain preapproved narratives” – is pretty damned serious: the editors of Nature and other top journals are curating the scientific message they put out. You’d imagine Brown would back up that accusation with some solid evidence. But no, it is all assertion. It seems it’s “obvious” that Nature editors and those of other distinguished journals are biased because Brown’s own papers have been previously rejected by said journals. What other reason could there have been for that, people, than editorial bias?


Still, Brown does cite one bit of evidence in his favour: he says that some scientists err on the side of using worst-case climate scenarios. “It is standard practice to calculate impacts for scary hypothetical future warming scenarios that strain credibility,” he says. And here he points to an article that (rightly) decries this tendency and calls for more realistic baselines. Yet that article was published in – good lord, who’d have thought it? – Nature, the journal that allegedly always wants you to believe the worst. I’m not sure this is really helping his case.


Brown apparently knows for sure that his paper would have been rejected by Nature if he’d included all the complexities, such as considering the other, non-climate-related factors that could have influenced changes in the frequency of forest fires. For example, if the number of fires has increased, perhaps that might be partly due to changes in patterns of vegetation, or of human activities (like more fires getting ignited by humans either deliberately or by accident)?


How does he know that the Nature editors would have responded negatively to the inclusion of these caveats, though? The scientific way would, of course, have been to conduct the experiment: to send the fuller paper, including all those nuances, and see what happened. But Brown did not need to do that, it seems; he just knew. We should trust him.


Even Ted Nordhaus, director of the Breakthrough Institute in California where Brown now works, has admitted that this counterfactual does not exist. So Brown’s claims are mere hearsay. (Why has Nordhaus weighed in at all, given that he was not involved in the research? I’ll come back to that.) 


On his blog Brown says that he omitted those caveats from the study because they would just get in the way of a punchy conclusion that, in his view, would maximize the chances of getting published in Nature:

In my paper, we didn’t bother to study the influence of these other obviously relevant factors. Did I know that including them would make for a more realistic and useful analysis? I did. But I also knew that it would detract from the clean narrative centered on the negative impact of climate change and thus decrease the odds that the paper would pass muster with Nature’s editors and reviewers.

The trouble is, these days Nature provides the referees’ reports and authors’ responses to published papers online. And these contradict this narrative. It turns out the one referee highlighted precisely some of the issues that Brown and colleagues omitted. He said:

The second aspect that is a concern is the use of wildfire growth as the key variable. As the authors acknowledge there are numerous factors that play a confounding role in wildfire growth that are not directly accounted for in this study (L37-51). Vegetation type (fuel), ignitions (lightning and people), fire management activities ( direct and indirect suppression, prescribed fire, policies such as fire bans and forest closures) and fire load.


And Brown responded that his methods of analysis couldn’t handle these other factors:

Accounting for changes in all of these variables and their potential interactions simultaneously is very difficult. This is precisely why we chose to use a methodology that addresses the much cleaner but more narrow question of what the influence of warming alone is on the risk of extreme daily wildfire growth.


In a very revealing interview with Brown for the website HeatMap, Robinson Meyer pushed further on this issue. If Brown agreed that these were important considerations, and the referees asked about them, said Meyer, why didn’t he look into them further? Brown says:

I think that, that’s very good that the reviewers brought that up. But like I said before, doing that is, then, it’s not a Nature paper. It’s too diluted in my opinion to be a Nature paper.

This is what I’m trying to highlight, I guess, from the inside as a researcher doing this type of research. Reviewers absolutely will ask for good sensitivity tests, and bringing in caveats, and all that stuff, but it is absolutely your goal as the researcher to navigate the reviews as best you can. The file even gets automatically labeled Rebuttal when you respond to the reviewers. It’s your goal to essentially get the paper over the finish line.

And you don’t just acquiesce to reviewers, because you’d never get anything published. You don’t just say, Oh you’re right, okay, we will go back and do that work for five years and submit elsewhere. The reality of the situation is you have to go forward with your publication and get it published.

On the one hand, this is all honest enough: peer review is something of a game, where referees tend to want to see everything addressed and authors take the view that they’d never be ready to publish if they had to do that, so they generally aim to get away with doing the minimum needed to push things past the reviewers. That’s fair enough.


But it is totally at odds with the story Brown is now trying to tell. On these accounts, Brown did not in fact omit the confounding factors because he thought they would complicate the kind of message Nature and its referees would demand. He omitted them because they were too difficult to include in the study. And far from being pleased by an incomplete study that supported the narrative Brown had decided the editors and reviewers would look for, the reviewers – one of them, at least – called for a more complete analysis. It seems then that the reviewer would have been more pleased with the more complete study. Brown is admitting that it was he who tried to push the paper past the finish line in the face of these concerns. 


Some climate sceptics have still tried to make this sound like a shortcoming of the journal and the reviewers: ah look, they didn’t push very hard for that extra stuff, did they? But this won’t wash at all. First, the authors were commendably upfront about the limitations of the study – the paper itself says

Our findings, however, must be interpreted narrowly as idealized calculations because temperature is only one of the dozens of important variables that influences wildfire behaviour.

For the referees to pass the paper once it included this word of caution is entirely reasonable. After all, Brown stands by it even now:

You might be wondering at this point if I’m disowning my own paper. I’m not. On the contrary, I think it advances our understanding of climate change’s role in day-to-day wildfire behavior.


In short, there is not a problem here, beyond what Brown seems now keen to manufacture. If, as he says, the paper is “less useful than it could have been”, it is clear who is responsible for that.


Note by the way that, in response to a Nature news editor (independent from the manuscript handling team) who raised this issue, Nordhaus (again) said “The reviewer did not raise an issue about "vegetation and human ignition pattern changes". The reviewer raised an issue about holding absolute humidity constant.” As you can see above, this is clearly untrue. Nordhaus is simply referring to a different reviewer – despite surely having all of the reviewers’ reports available to him. I’m going to be charitable and assume he didn’t read them properly. But you will have to forgive me if I suspect an agenda behind Nordhaus’s involvement in the whole affair.


Talking of agendas: back to Matt Ridley, who has mentioned none of this in his column. He claims that the episode proves that “Editors at journals such as Nature seem to prefer publishing simplistic, negative news and speculation about climate change.” 


Matt’s story suggests that the publication of Brown’s paper has exposed the fact that climate scientists are hiding facts from us that are inconvenient to their narrative about catastrophic climate change.


Well, Brown’s paper is hiding from us facts that suggests the problem he looked at might not be as bad as it looks. But is this because he is a climate scientist with the agenda of doing so? No, it is because he knowingly withheld those facts - seemingly, did not even bother to investigate them, although to be fair that might be because he was unable to. But does the publication of his paper suggest that other scientists were prepared to turn a blind eye to that? No, because one of the reviewers raised the omission as a problem. Does the publication of the paper show that indeed there is a bias in the literature whereby papers that present an unmitigatedly bleak picture of extreme climate change get accepted but those that are more nuanced get rejected? Evidently it shows nothing of the sort. The only “evidence” for that is that Brown says so. Matt has not challenged that assertion, or asked for evidence, but recycles it as fact.

Matt then echoes Brown’s line that “the problem is all solutions [to climate change] are taboo [in the scientific literature].” He says:

If I waved a magic wand and gave the world unlimited clean and cheap energy tomorrow, I expect many climate scientists would be horrified: they would be out of a job. 

It is hard to know what to say about this, other than that it is one of the most absurd things Matt has ever written (yes!). Climate scientists are in fact horrified by what is happening to the climate. So am I. Like them, I would be beside myself with joy if Matt were able to do this. (This is one of the reasons why I value work being done on nuclear fusion, which could ultimately provide a significant, clean source of power, albeit not soon enough to rescue us from the current climate crisis.)

Frankly, for Matt to say this of climate scientists is not just absurd but deeply offensive.

This idea that climate scientists have to play up global warming to protect their jobs is on the one hand risible and on the other hand a standard trope of conspiracy theorists: climate scientists have their self-interest at heart. It is really very peculiar that Matt and others seem to believe that if climate change ended, there would be no more climate. For that, folks, is in fact what climate scientists study. There are so many things left for them to study, so much we don’t know about climate. I imagine some climate scientists dearly wish they could study things other than global warming (and of course lots of them do).

What is ironic to the point of hilarity about the episode is this: Ridley and others are claiming that this is a story about how climate science insists of a simplistic narrative that ignores all nuance, but in order to do that they must create a simplistic story devoid of all nuance. The fact is that the story is deeply, deeply odd. For Brown’s version amounts to something like this:

Climate science is biased and broken and ignores complexities that don’t fit its narrative, creating a misleading picture. Meanwhile, I have published a paper that ignores complexities that don’t fit that conventional narrative and is therefore misleading. But the paper is in fact good and I’m not at all ashamed of it, and its conclusions still apply. But also it is also a deliberate partial falsification. I was forced to do this for career advancement, but only because I’d decided that was the case – I didn’t bother to submit the paper I should have written to see if my preconceptions were correct, and in fact I didn’t even try to do the work that would have required. The fact that Nature published the paper just shows that they only look for the simplistic narrative, even though their peer review process asked me to go into the complexities but I told them that was not possible and they and the referees accepted my explanation on good faith. So shame on Nature for publishing this poor work which is in fact also perfectly respectable and useful work, because I did it, but not as useful as it could have been if I’d done the other things that needed doing but which I didn’t do because I chose not to or couldn’t. And it’s all a scandal!

Sorry, it really doesn’t make any sense, does it? But there you have it.

Monday, September 04, 2023

Should we colonise space? How not to debate that question.

Software engineer, astrophysicist and human spaceflight enthusiast Peter Hague has commented on Twitter about my Guardian “Big Idea” piece assessing the notion of colonising other worlds. I debated whether I should respond, given that Hague’s critique is steeped in the kind of vituperative ad hominem attacks that seem to characterize a lot of the discourse coming from advocates of space colonization (something remarked on by Erika Nesvold, whose excellent book partly inspired my piece). But perhaps a response will serve to illustrate some of the challenges of debating the issues. So here goes.


Hague says:

Ball claims there is “a dismaying irrationality in the answers”, and then proceeds to quote mine and cherry pick answers without adequately demonstrating that they are in fact irrational. Or, in fact, being specific about what he means by irrational. It’s actually important, because whether some action is rational or not is entirely contingent on what you are trying to accomplish. Ball’s statement has embedded values, even though he leaves them unstated – perhaps relying on the Guardian audience to share them. In that case, ‘irrational’ just becomes a word that can describe more or less anybody who doesn’t share that worldview.


I have not quoted anything by Hague (unless he believes he is Stephen Hawking). I had no idea what Hague might or might not have said on the issue. I’ve simply no idea what he’s talking about there.


The irrationality I have in mind is illustrated by what follows, but also by the ad hominem aspects mentioned above. One might imagine, for example, that Hague would start by finding out something about the author of the piece he is attacking, which would have very quickly revealed that I am not a “Guardian writer” (unless every single person who has ever written in the Guardian becomes that by default).


Hague quotes me thus:

"The timescales just don’t add up. Climate change either will or won’t become an existential risk well before it’s realistic to imagine a self-sustaining Martian settlement of millions: we’re talking a century or more. Speculating about nuclear war post-2123 is science fiction. So the old environmentalist cliche is right: there is no Planet B, and to suggest otherwise risks lessening the urgency of preserving Planet A. As for the threat of a civilisation-ending meteorite impact: one that big is expected only every several million years, so it’s safe to say there are more urgent worries. The sun going out? Sure, in 5bn years, and if you think there will still be humans then, you don’t understand evolution."


He then says:

Ironically here Ball vindicates a point I have made myself. A century probably *is* a timescale for when migration off Earth becomes a significant contributor to resolving pressure on the biosphere. But this means we need to get started now, so that we can get to that point in a century. Doing so means we only need to juggle human and environmental issues for a finite time, and we don't have to just slowly wind down human civilisation.


Huh? Is anyone suggesting we must “wind down human civilization”? (Well I guess some might – you can always find someone saying anything. But it is hardly the default position.) Anyway, I don’t follow this “resolving [presumably meaning “relieving”] pressure on the biosphere”. Many forecasts suspect that human population will peak around 2075-2080, and then stabilize. I don’t see many arguments that off-planet settlement is needed to absorb an excess of humans – but presumably to make a real difference, we’d need to see a billion or so decamp on that kind of timescale. Is that likely to happen? I have to say it seems hard to imagine. At any rate, my point is elsewhere, specifically about the popular idea that an off-world colony would be a back-up for civilization on Earth going off the rails. The threats we currently face can’t credibly be extrapolated to the point where a human settlement on Mars (say) might plausibly be entirely self-sufficient. And in any event, the argument seems incoherent. It’s like saying that, because Johnny’s behaviour is wreaking havoc in his neighbourhood, the solution is to send him to the next town, where somehow he’ll stop being so antisocial.


Hague adds:

His complacency about asteroids is not shared by those who study them, and the argument about the lifetime of the Sun is not used as an argument for immediate settlement by anybody I know of, and he doesn't attribute it, so we can move on from that.


This is what I mean about rationality. Sure, we are right to want to monitor asteroids and meteorites because a Tunguska-size blast over a major population centre could be devastating. And bigger ones would be terrible indeed. But a blast so great that it poses a truly existential risk to the planet? I give specific figures for at kind of threat – the chance of it happening in the next couple of centuries, say, is minuscule. If you’re kept awake at night because of that fear to humankind, you have an impressive capacity for displacement. But does Hague address this? He does not; he simply tries to imply that the issue here is a lack of expertise.


Hague then quotes me:

"For some, the justification for planetary settlement is not existential fear but our innate drive to explore. “The settlement of North America and other continents was a prelude to humanity’s greater challenge: the space frontier,” reads a 1986 document by the Reagan-appointed US National Commission of Space, rather clumsily letting slip who it was and was not speaking for. But at least “Because it would be cool” is an honest answer to the question: “Why go?”"


And he replies:

This is a low blow. He is cherry picking a forgotten government document to try and lob a vague accusation of racism around. If he wanted to look seriously at the argument that there are parellels [sic] between the opening of the American frontier and the opening of the space frontier, he might address the work of @robert_zubrin, who has articulated this far better. There is no indication the author has even heard of Zubrin though, which doesn't speak well to his knowledge of the argument he believes he is rebutting.


OK, there’s a fair bit to unpack here. First, there’s the question of whether you really want to hear from someone whose argument goes like this:

“Anyone who hasn’t heard of Zubrin is probably not qualified to write on this issue, and I’m going to totally guess that the author hasn’t heard of Zubrin, so there you go.”


What’s even more absurd is that, when it was pointed out to Hague on Twitter that in fact I very much know of Zubrin (as he could have discovered without too much trouble), he says in effect “Well that proves my point! – he knew of him but didn’t mention him!” Specifically:


“Then it’s especially ridiculous that Ball ignores his advocacy in favour of skimming ancient NASA documents for some hook to launch his fatuous accusation. It’s possible that he has forgotten who Zubrin is, seeing as his interest in the subject is clearly surface level.”


Ah, so OK I knew Zubrin but perhaps forgot about him. Sorry, but Christ on a bike.


Also, about that “forgotten government document”: someone on Twitter kindly pointed out that it is on the contrary it is a significant text, whereupon Hague says Sorry for dissing the document! Bear in mind I was 5 when it came out. So how does this work? Should I be confining myself only to things that were known or published after Hague grew up?


Moving on, Hague says:

Now he takes a swing at Gerald O'Neill. Or, more correctly, he takes a swing at Don Davis for his famous illustrations of O'Neill colonies, given that the dismissal of O'Neills entire work seems to be based entirely off aesthetics and lifestyle - a lifestyle, by the way, that although it isn't approved of in the Guardian, migrants literally risk their lives every day for a chance at.


Sorry, what? Let’s come back to the point, yes?


And my point is that there is a long history of presenting life in space as utopian, in the case of those famous illustrations at the expense of all scientific credibility (just cut out a slice of the American natural ecosystem and plant it in a rotating space colony). I don’t see a response to that here.



At last we get to the meat of the objection:


"If you want to know what to expect from colonies established by “billionauts” such as Musk or Jeff Bezos, perhaps ask their employees in Amazon warehouses or the Twitter offices. Many advocates for space settlement are “neoliberal techno-utopians”, says the astrophysicist Erika Nesvold, who sell it on a libertarian ticket as an escape from the pesky regulation of governments. The space industry doesn’t talk much about such things. As Nesvold discovered when she began quizzing commercial space companies in 2016, ethical questions such as human rights or environmental protection in space typically meet with a response of “we’ll worry about that later”. The idea is to get there first."


Hague says:

Ball presents Nesvold as an authority, and not an activist, which is what she is - and gives her a platform to basically label "bad" labels on the enterprise.


So anyone who has a view different from his (even when articulated carefully, calmly and in a deeply informed way, as in Nesvold’s book) is dealt with not by addressing those arguments but by dismissing said person as a mere “activist”. You see what I mean about longing to see a more rational debate?


He says:

It’s not explained why space colonies being libertarian is bad, nor why they would be run like Amazon warehouses. This is just a collection of boo words for the particular audience of this paper.


I think Hague is having a lot of trouble distinguishing the piece from the platform in which is appears, with which he clearly has lots of issues. In any case, if a powerful person has an ambition to establish an enterprise, I’d be curious to see how they have run other enterprises in the past. Call me naïve, but I just have a hunch we might learn something from it. Sure, I can’t speak for anyone but myself when I say that I’d not want to be living on Mars under the aegis and whim of a Musk or a Bezos. I just feel governance is an issue some might like to think about.


Hague quotes me thus:

"If the notion of a “colonial transporter” gave you a twinge of unease, you’re not alone. Associations of space exploration with colonialism have existed ever since it was first mooted in the 17th century. Some advocates ridicule the comparison: there are surely no indigenous people to witness the arrival of the first crewed spaceships on Mars. But the analogy gets stronger when thinking about how commercial incentives might distort rights afforded to the settlers (Musk has floated the idea of loans to get to Mars City being paid off by work on arrival), or how colonial powers waged proxy wars in far-off lands. And if the argument is that these settlements would exist to save us from catastrophe on Earth, the question of who gets to go becomes more acute. So far it has been the rich and famous."


Then he says:

Correctly sensing he may be ridiculed for this argument, Ball tries to preempt this but then continues to make equally ridiculous arguments, simply because the word 'colonialism' is bad, and anybody using it must be planning to become the next East India Company. Reasoning by analogy is not valid.


I’m curious to know what is “ridiculous” here, but there’s no indication, so it is hard to know what to say. Personally, I think history has things we can learn from, so it is worth heeding it. I think that’s probably quite a common view among historians.


Hague goes on to quotes me:

"Perhaps the most pernicious aspect of the “Columbus” comparison, however, is that it encourages us to believe that space is just another ocean to sail, with the lure of virgin lands to draw us. But other worlds are not the New World; space is harsh beyond any earthly comparison, and it will be constantly trying to kill you. Quite aside from the cold and airlessness, the biggest danger is the radiation: streams of charged, high-energy particles, from which we are shielded by the Earth’s magnetic field. Currently, a crewed mission to Mars would be prohibited by the permitted radiation limits for astronauts. We don’t have any solutions to that problem."


He says:

In the single point where he makes any kind of technical argument, Ball immediately fumbles. It is not, primarily, the Earth's magnetic field that shields us from cosmic rays,


Well you know what, I think I’ll go with what NASA says here, as they actually send people into space.


…and they are not as lethal as he believes. If they were, every geomagnetic reversal would be a mass extinction event.


The possibility of mass extinctions associated with geomagnetic reversals has in fact long been discussed – many palaeo scientists anticipate that this might happen. But it has been hard to assess, not least because it is not clear to what extent the geomagnetic field really does drop to nearly zero during a reversal. Some studies suggest that, while the field rearranges, it remains substantial enough to provide a fair degree of shielding. NASA again: “During a pole reversal, the magnetic field weakens, but it doesn’t completely disappear. The magnetosphere, together with Earth’s atmosphere, still continue to protect our planet from cosmic rays and charged solar particles, though there may be a small amount of particulate radiation that makes it down to Earth’s surface.” During the latest reversal 780,000 years ago, the magnetopause may still have existed a considerable distance from the Earth’s surface. It’s also been suggested that the solar wind could itself induce magnetic shielding from cosmic rays in the absence of a geomagnetic field.


Humanity has, in fact, survived many of them.


The last known geomagnetic reversal was that one 780,000 years ago. The earliest known Homo sapiens fossils are around 315,000 years old. But whatever.


What does protect us is the thick atmosphere of this planet, and in that we see not only is the solution known it is blindingly obvious - mass. A few metres of rock on a Martian habitat will block the radiation, as will to some extent the atmosphere of the planet.


Yes, there is talk of building permanent settlements inside caves on Mars, or in empty lava tubes on the Moon. It’s a good sci-fi scenario: underground cities that never see the light. I’m not envisaging that those stories would be very rosy ones, but we can make up whatever we like, I guess.


As for NASAs limits - he does not cite a source so its hard to tell where he is getting this from,


Maybe he should read Erika’s book instead of just criticizing it.


but its contingent on travel time, shielding, and risk tolerance. The danger is not of some horrific case of radiation poisoning - its a small increase in the lifetime risk of getting cancer. Despite sounding scary, radiation is not really the top technical hurdle.


Again, I think I’ll go with NASA on this: in terms of health risks, it is absolutely seen as one of the major risks.


I don’t want to be uncharitable, but it does rather seem as if Hague is just making confident-sounding sciencey assertions that are out of touch with the facts, and assuming he’ll sound more authoritative than a “Guardian writer”. I do think there’s an interesting discussion to be had around, and responses to be made to, the points raised in my piece. But I’m afraid it’s not to be found here.