What is life and how does it work? - with Philip Ball

thank you, thank you, it's so nice to be back in the best scientific conference theater in the world and I've been giving talks here for over 20 years, I realized, but I don't think I've ever had one. There are a lot of people like that, so I I feel very flattered and a little nervous tonight. There are times when we really could use a human instruction manual. Imagine if every time something went wrong, we could look for the right solution. In the manual of viral infection an allergy or

what

ever we simply look for it, but the truth is that after reflecting on this question for thousands of years we still have a very vague idea of ​​the answer, now one might think that to answer this question We really should start with another one and some very smart people have pondered that question over the years, but no one still agrees on the answer.

I'll go, for the moment, at least with the answer given by British biologist JBS Haldane. he gave at the beginning of his 1947 essay with this title where he simply said this, um, so we can park that question for now. I'll come back to it, but the fact is that I know I'm alive and I know you're alive. and then we can ask ourselves how we

work

well. This is where we'll start with that pub question, specifically the Eagle Pub in Cambridge, which was where, according to American biologist James Watson, he and Francis Crick burst into Crick's in 1953 to exclaim to everyone: We've discovered the secret of

life

.

Watson recently admitted that he actually simply made up this story for his book. Despite having revealed this plate to that effect, he invented it for dramatic effect in his 1968 book, The Double Helix. because it was that double helix molecule that he and Crick had just deduced the structure of DNA, the double helix of the DNA molecule, and Watson wanted us to clearly believe that this was the secret of how

life

work

s. At that time, it was widely thought that DNA was not By everyone, but it is very widely believed that it is where the genetic information that is transmitted between generations is stored, and in this double helix structure, Crick and Watson had seen how it may be that our DNA is capable of of storing this genetic information in each of the twin strands. uh of the double helix of DNA um is a chain of a succession of just four different chemical building blocks um that we denote with the initial letters of their names so c g t and a and this they said then acts as a code just like strings of binary digits ones and zeros that were then used to encode information on the magnetic tape that digital computers used, so each of our genes is a um is a short segment of this code and we have many thousands of these um genes in the chain of letters of chemical letters which for us humans extends up to three billion of these letters and which we call the genome, so apparently here was how we work with the one fertilized egg that we all come from, it comes loaded with a set of instructions in the genome and all that has to happen then is for these instructions to be read to build us, so all we had to do now was read the instructions and that is

what

was done in the Human Genome Project which began in 1990 and was completed in at least as a draft by the turn of the millennium, as Bill Clinton said when that draft was first publicly announced today, we are learning the language in which God created life, so here is our instruction booklet, as It is often called, or our all-letter plane. of the human genome that you can read if you want in these 109 volumes found in the welcome collection on Houston Road, then the secret of how life works well some people have wondered if this blueprint or metaphor of the instruction booklet is really The correct way to think about the genome, Oxford physiologist Dennis Noble, has suggested that perhaps a better analogy might be a musical score and that is certainly better I think in some respects, so what is the cause of this music?

Well, some might say it's the score. composed by Beethoven, but

does

that answer remind me of Russian violinist uh jasher hyet's comment when he was once congratulated by an admirer after a concert he gave and came up and said that his violin has such a beautiful tone? and hitz took his instrument and said: I don't hear anything and his point, of course, was that that beautiful tone

does

n't just happen, it's not inherent to the violin, it takes something else to produce it in the same way, if you put the human genome, If you put it in a glass of water, it will just sit there, it will never create life, it will not produce a single cell, let alone us, well, obviously, of course, I mean, obviously, you need an orchestra to actually understand any music. , so one of the reasons I think Dennis's metaphor is quite nice is that it helps one see that, um, it's not so much that the musical score is the cause of the music, but that the different scores Musicals when played by an orchestra count.

In a certain sense, due to the differences between the music they will make, the problem with saying that the genome is the secret of life is evidently that the genome is not what makes life happen, surely life will not happen without it, as in Beethoven's Third. Symphony wouldn't happen unless we had prepared a score, but what we're really saying is that for life to happen, the genome needs to get into a system that's already alive, so really the story is oops, sorry , I moved forward quickly from there. I don't know if oh, I was floating over the music, so this is really the right way to tell the story.

Life is, in other words, a genome plus life or, to put it another way, this is the picture. which we are often given um and told that what happens in this black box is so horrendously contemplated that you're probably better off not looking inside it at all, but rest assured, scientists are working on it. and one day they will have it all figured out. However, that advice ignores this inconvenient fact, so to understand how life works, I'm afraid yes, we really have to take a look inside this black box and I'm going to do it. I'll try to give you a little glimpse of this, uh, inside tonight and you know, I won't deny that in all its glory it's really terribly complicated, but I hope to persuade you anyway that we can make some sense of it and, what's more. that over the two decades or so since the Human Genome Project was completed, the sense we have had paints a quite different picture than what we have traditionally been told in the genomic era.

Well, Francis Criek opened up that black box a little bit and this is what he saw. This is what he in the late 1950s called this central dogma of molecular biology. That's a strange name, isn't it? Because science should not have any dogma, but should be a provisional and subjective review. but Crick later admitted that he called it that because he didn't really know what Dogma meant, but anyway calling something Dogma in science is a bit of a red flag for a bull because it has gone down a lot of people. to spend a lot of time and energy trying to argue and show that the central dogma of cric is wrong, I'd say a better way to look at it is that it's not so much that it's wrong but that it's a bit like the Saint.

The Roman Empire, which was once said to be neither holy, nor Roman, nor really an empire, so the central dogma is not so much wrong as it is not a dogma and is not really that central, but let's take a look at it. glance. It concludes. What was already thought to be so and what was soon shown to be what genes actually code for are instructions for making these molecules called proteins and you probably remember the common cliché about proteins: they are the workhorses of the cell which means which are the molecules that make the biochemical reactions of the cell occur generally acting as catalysts that help convert one biological molecule into another and the way the code is in the genes is read and converted into proteins is in two ways. step process, so the first step is that the code of a gene, a given gene, is copied and the technical word is transcribed into a molecule very similar to DNA called RNA, um, so only that small part of the genome is transcribed into what is called Messenger RNA Molecule and then this MRA moves away.

The mRNA moves away and is captured by another piece of molecular machinery in the cell called the ribosome, which uses the information that the RNA encodes to join a particular chain of amino acids into a so-called chain. polypeptide chain which then folds into this compact shape and that is the protein molecule so the protein has a particular shape and this is the process called translation and there are thousands and thousands of these proteins in each of our cells here there are a snapshot of the inside of one of those cells and this is not just some kind of computer cartoon of what it might look like.

This is a computer generated image using real data of the inside of a cell, so this is what the inside of every cell in our bodies looks like and you can see it's incredibly crowded, but never mind the usual story, because each one of those Protein has, as I say, a very particular shape that fits like a lock and key with the molecule it must transform, so you only go to work on that molecule and ignore all the others and through this series of highly specific molecular interactions , proteins somehow bind us together well, that's how it will be expressed within the context of Cric's central dogma, so this fancy word here, phenotype, basically just means all the traits we have, the shapes we take, the height What we have, the color of our skin and our eyes, or even what behaviors we have, basically the phenotype is basically our individual being and in this picture, everything comes from what is encoded in the genes. in the soal genotype, but since the Human Genome Project was completed, more and more complications and problems have arisen with this story and I want to tell you about some of them, so I said we have thousands of um and uh genes and they produce thousands. of different proteins, how many genes do we have exactly?

Well, a banana has 36,000 genes. Now think very carefully before answering this question. Which organism is the most complicated? Well, then it stands to reason that I'm going to need more than 36,000 genes, right? When the Genome Project began, a common figure that scientists would give for the estimated number of human genes was around 80 to 100,000, so I've shown it here with a dotted line because it's just an estimate, but very soon we received a sobering wake up call because the more we started to get into the project, those numbers dropped dramatically and when we actually started getting real data, the solid line here, we found out that it's much smaller, that it was something like 20,000 uh genes that code for proteins and Now some scientists think so. it could be even a little lower it could be 19,000 so it's about as much as a small soil-dwelling worm called a nematode has and it's just half of what a banana has and these numbers are often displayed now as a comical example of how wrong expert opinion is.

It may be, but I think the really important question is why they were wrong. Maybe we had the wrong idea about what role genes played well? Here's another thing: In the 1990s there were one or two genes that biologists couldn't seem to find. the corresponding responding protein and in the end they had to conclude that this is because there is none. These genes simply produce RNA and not the messenger RNA that the ribosome translates into a protein; RNA itself is the end, it has some biochemical function. it does the kind of things that we thought proteins do and these RNAs that code for genes and I just marked them in red here are called non-coding genes, not clearly because they don't code for anything but because uh genes don't code for proteins, which is what We thought that all genes did well, but biology is full of strange exceptions, except these were no exceptions.

Over the past two decades, the number of these non-coding genes continued to increase and eventually. Just a few years ago, that number surpassed the number of protein-coding genes, and what's more, current estimates are that it's going to continue that way and, in fact, it will turn out that there are many more of these non-coding genes that far outnumber them. genes that code for proteins and the picture is actually even more transformed because these are just the parts of the genome that code for these relatively long non-coding RNA molecules that qualify as genes, but it has been discovered that there are actually many other fragments of the genome, our genome, but also that of other large animals like us, called metazoans, which encode a lot of smaller RNA molecules and there are all these different families with these fancy names that do all kinds of tasks in the cellular protein, like tasks for that you know what it is. the genome is full of things that don't code for proteins, so you can see that thegenome is not really what we thought it was about and yet somehow it still feels like we're telling, we certainly heard the same story that was being told about it.

In the 1990s or even the 1970s that cannot be true, it is more as if cosmologists had said after discovering that four-fifths of the matter in the universe is made up of so-called dark matter that we cannot see. and which we know nothing about like they just shrug their shoulders and say this doesn't change anything, luckily they didn't say that, well actually it's even worse than the central dogma of this cric which says that genes code for proteins and that By that we mean that the genes actually program the proteins into particular shapes so that they can do their specific jobs, but here is one way in which this picture is modified now.

It didn't mean that each gene codes for a particular protein, in fact each of our genes can usually be used to produce several different protein proteins, on average each can produce about six different proteins, but some genes can encode dozens or even hundreds of different proteins, so We have many more proteins and no one knows exactly how many more, but many more than we have, protein-coding genes, how is that possible? Well, it's because, as first discovered in the 1970s, the messenger RNA that is transcribed from a gene is usually cut. It's edited and edited before it's translated, so there's another piece of molecular machinery, this thing called a sply, made up of several different proteins that takes over the messenger RNA, cuts it into fragments, throws out some pieces called introns, and puts the fragments together. remaining. called exons in various orders, what decides how this editing and splicing occurs is typically information coming from a higher level of the system, say, for example, from the overall state of the cell in which it is happening, so a gene in a tissue could produce one type of protein and in a different tissue it could produce a different protein;

In other words, the flow of information here is not as at least the central dogma implies, it is not everything from the bottom up, from DNA to RNA to proteins, some information crucial to producing proteins is coming from the outside at some point. sense and this is just one of the ways in which, to build us and keep us alive all these years, information not only flows upward from the genes to higher levels of organization, but it flows up and down and in between and in all kinds of directions between them it is an open information system, not a closed one and here is another change in the picture in the analogy of the genome with a musical score, we could say that the score is what prevents the orchestra from simply playing a bunch of random notes making a fuss because it tells each musician exactly what notes to play and when um and that's the equivalent of the way a protein gene codes for a way like this tells it what to do in the cell what molecules to grab and which ones to ignore, so I mentioned this lock and key aspect earlier, but we now know that for many of our proteins, including some with some of the most important functions in the cell, DNA scoring is not like that at all. much more open to interpretation and what I mean by this is that some genes code for proteins without assigning them a structure, which leaves them loose and flexible or, as biochemists say, they are intrinsically disordered and this is not a fault of the genome to Giving proteins a proper shape is clearly a deliberate feature that Evolution has chosen, so to speak, because you see that there is much less of this intrinsic disorder among the proteins of simpler organisms like bacteria, so Evolution clearly was fine with giving all proteins a very specific structure, but it seems that he has found it useful or perhaps even necessary to rearrange proteins to create more complex multicellular, multitissue organisms like us, since many of our proteins, perhaps one-third , half or maybe even more, have parts or holes that are disordered in this way since it seems a little strange that we didn't really know about this until the last few decades, but that's because the methods that scientists have used in The past to look at protein structure generally only works well for types of proteins that are ordered and have a fixed structure, so they pack together and form nice ordered crystals, which is what is needed for those methods.

It's a bit like the way we overlooked non-coding genes for so long. We only see the things we expect to see and we tend to study only those things that we have techniques to study, so proteins with this intrinsic disorder, these flexible proteins, are much less picky about what other molecules they attach to, they are more very indiscriminately sticky. say that they are quite promiscuous in their molecular junctions, so that old idea that the molecular chaos of the cell is somehow kept orderly and tamed because each of the proteins is highly selective about what it interacts with, that idea really doesn't work and lets I show you a particularly important example of this kind of molecular promiscuity in action, so the standard argument about how we got so complex with so few protein-coding genes goes something like this: Well, it arises from the complexity of all the different interactions between those molecules that interact in these really horrible looking networks where you know each one of these spots represents a protein and it looks pretty horrible, right?

If you open a copy of nature at random, you will surely see images. Sort of like this and it's tempting to think of them as cartoons of what the various molecules moving around the cell actually do, but once you remember how complicated a cell really is, on the inside, you wonder how it is possible that in the Earth produces a complex dance of molecules. Anyway, this could be orchestrated, the idea being that this molecular interference explains how it is that, for example, different genes are turned on and off in different types of cells in our body, making heart muscle cells different from skin cells or even liver cells.

Although they all have the same genome, the idea is that the proteins produced by one gene could, for example, act as a kind of switch to control the transcription of another gene, so that it is turned on or off if that gene is transcribed and translated. . and that process is called genetic regulation. We have now known for a long time, at least since the 1960s, that gene regulation occurred. It was at that time that French biochemists Jack Mono and François Jaob showed how this process worked for a particular type of genetic regulation in the bacteria eoli now eoli can digest two different types of sugar, it can digest glucose and lactose, but it is not very efficient if the bacteria constantly produces the two enzymes necessary for those two processes when there is only one. sugar or the other thing around and then there is a switch that mono and jackob call the Lac operon a switch to turn on and off the production of the so-called Lac enzymes that are the ones that digest lactose, so in summary, this is what happens, there is this protein this green G uh thing here that I can recognize and stick to a little patch in the DNA this yellow patch just before the Lac genes and if it sticks there then it blocks this pink spot that the RNA polymerizes that produces transcription that produces RNA, blocks it and sort of turns it on so it can't do its job and stops the trans transcription of the missing genes, so it's like a nice simple digital switch, it has transparent logic and For a long time, the Molecular biologists thought that genetic regulation in organisms like us follows the same kind of principles that effectively connect our genes into a network a bit like a digital circuit like we have in microelectronic devices.

Well, you can probably guess what I'm going to do. I say that's not how it turned out very often. Genetic regulation in metazoans like us is much more complicated. These proteins that interact with parts of DNA to control gene expression are called transcription factors, and it turns out that many of our transcription factors are intrinsically disordered proteins. which are not as selective as these bacterial proteins in terms of what they bind to, maybe what DNA fragments they bind to or what other molecules um and that and the DNA fragments that regulate our genes like this kind of yellow section here there There is many of them in our genes and not all of them are next to the genes they regulate.

Some of them, strangely, are very far away on the DNA strand somewhere else entirely and these are regions called enhancers that somehow control the degree to which the gene is turned on or off, so gene regulation in the US tends to involve a lot of different components, transcription factors and other molecules often including some of those non-coding RNA molecules, most of them are regulatory, they have roles in gene regulation and then there are others. Things, there's all these bits of DNA that control the process in some way, some of which, because they're so far away, come in close by pulling out these big loops of DNA and sort of winding them up like they're pulling them out. a piece of wool from a tangled

ball

, um, and all of these components fit together into this kind of gigantic regulator assembly that's not, uh, something that just snaps together perfectly, it's a loose mass, it's a loose, messy mass, a dense clump sometimes called a condensate that forms as a kind of drop of liquid, a bit like a drop of vinegar, in the oil of salad dressing, so you know, it seems like a really complicated way to do this job, it's as if gene regulation in the US has ended. by these loose committees of molecules that talk to each other quite indiscriminately and it's really quite surprising that somehow all of these components still manage to make a reliable decision about whether to increase or decrease gene expression despite all this confusion between their interactions of this type. of fuzziness and the way it occurs Collective decisions rather than the simple digital logic we see in bacteria based on precise molecular junctions this fuzziness is a characteristic feature of our molecular biology we don't really understand how it works, but I think we can start to see why it is that for us life works in this confusing and quite open way that you see once you start to think about it, the more complex an organism is, the closer a blueprint or an instruction book comes to uh to Controlling how it works starts to seem like a terrible idea.

If the correct functioning of the organism depended on each of those instructions being executed perfectly in the right place at the right time in some kind of complex clockwork mechanism, then it just isn't going to work. . This happens mainly because the molecular world is not like clockwork, but is full of randomness and noise. It would be like trying to expect a mechanism like this to work perfectly if you dipped it in a bath and shook it. It's not going to happen, I mean, sure you can, you can, you can, and this was often the story that was told before contingency plans could be built, so if something fails, there is another way for the same thing to happen, like this The idea was that in these complex networks there is more than one route to the same end, so if this route fails, there is always this one, but when you think about it, that is not a good way to solve the problem, the answer to the fragility that comes from something that is very, very complex, if everything has to work perfectly, the answer to that problem cannot be simply to give it more complexity, but you need to use totally different design principles to do it and it is surely because that we have these fuzzy molecular mechanisms where the details often don't really matter committees can still come to good decisions even if some of the members are absent or asleep what these principles really mean what this idea really means is taking responsibility for the correct functioning of the whole thing remove the lower levels of the system and move it to some higher level;

In other words, we work in a way that is designed to take the pressure off our genes so that, in general, they are no longer the real cause of our traits and behaviors of our phenotype so that errors and malfunctions at lower levels can offset at higher levels and this actually happens at other types of levels in the stratum in the hierarchy of the way complex organisms like us function, so that, for example, if cells during the development of an embryo do not end up where they are supposed to end, there is often a way tocompensate for that later in the line of development so that you still end up with a perfectly viable organism and let me briefly give you a couple of examples of how these higher level principles that help organize our tissues and bodies reveal this type of dispersion of responsibility so they involve genes without in any sense being modeled by them, which is why the surfaces of our intestines are covered with these finger-like little fingers. protrusions called villi that greatly increase their surface area so that they can absorb nutrients efficiently into the bloodstream and these are basically protrusions on the surface layer of tissue called epithelium and their growth is caused by a protein that rejoices in twists.

The reasons for the slightly silly name Sonic Hedgehog do not ask, but this does not in any way imply that this Sonic Hedgehog protein or the gene that codes for it is a gene for villus growth; in fact, Sonic Hedgehog is all-purpose, which some find embarrassing. To what extent is it a commonly used ingredient that keeps showing up again and again in development and in this case what happens is that it, in effect, has the effect of changing the types of cells in the epithelial layer so that some can continue growing. While others stop and this is basically what happens, you have this layer of tissue and if some of the cells start giving off Sonic Hedgehog protein, if by chance a little lump develops in that tissue as it grows, then this concentrates Sonic Hedgehog protein. to a point where you can flip this switch and stop the growth of some of the cells so that they continue to grow at the base of this unit and the rest are pushed further and further up into this sort of finger. like protrusion and is a self-amplifying process, the more it is limited, the better the trap for the Sonic Hedgehog protein, so the real cause of these Vile is really mechanical, it involves changes in rigidity. of the epithelial layer here's another example, we generally have five fingers on each hand, um, but there's no gene that specifies that, there's certainly no gene that specifies this number five, the way our fingers are now thought to grow is that in the palette like uh Developing limb bud in In the embryo there is a small set of general-purpose developmental proteins that interact with each other in a particularly complex way, a way first talked about by the British mathematician Alan Turing in 1952.

The applause demonstrated how it is possible for a soup of reacting chemicals to occur spontaneously. they segregate into stripes of different composition, different um uh concentration of the ingredients and that's what seems to happen in the development of the fingers that the stripes radiate. The stripes develop on this growing limb bud and these concentrations, these stripes in turn trigger the growth of bone which becomes the finger bones and the reason there are five of them is because the stripes have only an intrinsic width that depends on the properties of the proteins and they grow just at the stage where five of these stripes fit.

Within the Bud embryonic limb the entire growth process is now more complex than it ever is in biology, but it seems that just a small adjustment in the growth conditions or the timing of growth could be enough to generate more or fewer stripes and That's possibly what we see down the road for pickled fish, they have more of these stripes that develop on their fins, so you can see here that the genes provide resources for the body plan, but that plan doesn't exist in any meaningful way. inside. the genome itself, the key genes and proteins involved in both processes and many others, are just general purpose developmental proteins, as I say, they are not proteins for developing any particular body type, the story is not really about they.

As such, it is about the cells and tissues of the developing organism being activated to produce those proteins at the right time, place and sequence and this change in the location of the true causes in biology is not just a metaphorical way in which What I'm using to talk about what's happening is something we can measure when the root causes of some complex system's behavior arise not at the lowest levels like they do with Clockwork, where all the gears have to fit together, you know, in the same way. correct way, but yes. They appear at higher levels of organization, that's something scientists call causal emergence and we can see it all the time in our social structures, for example, in the way a company can still operate if some of the workers are sick, because There are usually ways. that the others can compensate for their absence and we can see this in flocks of birds, for example, so that if there is a focused or tired species of bird somewhere in this flock that is doing something different, it does not cause chaos and confusion among The whole, the larger scale organization is robust against any small perturbations at lower levels like that and there are ways to measure the amount of causal emergence in complex systems and when a team of scientists applied those methods to look at the mechanisms that are used by simple organisms like bacteria, the so-called prokaryotes, and in more complex organisms, the so-called eukaryotes, like us, could see a clear difference: we, the eukaryotes, have more causal emergence and I call this causal propagation and it is propagation instead of just a change in where causality occurs because the cause really extends across a variety of levels, so there are still some traits, like diseases like cystic fibrosis, that can really be attributed to a single gene.

There are some traits that are significantly caused by that gene. but most of our traits are caused at levels above the genes, although genes can still influence them, perhaps the ultimate expression of this causal spread is the brain in the selfish gene Richard Dawkins sounds almost offended, uh, Our behavior sometimes seems to go against what a selfish genetic picture should lead us to expect, but I think this is precisely the point of the brain: you see the challenges that bacteria face and the decisions they have to make are really not that diverse, you know where the food is, where the humidity is, how.

Do I have to move to get there? They tend to live in unique environments and tend to die if they leave them, but we go everywhere and every day we face situations and challenges that we have never encountered in that way before in our lives. or that our ancestors have found before, so no genetic program is going to tell us what we should do in each eventuality and the responsibility for that decision must be passed to some level higher than our brains, which do not have a type of program that is capable of calculating exactly what we should do in any given circumstance but being able to improvise in the face of the unexpected, improvise using confusing rules of thumb, not some precise digital calculation, and this way of behaving in a way that is not entirely automated and predictable response to stimulus similar to a machine, but through genuine cognitive processing this is not only a good analogy for how life works at all levels, even down to the level of individual cells, some biologists argue that it is actually literally like that, that knowledge All Living things must be considered genuinely cognitive systems, as biologist Mike Levin and philosopher Dan Dennit have said.

Life is cognition in every sense and this does not mean that bacteria have any kind of mind worthy of the name, much less so. any kind of consciousness, um cognition, doesn't have to require consciousness to be genuine cognition, well no matter how you feel about this way of thinking about life, I think it captures an important truth about the way life works. and the best thing is that the metaphors to talk about it do not come from clockwork technologies or computers, but are metaphors extracted from life itself. What really distinguishes living beings from any machine we have created so far is that they are not automatic, but they have real functions. agency and what I mean by this is that they are capable of manipulating and altering themselves and their environment to try to achieve some self-determined goals.

Now, when we recognize that organisms have goals, we generally say, well, everyone's goals. Organisms must survive and reproduce correctly, but while a lot of behavior can of course be explained that way, I don't think it's enough. I'll make Hazard's assumption that his goal in coming here tonight was not to eat and reproduce, and if it was, I'm afraid you'll probably be disappointed, although who am I to say? But I think we are not the only animals that have our own agendas and purposes and decide that. are not obviously linked to evolutionary imperatives and are not entirely predictable, even single-celled organisms and the individual cells of our body set their agendas to some extent so that, for example, what may appear to be identical cells could behave in different ways when faced with a identical stimulus because it is not an internal configuration that they have, that determines that, if they wish, they have made their own decisions, they have their own objectives.

I think showing agency is actually a more fruitful and more general way of thinking about what it is to live. Organisms are trying to come up with some kind of checklist of you know what life is like, so reproduction, you know, metabolism, homeostasis, etc., so to get an overview of how the life, I think biology needs an understanding and ideally. really a theory of agency, what the basic ingredients they would require, we don't really know, although this new book by the closer scientist, Kevin Mitchell, makes an excellent attempt at starting that conversation and, along the way, showing what that looks like. .

What we call our own free will is really just one aspect of the kind of agency we, as complex cognitive and conscious beings, possess, but I think we could look at some of the things that agents will likely require. for example, they need to make predictions about their environment so that they are not constantly trying not to constantly waste energy dealing with things that they could have anticipated and avoided, and to do that, an agent needs some kind of memory in which it can accumulate and store information about their environment, which in the end amounts to a kind of representation of a crude model of their environment and we all have that, you know, if you leave here tonight and go back to the Green Park tube and start.

By heading north on Alile Street, then you really haven't stored a good internal representation of your surroundings because the other way around is south, so you've wasted energy, which in that case is not a matter of life or death, but sometimes make the right prediction. It might be nice, this new view of how life works. I think it's especially important when life isn't working so well and when we want to fix it. It is important for medicine. This question of causal propagation is important for medicine because if we want to. To effect some change in a system, the best thing we do is intervene at the place where that result occurs, is it the cause of this or that disease, some gene that we should target, you see what we tend to hear in discussions about Gene-based topics.

Medicine is the rare case where the cause actually lies in a particular identified gene, for example in recent announcements of the use of gene editing gene therapy to treat CLE cell disease, which is mainly caused by mutations in a single gene, so that we can In principle, you use genome editing to go into that gene and fix it, but I think it's a pretty well-kept secret that most of the regions of the genome that are associated with The most common diseases are not even within the genes. found within non-coding regions that are presumably involved in some way in genetic regulation and anyway it is often very difficult to make effective interventions at that level for one reason because genetic effects tend to involve many very small distributed effects. in many different regions of the genome, but I think ultimately the reason it's difficult is because the real causes of these conditions operate at a higher level of organization than genes, for example, in the functioning of the system immunological, which is common, so we could still see associations of the condition with particular parts of the genome, but in some sense all we are seeing are weak.

The echoes of genuine causality come down from higher levels, which may explain why genetic approaches to cancer treatments in particular have been so disappointing, because we know that cancers can arise from mutations thatThey can happen to our genes, maybe just because we get older or because we've been exposed to something in the environment that causes them and that's how it used to be. We thought we could find cures by looking at the genetic roots of cancer, but it increasingly appears that the most effective levels of intervention are the highest, and again, in particular, intervening in the immune system to help the body itself fight cancer. , as cancer biologist Michael Yaffi states. said in 2013 that we spent fruitless years searching for cancer linkx genes, not because we ever had any reason to think they were the key to developing new treatments, but because we had the techniques to search for them, as yafi said, as data junkies, we continue looking to genome sequencing when clinically useful information for cancer therapies may lie elsewhere: this broader view of what governs the behavior of our cells, tissues and bodies.

I think it's also important to understand the kinds of things that, for example, we can produce. In the last two decades we discovered that our bodies can be modified so that our cells change between different states, so that the cells in our body that have already developed into a mature type of tissue, a particular type of tissue, can regress and change into a stem cell-like state from which they can develop into any type of tissue and I have experienced this first hand. They took skin cells from my shoulder, reprogrammed them into that stem cell-like state, and then developed them into neurons that grew into structures a little like this, called brain organoids, which look a little not just in color and size, etc., but actually in anatomy they look a bit like developing embryonic brains and this looks like a normal embryo in reality.

This is like a normal mouse embryo, they are made of mouse cells, but it is a structure that has spontaneously assembled from stem cells. No egg or sperm participated in the creation of this so-called embryo model, so what our cells can produce is not like that. prescribed or preordained, I think it's best to think of them as being imbued with the potential to assemble into shapes and if we can understand what those higher level assembly principles are, then who knows what new shapes we might create. It is also a good reason to understand these questions to understand how life works simply to make us appreciate even more how amazing life is.

The idea that what makes living matter alive and different from a rock is simply that it has been programmed to be alive and is not just incomplete. but it's a bit boring. One of the sobering things about a gene-centered view of evolution and life is that it turns out to be a puzzle about why organisms exist. Richard Dawkins has called this the organism paradox, now I don't know. I know about you, but if my theory to explain the profusion of wonderful life forms ended up implying that those life forms shouldn't even exist, then I wouldn't call it a paradox but I would go back and think about where I went wrong.

There are ways to think about this paradox within the selfish view of life and the gene. That's interesting to do, but I think it's not too difficult to see ultimately why this paradox arises if you've taken all the genuine agency that exists. into real organisms and has been put into genes to make them look like little organisms themselves. If they all exist and compete with each other in some undifferentiated group with agency they do not possess, then it is no surprise that they no longer seem to need real agents at all. The idea that an explanation of life can be found by this gradual increase in magnification all the way down to the molecules is a fantasy and that is something that the Nobel Prize-winning biochemist Albert Georgie understood very well when he said this, he said that my own Scientific career was a descent from a higher dimension to a lower one led by a desire. to understand life I went from animals to cells to cells to bacteria from bacteria to molecules on my path life ran out between my fingers what this boils down to then is looking for an explanation of how life works that really does justice to what Truly amazing nature of life itself To say that life is just a machine made by genes or a computer that runs a program is not only incorrect from the perspective of what modern biology tells us now.

I think he banishes life completely from biology, sterilizes it, the eminent physicist Michael. Barry told me recently that he was once asked what the biggest unsolved problem in physics is and thought the questioner was probably expecting him to give some standard answer like dark matter or quantum gravity, but he found himself saying that Yes, as we think, all matter It is described by quantum mechanics, so where does the vitality of living matter come from? He didn't mean, thank God, that it must have some quantum explanation, but he meant that living matter is profoundly different from other kinds of matter. and we don't really know why parts of the universe, all these parts have become aware of themselves and their place within it.

Biologists must never forget that what they are really trying to do is understand and explain that it is no wonder that it is really difficult, but I think we should refuse to accept too cheap an answer to this question, the most profound question in science. , thank you.