ALL MODELS are WRONG
How Life Works by Philip Ball review – the magic of biology
by Adam Rutherford / Jan 2024
“You might think, with the completion of the Human Genome Project 20 years ago now, and the discovery of the double helix enjoying its 70th birthday this year, that we actually know how life works. In physics, the quest for a so-called Grand Unifying Theory has preoccupied the most ambitious minds for generations, alas to no avail. But in the life sciences, we managed to find four grand unifying theories in the space of 100 years or so. Three are well known: cell theory – all life is made of cells, which only come from existing cells; Darwin’s evolution by natural selection; and universal genetics – all life is encoded by a cypher written in the molecule DNA. The fourth, no less important, goes by the chewy name chemiosmosis, and describes the way that all living things live by drawing fuel from their surroundings and using it in a continuous chemical reaction.
In summary, life, made of cells that extract energy from their environment, comes modified from what came before. Job done; suck it, physicists! However, biology is messy, and though we have these laws in place to describe all life on Earth, people like me remain gainfully employed because our understanding of how chemistry becomes biology is far, far from complete. These grand unifying ideas are unbeatable, but they lack detail, and in biology the devil lies at a molecular level of complexity that is hard to understand. Nowhere, as Philip Ball (a physicist by background) points out in his excellent new book, was this more starkly apparent than when an invisible virus turned the world upside down in 2020, killing millions, infecting many more. But while for some people it was lethal, or created myriad symptoms that would last for months or even years, for others it was akin to a mild cold, or even entirely symptomless. We do not know why this was the case.
How Life Works is a much more appealing title than the rather overused question of “what is life?” that was the one given to a series of influential lectures and an accompanying book in 1944 by Erwin Schrödinger – more famous for his hypothetical box containing a non-committal quantum cat – and ever since, this question has been borrowed by many wishing to seem profound. I find it largely pointless, and somewhat antithetical to scientific thought itself. We should be less concerned with what a thing is, and rather more focused on what a thing does. To define a living thing is a kind of creationist question, for it implies an immutable ideal type, but this runs counter to one of our grand unifying laws: the Darwinian principle that living things are four-dimensional, ever changing in time as well as space.
Lightning during volcanic eruptions may have sparked life on Earth https://t.co/E7qWIpQGC4
— New Scientist (@newscientist) February 7, 2024
But it’s an idea that is deeply embedded within our culture: a vital force, the spark of life, an elusive but essential quality that distinguishes the quick and the dead. What is life? Tricky to pin down, but we know it when we see it, to paraphrase US Justice Potter Stewart in 1964 (admittedly, he was referring to an intangible definition of pornography). Ball points out that we rely on metaphors and analogies to explain and explore the wicked complexities of life, but none suffice. We are taught that cells are machines, though no machine we have invented behaves like the simplest cell; that DNA is a code or a blueprint, though it is neither; that the brain is a computer, though no computer behaves like a brain at all.
A previously unknown type of replicating agent, far smaller and simpler than a virus, has been found in the human gut https://t.co/HsGhuI2yXh
— New Scientist (@newscientist) February 7, 2024
It’s a funny thing that we strive to reduce the most complex entities in the known universe – living things – to a simple description. We crave narrative satisfaction in untangling systems, but evolution has a 4bn-year head start on us, and had no plan, nor any concession to ever being understood by one of its clever fruits. James Watson, half of the pair who published the double helix structure of DNA in 1953, once wrote that the other half, Francis Crick, had burst into the Eagle pub in Cambridge and declared that they had discovered the “secret of life” (though in 2017 Watson himself admitted that he’d invented the whole scene for dramatic effect).
“‘The situation has become appalling’: fake scientific papers push research credibility to crisis point.
Last year, 10,000 sham papers had to be retracted by academic journals, but experts think this is just the tip of the iceberg”
— Brian Roemmele (@BrianRoemmele) February 7, 2024
Ball points out that we don’t try to do this with art, or other matters of extreme beauty: no reader or scholar tries to isolate and distill the “secret of Dickens”. These simplifications and analogies arise because it’s not good enough to simply deploy the condescending mantra “it’s a bit more complicated than that” and expect students not to be overwhelmed and bored. But Ball wonders if the models we use in our teaching reduce complexity without acknowledging that it’s there, as if we are trying to get that complexity out of the way so we never have to think about biology again. I am reminded of a better mantra, that of the statistician George Box: all models are wrong, but some are useful.
Ball builds a nice analogy with language, as we often do in genetics. How do you get from the dictionary to literature he asks? Well, it’s something like: words (+magic) > sentences (+magic) > chapters and books. The equivalent in a living organism is: genes (+magic) > proteins (+magic) > cells (+magic) > tissues and bodies. Except of course the magic is not supernatural, it’s just the stuff that we don’t yet know, or can’t explain simply, which is the meat of how life works. The book follows the flowchart: there’s an exploration of the fundamentals of genetics, of how the way we teach and think about genes is not reflected in what geneticists know. There are no specific genes for complex human traits or behaviours, yet this misconception – often deployed in headlines as “Scientists discover the gene for … ” – is culturally embedded. Emerging evidence suggests that the way we teach genetics to children reinforces not only this error, but a version of racial essentialism long abandoned by science.
Ball scales up from genes to proteins, and cells and networks, and in doing so we get stuck into the unexplored magic that gets us from chemistry to biology, all the while dismissing the egregious idea of nature v nurture: “I cannot stress enough,” he intones, “life works at all only in relation to its environment.” Ball is a terrific writer, pumping out books on incredibly diverse subjects at a rate that makes me feel jealous and inadequate. There’s a wealth of well-researched information in here, some details that are a bit chewy for the lay reader, and I question the utility of black-and-white illustrations of proteins that are unrevealingly complex and thus unenlightening. But other than that, the book serves as an essential primer on our never-ending quest to understand life. Ultimately, “what is life?” is a question without a useful answer. “How does life work?” is the question that should drive the next wave of aspiring biologists from the cradle to the grave.”
[Adam Rutherford is a scientist and author of Where Are You Really From]
INDISTINGUISHABLE from MAGIC
It’s time to admit that genes are not the blueprint for life
by Denis Noble / 5 February 2024
“For too long, scientists have been content in espousing the lazy metaphor of living systems operating simply like machines, says science writer Philip Ball in How Life Works. Yet, it’s important to be open about the complexity of biology — including what we don’t know — because public understanding affects policy, health care and trust in science. “So long as we insist that cells are computers and genes are their code,” writes Ball, life might as well be “sprinkled with invisible magic”. But, reality “is far more interesting and wonderful”, as he explains in this must-read user’s guide for biologists and non-biologists alike.
When the human genome was sequenced in 2001, many thought that it would prove to be an ‘instruction manual’ for life. But the genome turned out to be no blueprint. In fact, most genes don’t have a pre-set function that can be determined from their DNA sequence. Instead, genes’ activity — whether they are expressed or not, for instance, or the length of protein that they encode — depends on myriad external factors, from the diet to the environment in which the organism develops. And each trait can be influenced by many genes. For example, mutations in almost 300 genes have been identified as indicating a risk that a person will develop schizophrenia. It’s therefore a huge oversimplification, notes Ball, to say that genes cause this trait or that disease.
The reality is that organisms are extremely robust, and a particular function can often be performed even when key genes are removed. For instance, although the HCN4 gene encodes a protein that acts as the heart’s primary pacemaker, the heart retains its rhythm even if the gene is mutated1. Another metaphor that Ball criticizes is that of a protein with a fixed shape binding to its target being similar to how a key fits into a lock. Many proteins, he points out, have disordered domains — sections whose shape is not fixed, but changes constantly. This “fuzziness and imprecision” is not sloppy design, but an essential feature of protein interactions.
Being disordered makes proteins “versatile communicators”, able to respond rapidly to changes in the cell, binding to different partners and transmitting different signals depending on the circumstance. For example, the protein aconitase can switch from metabolizing sugar to promoting iron intake to red blood cells when iron is scarce. Almost 70% of protein domains might be disordered. Classic views of evolution should also be questioned. Evolution is often regarded as “a slow affair of letting random mutations change one amino acid for another and seeing what effect it produces”. But in fact, proteins are typically made up of several sections called modules — reshuffling, duplicating and tinkering with these modules is a common way to produce a useful new protein.
Later in the book, Ball grapples with the philosophical question of what makes an organism alive. Agency — the ability of an organism to bring about change to itself or its environment to achieve a goal — is the author’s central focus. Such agency, he argues, is attributable to whole organisms, not just to their genomes. Genes, proteins and processes such as evolution don’t have goals, but a person certainly does. So, too, do plants and bacteria, on more-simple levels — a bacterium might avoid some stimuli and be drawn to others, for instance. Dethroning the genome in this way contests the current standard thinking about biology, and I think that such a challenge is sorely needed.
Ball is not alone in calling for a drastic rethink of how scientists discuss biology. There has been a flurry of publications in this vein in the past year, written by me and others2,3,4. All outline reasons to redefine what genes do. All highlight the physiological processes by which organisms control their genomes. And all argue that agency and purpose are definitive characteristics of life that have been overlooked in conventional, gene-centric views of biology. This burst of activity represents a frustrated thought that “it is time to become impatient with the old view”, as Ball says. Genetics alone cannot help us to understand and treat many of the diseases that cause the biggest health-care burdens, such as schizophrenia, cardiovascular diseases and cancer.
These conditions are physiological at their core, the author points out — despite having genetic components, they are nonetheless caused by cellular processes going awry. Those holistic processes are what we must understand, if we are to find cures. Ultimately, Ball concludes that “we are at the beginning of a profound rethinking of how life works”. In my view, beginning is the key word here. Scientists must take care not to substitute an old set of dogmas with a new one. It’s time to stop pretending that, give or take a few bits and pieces, we know how life works. Instead, we must let our ideas evolve as more discoveries are made in the coming decades. Sitting in uncertainty, while working to make those discoveries, will be biology’s great task for the twenty-first century.”
1. Noble, D. Prog. Biophys. Mol. Biol. 166, 3–11 (2021). Article PubMed Scholar
2. Noble, R. & Noble. D. Understanding Living Systems (Cambridge Univ. Press, 2023). Scholar
3. Vane-Wright, R. I. & Corning, P. A. Biol. J. Linn. Soc. 139, 341–356 (2023). Article Scholar
4. Corning, P. A. et al. (eds) Evolution “On Purpose”: Teleonomy in Living Systems (MIT Press, 2023). Scholar