In college, I thought biology was interesting, but tedious with lots of facts to memorize. I was also doing poorly at experimental lab work. Cells died under watch and I couldn’t get the data I needed. Some of my lab partners were flaky. It wasn’t the most positive experience. At the same time, I was finding both organic and inorganic chemistry intellectually stimulating! It was a no-brainer. I chose to major in chemistry.
Thirty years later, I wonder what younger self was thinking. Biology is fascinating and remarkable! My segue into biology began when I got interested in learning more about the chemistry of the origin of life – a complex self-assembly problem. Before long, I started to read more papers in biochemistry and molecular biology. More recently, I’ve begun to appreciate the importance of systems biology and ecological thinking. To complement the scientific articles, I’ve also been reading more big-picture books that straddle into the philosophy of biology. My most recent foray is Philip Ball’s How Life Works, subtitled “A User’s Guide to the New Biology”.
The New Biology isn’t all that new. Rather it’s a shift in perspective to a more holistic view. The discovery of the DNA double-helix set biology on a path that privileged genetics over other areas. This led to significant advances in our knowledge of biology, but it also revealed the dearth of what we know about how life works. Genes turn out to be a part of the story, but not the most important part. Nature is both more complex and subtle. Today’s post will be about things that jumped out at me in two chapters from Ball’s book, “Networks” (Chapter 5) and “Agency” (Chapter 9).
Ten years ago, I was a fly-on-the-wall of a back-and-forth argument among several biologists about the ENCODE project. I was surprised at the vehemence of folks who thought the project was one of the most worthwhile and important things to be doing, and others who thought it was useless bunk and a waste of resources. The inner workings of the cell are not just about DNA, but RNA (all sorts of different kinds), proteins, and a bunch of other biomolecules ‘talking’ to each other, and somehow in that glorious mess doing the business of living. Ball goes through that story, and I appreciate seeing the big picture now, which I didn’t see then. We also didn’t know as much then – the growth in new biological information has been tremendous over the last decade.
I’m amazed by how all the different biomolecules interact with each other to do their thing. Not just one thing. Many things. Many different kinds of things. And it all looks like chaos! Molecules bump into each other, form transient complexes, and dissociate. Ball goes into detail discussing gene regulation and transcription, homing in on topologically associating domains (TADs). He calls them “ephemeral committees”. It’s as if “chromatin is a building with several floors (compartments), each with many rooms (TADs) containing separate committees. The committees have much the same membership in different cell types… molecules that are inclined to gather together. But exactly where they gather… varies between one cell and the next.”
It gets more complicated: TADS aren’t a “Lego-like assemblage of many molecules… like assigning everyone in a committee a specific place at the table and being unable to begin the meeting until all are correctly seated… it would take hours to get all the molecular members together in the same room and seated in the right place before any decision can be made. And this assumes that some members don’t drift away in the meantime, as perpetually restless molecules are apt to do.” Turns out the actual time spent is about six seconds, so “the committee needs to be very flexible. There might be no seating plan, nor any requirement that all members are present, so long as they have a quorum. The process may be literally rather fluid.”
The cell is not a factory running in what seems like organized lockstep; it’s a disorganized zoo with enclosures that are not totally enclosed. Ball highlights the potential importance of disordered proteins: “their propensity to form many indiscriminate and transient interactions with other molecules, seem to be ideally suited for promoting condensates.” I briefly discussed disordered domains in proteins when teaching biochemistry for the first time last semester, but I don’t think I really appreciate it due to my lack of knowledge. Further it highlights the incongruity between “digitally precise information [encoded] in the sequences of DNA, RNA, and proteins” that are then utilized in a “hazy environment… like telling each committee member exactly who may they talk to and what they may say, only to then create extremely lax rules about who comes to the meetings, how long they stay, and so on.”
Ball, however, sees an opportunity for this messiness: it’s what you need for a system to be robust instead of fragile. Ball compares it to a committee sufficiently diverse to include experts in specific areas, but also generalists, and mavens who are “good at connecting others and reconciling their points of view”. If you need “reliable generic decisions amid a tremendous diversity of experience and circumstance… lots of details [must] be weighed, filtered and integrated.” It comes down to information management and “not a concentration but a dispersal of power”. Those mavens? Their equivalent chemical skill is molecular promiscuity and leveraging combinatorial “fuzzy” logic. That’s why a “cell’s wiring can’t be compared to a complex electronic [computer] circuit”. Cell logic is wet and sloppy and needs to be!
Living seems to be an emergent process. Ball calls this causal emergence, and recapitulates the notion of biological relativity; no particular level of causality is privileged. The reductionist claims that all “macroscale causation is fully reducible to microscale causation”. The emergentist disagrees. One common thread in examples of causal emergence is noise reduction: “independence of the outcome on random fluctuations or chance events at the microscopic level”. The genetic algorithms and neural nets instantiated by 0’s and 1’s in a computer circuit are not like this – in fact we design them with high precision so the parts “don’t go wandering randomly out of place. But molecules do!” Ball compares the causal emergence we observe in living systems to human language, in which “meaning and indeed causal power… increase as we go up the scale from letter (or phonemes) to words, sentence, paragraphs… Zoom in on a text’s component characters and you lose all meaning.” But there’s more. Causal emergence leads to causal spreading, and Ball thinks that’s a key to how multicellularity emerged. The genomic expansion seems to be mostly in the regulatory elements. I admit that I don’t quite understand enough of the biology to grasp all this.
That brings us to agency. Ball’s definition: “the agent itself acts as a genuine cause of change: agents act on their own behalf.” Even in the chemistry classroom, I often use the language of agency when referring to a molecule: it wants to do something, it is attracted to something, it sees something in a neighboring molecule, it tries to lower its energy any way it can, it needs to pick up an electron, it is stable and “happy”. In the next breath, I warn my students about getting carried away with anthromorphizing molecules. Similar language is used in biology. I appreciated a footnote Ball provides from the philosopher Annie Crawford that “scientists who… consider their metaphors to be merely decorative additions that can be abstracted away from the meaning seem not to have thought very deeply about the nature of language… metaphors do real conceptual work.” I’ve become much more cognizant of this as my reading has branched into such philosophical realms.
Ball prefaces all this with a detailed discussion of Maxwell’s demon in the context of thermodynamics. This was familiar territory to me – an argument about the interconvertibility between information and thermodynamics. Ball then makes some intriguing and lucid statements (backed up by examples): “an organism can make use of the environment by becoming correlated with it… implying that they share information in common… such correlations become established in the process of evolutionary adaptation… [they] may also be engendered through learning from experience… it is shared information that helps the organism stay out of equilibrium… tailor its behavior to extract work from fluctuations in its surroundings… Life can then be considered as a computation that aims to optimize the acquisition, storage, and use of such meaningful information. And life turns out to be extremely good at it… The best computers today are far, far more wasteful of energy than [the Landauer] limit [apparently six orders of magnitudes more, compared to one order of magnitude in cells]… biology seems to take great care not to overthink the problem of survival.”
Mind blown.
Ball says that “having a mind is a good adaptive strategy for an organism that experiences a very complex environment”. The alternative of trying to “equip the organism with a suitable automated response for every stimulus it is likely to encounter”. That might work for something with limited functionality, but to be robust in a complex environment requires… well, you can see the challenges with automated-driving cars, and even then they only have a very limited function in the grand scheme of things. It’s amazing what our human minds can do. Ball thinks that it’s okay to bring the language of purpose back into evolutionary biology. He thinks the reason why biologists are uncomfortable is because biology “can’t deal systematically with agency and so has to infuse it into entities as a kind of magical capability… that arguments about human free will persist (often rather tediously) because we lack any account of how agency arises.”
It's clear I don’t really understand biology. Perhaps, like quantum mechanics, no one does. But I appreciate Ball provocatively pushing me to think both broader and deeper to do so. I think I understand a lot of chemistry, but maybe deep down I really don’t. The wonderful thing about being a teacher is that every now and then I have a small panic when I anticipate a profound question a student might ask in class (the reality rarely happens) and do a quick frenzied search about some conceptual underpinning. Inevitably, I learn that the concept is both complex and subtle; then I come up with a good-enough arm-wave explanation which I rarely have to use. But it’s the asking of deeper questions that matter, so I’m glad that I continue to ask them! How Life Works is thought-provoking in such a way that I will be re-reading it, just like Ball's book on quantum mechanics.
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