What is Life? Sir Paul Nurse - 2020 James Martin Memorial Lecture

good evening my name is Giles Godfrey home director of the Oxford Martin school and it's my great pleasure to welcome you to the fifth James Martin lecture a lecture in which we commemorate the memory of James Martin Jim Martin was a computer and information scientist who wrote prescient prescient Lee about the challenges faced by Humanity in the 21st century both natural challenges and challenges associated with technology Jim with an enormous generosity endowed the Oxford Martin school with a challenge to the University to do major work to address the major challenges that mankind humanity will face over the coming over the coming decades it's a great delight that we retain a close contact with the Martin family and I'm really pleased to say that Jim's wife Lillian and Lillian's daughter Jaron are in the audience with us this evening so our speaker this afternoon is support nurse Paul nurse and and Paul is one of the UK's most distinguished scientists he's a geneticist a cell biologist whose work on the cell cycle the proteins that can control the cell cycle led to him being awarded with Leyland Hartwell and Tim Merce the 2001 Nobel Prize this work is of fundamental importance fundamental basic science importance because the mechanisms are conserved all the way from yeast up to humans and because of that it is a great medical significance as well especially around cancer poised not only a scientist but an extraordinary science leader and if I stood here and said everything he's done over the last 20 years there been no time for his lecture so I'm just gonna mention a few things beginning slightly parochially he was a chair in the 1980s I think of our department of microbiology here he's been president of the Rockefeller of Rockefeller University in New York it's been president of the Royal Society and he was one of the people who conceived of the extraordinary Francis Crick Institute at Kings Cross in London and as an is its first director and chief executive Paul is on a huge number of things in government including the the review that led to the restructuring of the research councils and the creation of UK our eye on television and radio Paul is a fabulous and might essay sometimes slightly wicked performer a dirty defender both a good science and the importance of supporting science tonight Paul is going to tell us what is life [Applause] well thank you Charles for that introduction and thank you all for coming it's a complete honor to speak in the show down in and also to speak bare back the University where I spent five years it's true in the 1980s a long time ago a pleasure also to meet Lillian Lillian Martin can I just tell you it's a wonderful school the Martin school taking on big problems and putting together interdisciplinary approaches to solve them so thank you and your family enabling that and allowing it to happen so I'm going to talk about well what is for me one of the most fundamental questions in biology perhaps the most fundamental really which is what is life it's only three words it's very easy to ask that question but actually it's not so easy to answer it there's AB wildering diversity of life on our planet all around us there are bacteria fungi plants animals and of course ourselves human beings the living organisms found on earth are physical entities that maintain themselves grow self-organized reproduce making more copies of themselves but what is it which links these different life forms all together for example what do we have in common with this yellow brimstone butterfly behind me here I like insects I should say I particularly fond of beetles somebody said that before in actual fact I'm particularly fond of beetles but I thought in the show Tony in a brimstone yellow would be more appropriate and you'll see it flicking about your goblins in a couple of weeks time it's a harbinger of spring and it's gonna flit about my lecture a bit as well I'll refer to a couple of times so what links this butterfly with us in short what are the core principles that underlie life now I'm not the first artist question of course I should have here the first title page of a book also called what is light it was written by the famous physicist Erwin Schrodinger in 1944 his book was influential if somewhat incomprehensible we all read it I did 50 years ago I will quote from it but I think we remember it in a different way from what it actually is to be quite honest with you anyway I walked quite a cup one or two passages from it however now my approach to the same question that Schrodinger asked here is to consider some of the important ideas of biology I'll describe where they came from explain what they are none of these ideas are particularly new I hope I'll be able to explain them to you in perhaps a new sort of way but they've stood the test of time and I want to pull on those ideas to develop these principles that are fundamental to life I should also say at the beginning that biologists don't often talk about fundamental principles this is his talk about me all the time of course but biologists tend to like to describe details you know we I sequence genes and ecologists will count how many species there are in the habitat we like making lists but actually from what we know about biology there are principles and I want to try and develop them as we go along now the first idea I'm going to talk about is a simple one it's the idea concept of the cell the cell is the basic structural and functional unit of life I call it here lies Adam they were discovered here in Oxford if you go down to the high street you'll find a plaque recording this they were discovered by Robert Hooke one of the founders of the Royal Society a polymath as many were then an architect designing churches in London an artisan and experimentalist inventor of Hookes law which we all had to learn involving Springs at school but he also discovered and described cells and this is the picture on the your right here sorry your left yeah using this microscope which he constructed or one like this and what he did is he used a razor to cut slivers of cork a plant core then examined them under a microscope like this and what he saw were neat arrays of boxes he called themselves after the Latin word cellar for small cubicle it's shown here in this drawing published in 1665 in a popular book at the time called micrographia I've put on the other side there the yellow one which is a scanning electron microscope picture of the same sorts of material so these are the first cells the basic unit of life few years later a rather humble Dutch Draper Antony von learn Hooke working in Delft in the Netherlands scraped between his teeth put it under a single lens microscope which was actually a very good one and discovered single-celled life what we now know as bacteria hmm let me good this is a pitch from lone hook he sent this picture to the Royal Society in the 16th 17th or 16-8 it's rather charming if you look at the figure BCD up there obviously under the microscope this bacteria done just a loop-the-loop swimming about under the microscope he was a bit disturbed by this discovery of these little animals which he called animal cools because he found them between his teeth and he was rather proud of his dental hygiene and felt disturbed finding little animals living in his teeth he was a close laborer in Delft to the painter Vermeer and Vermeer unusually for an artist actually both in and now painted pictures of scientists he did two pictures and he only has about 14 years onra and this is the one in the Louvre I'm getting better at it this is the one in the Louvre called the astronomer I like to think that this might have been stimulated by Loen hook there's no evidence for this of course pure speculation although when Vermeer died Loen Hooke was appointed as his executor so it's very likely that they did know each other anyway let's imagine it could be low and hook the discoverer of single-celled life now over the next two centuries it became clear that all living organisms consisted either of a single cell or a collection of cells and this led to at the early 19th century because it took two centuries really to sort all this out it's quite difficult to examine the Bing material under microscope particularly animal material over the next two centuries it became clear that cells were everywhere and Theodor Schwann German zoologist here in 1839 summarized all this up when he concluded that all organisms are composed of essentially like parts namely that so there were many who contributed to this he was one of the better publicists so we tend to give him a schleiden and schwann schleiden was a botanist the credit for that but it has to be said he they were just better publicist probably but as well as cells being the basic structural unit of life which is how we generally talk about it at school they are also the basic functional unit of life and as was argued by another German scientist pathologist this time Reid or Birkhoff who in 1858 from 30 years later wrote that every animal we see up there appears as a sum of vital units each of which bears in itself the complete characteristics of life what that means is is that cells are living organisms rooms themselves they they are alive they bear the characteristics of life and he also argued that all cells come from cells on this cellular a cellular in Latin that was important too because at the time it was thought that maybe living cell was just a rose spontaneously in some way that wasn't fully understood and indicating that all cells were derived from pre-existing cells my cell division with rather fundamental if you think carefully about it it means that there's a stream of connection between cell generations through a process of cell division that stretches back through the development of all living things including ourselves but also extends eventually back into deep time during the evolution of life in this planet connected through repetitive cell division now I hope I've convinced you that cells aren't interesting but if you are still doubting it I'll show you this this is an egg be fertilized by a sperm and perhaps I should remind you that every one of us once looked like this we will all once a single cell we've all been derived from a single cell and if you're not interested anymore there is a door over there you know cells are generally considered to be the simplest entities which exhibit the characteristics of life I will talk a little more about that later but this means understanding cells is key to understanding life so they will figure at several times quite prominently in the rest of my talk so what can we learn about cells that is relevant to understanding life this is a modern picture of a cell well first let's state the obvious cells are bounded physical entities they are separate from their environment they're surrounded by a semipermeable lipid membrane which separates them from their surroundings but allows communication with those surroundings this for example allows nutrient chemicals in the environment to become concentrated in the cell so there are physical entity in communication but separate from the environment this means this separation that order can be built up in cells at the expense of increasing disorder outside cells in this way life does not contravene the second law of thermodynamics which states the universe as a whole moves towards increasing disorder I mention this because when physicists think about life and they get very worried about this and there is no need for them to worry life has solved the problem it doesn't contravene this law of physics it worries Schroedinger a bit as you can see in this quote here and this is a the first quote up here an organism's astonishing gift of controlling a stream of order on itself and thus escaping the big into atomic chaos it's quite sort of exaggerated of course in its language but what it implies is that that life avoids the problem of the second law of thermodynamics and he was very very concerned about that but it's banned the fact that it's bounded deals of that issue he was astonished that life could escape that decay into atomic case as he said here and he proposed that a way of solving this was the chromosomes which we'll come to in a moment it could be explained in some terms of a code script which was passed on through the generations and that is a link to the second idea I'd like to discuss with you and that is the gene which explains the mysterious phenomenon of inheritance the idea here is of course that the gene is the basis of heredity it had its origins with the work of Anna gasps Tinian monk Gregor Mendel abbot of Bruno Brno monastery in the now the Czech Republic I was there a couple of weeks ago this is Gregor I call in the gardening monk because he did a lot of experiments with plants crossing different plants with different characteristics to look at how those characteristics were inherited he had quite good facilities there and I'll show you a picture of the monastery in a moment but what Mendel did was to experiment with maybe half a dozen different plant species but then decided to focus on one where he seemed to be able to make sense of what he was observing I mentioned this because biology is complex and if you were to make sense of the complexity it helps greatly if you study biological material which actually you can make sense off because having made sense of it you can perhaps apply those ideas and principles to more complex situations and you could call it cheating in a way because you just focus on what you can make sense or but if you don't do that then you can never make sense of the complexity that we're looking at so he found people ants were good that have different characteristics and he analyzed the outcomes of thousands of the progeny produced in these crosses publishing his work in 1865 I first visited his monastery in 1981 wasn't so easy to go then it was the height of the Cold War and what you see here is his garden it now looks much better when I visit it a few weeks ago and he had a greenhouse which was even bigger I've established that among us a Christian monastery should have invested so much time in indulging a monk's curiosity which is essentially what was happening they would like a little Research Council really funding research except he didn't have to write grants and he didn't have to think about impact factors he simply was studying the crosses to see what he could learn from them he crossed peas of varied characteristics including plants of different heights different flower colors different seed shapes you see some examples up there now he was trained as a physicist he never got a degree in he was in Vienna I'm not sure he was good examinations but he was good at science but he took something from physics which was a respect for quantitation a respect for theory which was rather lacking in biologists of the of the time and this meant that he was very quantitative in his approach he was very careful about how he counted and class the different characteristics and only focused on those characteristics where he could make clear distinction and what began to emerge out of these crosses which had have not been noticed by others who were doing similar experiments were simple ratios and many of us at school would have learned the ratio had been taught the ratio of three to one for example I won't go into it but this eventually led these simple ratios to Mendel ISM the notion that heredity is based on indivisible particles or factors which are inherited through the germ cells like the pollen and ovules in these plants or sperm in eggs in animals and these indivisible components another example of just like the cell is like the structural functional unit of life and Adam this was the the unit of heredity these factors after Mendel because Mendel's work was ignored actually he became abbot of the monastery he got into a fight with the government about taxation and drifted off from counting his plants and he published his his his his work it was actually published in a decent journal I'm not sure what the impact factor was but I'm sure it was moderately good but he published there in Darwin Charles Darwin who even had a copy of it though he never cut he never read it by the way Darwin Charles Darwin also observed three to one ratios in crosses with snapdragons but he just recorded it more like a naturalist he didn't try to think about he didn't have good enough data to be sure that that ratio was absolutely clear and he didn't try to interpret it now some years after Mendel around 2530 years these factors were found to be linked to the chromosome which were discovered in in dividing so let me give you an example this is a picture from the late 19th century from an onion root tip showing chromosomes appearing when cells divided I think the nice one this one here where you can see these threads separating I like this particularly because I first saw cells and I first saw chromosomes in an onion tip squash just like this when I was 12 or 13 at school and saw it looked exactly like that except it was in color rather than black and white now these Mendelian factors are of course what we now call genes and genes were one of the most important discoveries of the 20th century and I want to say a little bit about those discoveries because it's important for developing our principles in the 1940s Oswald Avery in Rockefeller University New York which Charles mentioned I worked in for seven or eight years he showed that genes were made of deoxyribonucleic acid or DNA it was contentious at the time many he didn't believe it was published in 1944 and I when I went to Rockefeller they had a cocktail party to welcome me and this little old man came up to me and shook my hand to welcome me and he said his name was Matt Matt McCarty and I looked at him I said you're not the McCarty who was on Oswald Avery's paper in 1944 and he said yes I am that McCarty he was 91 and still coming in to the University anyway this was not an idea that was rapidly agreed with his own colleagues at Rockefeller were amongst his fiercest cricket critics by the way typical of that academics it's what we expect from my academic colleagues but he was certainly not immediately accepted however and come ten years later the next major step which are all very familiar with is the structure of DNA as a double helix was determined involved a number of people in London the experimentalist rosalind Franklin Ryan Gosling Maurice Williams Wilkins and in Cambridge Francis Crick and Jim Watson Crick and Watson famously proposed the structure based on the other experimental evidence of the double helix that could explain heredity through the linear sequence of bases of the making up the DNA and the pairing between these complementary bases you can see here the base adenine is pairing with thymine guanine with cytosine now this is a double helix which is this structure allows it to be replicated if you think of a double helix as like a twisted ladder and then the rungs of that ladder and are the paired bases then if you um if you untwist that and separate the rungs and then you use that pairing to make a new copy just as you see here you get a precise copying of the genetic material and we're all very familiar with this it's copied during the process of cell reproduction the cell cycle which I spent my life studying and accounts of course for heredity it explains Schrodinger's code script which I mentioned it explains the permanence of the gene between generations that bothered Schrodinger because DNA is precisely copied or almost precisely copied which are returned to every time a cell divides also the sequence of bases which encodes the information is tucked inside the double strand it's kept in the middle of the DNA polymer Crick went on with others then to propose what we call the central dogma what is the central dogma such a terrible name really dogma I hated it but it's what we all know it is it describes how the sequence of base is making up of a gene is copied from the DNA to RNA that's ribonucleic acid this acts as a messenger from the DNA located in the nucleus where the chromosomes are to the cytoplasm where the proteins are made the proteins being the structure of the proteins being encoded by the DNA sequence the sequence of the messenger RNA determines the structure of those proteins and this led in the 50s to the conclusion 60s to the conclusion that there's one gene for each protein the initial work which was done in a fungus actually was one gene for each enzyme these discoveries made in the 20th century mostly the second half laid the foundations of what we now call molecular biology and they are critical to understanding life central to it is the genetic code heredity is in a four letter code made of the four bases and one thing to emphasize here this way of storing information is the same as linear sequences in a book which you read that's a linear sequence in my talk I'm talking to you in linear sentences or in bytes in a computer they are all linear ways of storing information it means that this linear digital storage of information was invented by life probably three billion years before the computer age we are we learnt it if we only know where to look from life well the nature and function of the gene is an introduction to the next two ideas I'm going to talk about life as chemistry and then life as information how does chemical activity and physical forces bring about life because life is wonderful and yet it's based on chemistry and physics and this is why vitalism the idea that there was some special spark was so prevalent the this idea that the functioning of living organisms is can be understood in terms of chemical activity and physical forces an idea that can be traced back to French chemists the initial work was done by Lavoisier just before the French Revolution unfortunately his research was cut short because he met the guillotine being a tax collector for the ancient regime a great pity because he was well on his way to sorting this out but then it was handed on fifty years later or more to Louis Pasteur who we know as the father of chemistry but shown here in this heroic painting not as good as the Vermeer painting in my view but still a painting and he was carrying out experiments would you believe on sugar beet fermentation in the north of France it was before he was famous and it led to the concept that life can be understood in terms of chemistry what was he doing well he was um working in the north of France where a sugar beet was being used to make alcohol and the industrialists who were doing that were worried because many of their fermentations and failed instead of making alcohol they made acid and he by just looking at the fermentations demonstrated that for the successful production of alcohol you needed to have yeast in there a single-cell microbe yeast and if you had yeast there it would work if there wasn't yeast there and there was bacteria for example then the fermentation made acid and he concluded that it was the yeast that was critical now that was an applied project totally applied project he was work he was helping industry but he went on from helping industry to making a fundamental proposal what he concluded more generally was that fermentation was a physiological act yielding products for the sell in other words chemical reactions are an expression of the life of a cell what he was arguing was life is chemistry and let me as an aside just say that sometimes we argue a lot in our profession about the differences between discovery basic research translational research applied research they are much closer than is sometimes thought same principles apply same curiosity apply they do work in different ways in the case of pasta with what I just described to you they will completely mingled so pastor pastor proposed like is chemistry but it is very elaborate and special chemistry and I want to just describe that and briefly the first point you should be aware of that it is based on carbon polymers and this is going to be important links with other things I've said we've already met carbon polymers because they make up nucleic acids DNA and RNA and we're now going to consider them in how they make up proteins before going there though just to sort of keep you excited I want to remind you that carbon is central to life but it had its origins in the Centers of dying stars where it's made carbon comes from dying stars we literally have our origins in the stars now the substances from yeast that Pasteur was working on our proteins that act as enzymes and enzymes catalyze chemical reactions they make chemical reactions go faster proteins are polymers of amino acids based on carbon and nitrogen the carbon atoms form part of the backbone to that polymer and they can also link to chemically different side chains of the amino acids this is a little bit of a protein backbone and what I want you to see is the the atoms end seen in for nitrogen see for carbon aren't providing a backbone but then if you look that you see you have side chains and some of them are constant and oxygen and a hydrogen for example others which are down here as are very and they vary according to the different amino acids that are found in the protein now these different amino acid side chains are chemically very different and this is a very important sum of positively charged some are negatively charged some repel water some are big some are small there's 20 different amino acids that make up proteins there's only four different nucleotides that make up nucleic acids and we'll come back to that when I talk a bit more about principles here are some examples of the different amino acids and their different potential for different chemistry being positively charged like lysine or negatively charged like aspartate this results in a wide variety of chemistry that can produce elaborate structures which have the ability to carry out many and varied different chemical reactions and this contrasts with DNA which is stable is not chemical diverse in fact it's chemically rather dull which is why a breeze colleagues at Rockefeller opposed his ideas he just want an interesting chemistry proteins do have interesting chemistry now the chains of amino acids making up these protein polymers can fold up in many ways to make complex molecular structures here we have a protein it got a couple of hundred different amino acids and it's starting to fold make connections between different amino acid residues that make it up and if this generates a three-dimensional molecular structure that is derived from a one-dimensional chain which in turn is derived from a one-dimensional chain a linear information device and I emphasize so here we have a three-dimensional structure now these various structures combined with varied chemistry's is the reason why we and all living things can undertake a wide diversity of chemical reactions because of the huge variety of enzymes that can be that can be produced and they produce these chemical machines a huge variety of chemicals that are needed for us to operate for all life to operate they make new molecules they break them down they recycle them they generate molecular assembly they make polymers nucleic acid protein lipid carbohydrates all mostly done by these chemically device proteins they can also do physical work they can make motors which carry cargoes around the cell on protein based trackways they can act in hybrid ways combining chemistry and physics capturing energy from sunlight or from breaking down sugars to produce energy rich chemicals that drive all the activities that cells need to operate now what does this mean it means that the thousands of chemical reactions being carried out simultaneously and close to each other in living cells I've put up here just a fraction each of these dots is a chemical reaction that the biochemist stroke biologists in the room will know what this is in the middle here is the krebs cycle there are hundreds of reactions going on on this limited part of life's metabolism and all these reactions all of which require somewhat different micro environments to work a go simultaneously all the time in all cells at this moment in your body all the time how is that possible it's only achieved by compartment ation and this compartment ation is brought about by the surfaces and folds of the enzymes themselves by complexes of enzymes acting together and by membrane bounded organelles which we can see in the cell now I wanted to emphasize that because when you look at a cell you think oh these are bits that make up a cell I'd like you to think of them as actually organized compartments organize microchemical compartments that allow hundreds if not thousands of chemical reactions to occur simultaneously because without that compartment ation that could not work it schema ties here in this one which is probably from Scientific American where you can see some of the compartments that are actually they're generating the different chemical micro environments required for the elaborate of chemistry of life to take place now that allows the chemistry to take place but remember the cell and all life has to operate as a whole and that means that these different chemistry's have to talk to each other if they're not talking to each other then they cannot behave an act as a whole and that talking to each other is communication transfer of information which leads to my next idea is life as information and life as information is reflecting the fact that living things are complex systems that we need in those complex systems control for it to work properly together and that leads in turn to purpose the purpose that you see something happening which has a higher purpose than what the chemistry itself is providing surprisingly the idea of life as a complex system was first argued by the philosopher Immanuel Kant I I was taught this when I was at the University of Sussex and I didn't believe the person who told me and he's true the thirty pages of his book on moral philosophy which talked about life as a complex system in 1802 and no vehicles picked up on it now now we talk about system biology and so on and I don't think most know it had its origins 200 years ago now the operation of a complex system requires management of information it's only possible by managing information by having properly controls and I operative am I going to give two examples to illustrate this the first is to return to DNA you remember this the double helix now the structure of DNA is iconic it's beautiful although I get tired every time I go into a biological research in situ you immediately see a double helix so when I put up the crick I said I don't mind what art we put in there as long as it looks nothing like a double helix now it's beautiful but it's real beauty lies in the fact that it only makes sense when it's realized that this molecule is in fact a digital information storage device it's written as I've already said to you in the linear script of four letters this linear polymer DNA is ideal for storing information and the encoding base is being turned inside are protected from chemical change and as I've already explained but I wish to emphasize and therefore rip repeat this information can be turned into chemical action that can do work by encoding the chemical activities of the proteins as I've explained to you for me this is absolutely wonderful it's a wonderful characteristic of life the carbon-based polymers have both abilities to encode information in one dimensional stable linear structures and to carry out chemical and physical work in three-dimensional chemically active structures and it's worth pondering back I I was taught this at school University in everywhere but somehow any sort of realized this in recent years second example I want to discuss is regulation that is making complex systems in living organisms act as a whole to be able to behave in with purpose now to understand what I'm saying here I'm going to go to man-made machines and you may be like me I sort of understand most machines that were made before 1900 and increasingly less and less machines that were made after 1900 this is a picture I took on a steam boat in New Zealand I think and the boat was built in 1896 or something like that and it had a beautiful governor this is a governor what does this do it was invented by James of what in the 18th century and as the engine goes faster that spindle goes faster the balls are centrifugal force they lift up this valve here and that regulates the steam going into the engine and that slows the engine down the balls go back in and it puts more steam in and the engine goes up again it's a homeostatic mechanism designed to maintain a constant speed of the steam engine it's man-made is designed to do this purpose and that's what it does it's essentially a negative feedback loop the top up there which is shown in the context of a metabolic pathway in a Cell just imagine that you have three chemicals a being turned into B being turned into C by different enzymes as C accumulates the imaginate inhibits the enzyme that catalyzes a going to B then if you get too much C it will switch off its production it will drop and it will maintain homeostasis negative feedback and that is something that is used frequently in living cells it was well demonstrated by a brilliant pair of French geneticists Francois Jacob and Jacques I had the privilege of spending some time with Jacob earlier in my life who worked all of this out studying the regulation of sugar metabolism and bacteria simply by genetics abstract thinking and brilliant models of how it might work other control modules and I'm going to call them modules for example lead to a positive feedback that means as C accumulates it activates the A to B enzyme and so you get more of C and what this is is like a switch once you start going you rapidly go from one state to another now many such feedbacks and controlled modules operate in cells they maintain homeostasis that generates switches timers toggles oscillators for translating the chemistry into informational modules so you're going from chemistry now to managing information and they can be linked together to generate more elaborate routines and informational management I want to put this up as a metaphor for this this is a transistor radio and some Witte has put these red and yellow labels which are genes involved in cancer actually and just to show that the network that we are designed in a radio or a smartphone or whatever has similarities to the network that we see in in life must be said though a better metaphor rather than hardware is Denis Bray's proposal that it's wetware why did he say wetware what he means is these components are all hardwired together so you can't change the basic structure you can change the inputs and the outputs and you can get regulation but wait where connects the different components by diffusion through liquid and that means you can rewire the hardware for different purposes and that's something I suspect we haven't yet thought quite enough but it certainly has the potential to increase the versatility of these control modules now the management of life's chemistry by information allows the behavior of the complex system to act as a whole and that means it can act with overall purpose such as reproducing a cell making a butterfly maintaining ourselves so key here is life as chemistry life as information now for centuries generating purposeful behaviors in living things was thought to require a designer a divine creator it took evolution by natural selection to change this and that's going to be the final idea that I'm going to discuss with you before trying to pull it together now evolution by natural selection how living things come about now this beautiful idea and it is a beautiful idea probably the most beautiful idea in biology mainly due to Charles Darwin the idea has two parts actually the first is that life evolves over time the second is that a major mechanism for that evolving for evolution is natural selection now that life evolved was not really Charles Darwin's discovery it's been around quite a quite a lot before that hmm back yes we have Charles here on your right and this is his grandfather Erasmus Darwin and this idea that life evolves was discussed for 50 60 years before Charles by Lamarck jean-baptiste Lamarck whose gets rather a bad press today but actually he was a very good biologist and Charles his own grandfather Erasmus now Erasmus was a colorful character he's he was a scientist a doctor a poet he wrote most of his research up in poems I've got a I collect books and I've got a number of 18th century books all written in poetry he wrote a quite a famous book called the the loves of plants which is all about plants fertilizing each other carotene sort of classical illusions he was a Republican he was asked to be George the Third's physician which he refused to do he was a proponent of women's education he was a had a terrible stutter but was a great conversationalist he also argued for the evolution of life and he suggested that simple formulas life like mollusks found in a shower could evolve into complex animals and so he had a motto on his coach which said everything from shells now he lived in Litchfield at the time and he was in the cathedral close and the Dane of Litchfield didn't like this very much and began to preach against him and his wealthy his wealthy patients and because he was also quite an idealist he didn't charge his poorer patients his income depended on his wealthy ones and because he was getting a disrespectful reputation he had to paint out his motto from his coach anyway read about Erasmus really interesting Charles was actually rather more moderate sort of individual compared with his grandfather now the evolution of life that life changes implies as a tree of life that living organisms are related if life only arose once and only survived once on the planet that seems likely given the conserved chemistry encoding that we find then all life on Earth is related this is captured in the only illustration in Darwin's Origin of Species published in a 18:59 which where he illustrated the Tree of Life he wasn't quite sure whether life originated more than once look at the bottom a to error he was a um he didn't quite know about it but here we see a clear Tree of Life he gathered evidence in favor of this during his trip around the world in the Beagle and he proposed a mechanism natural selection now briefly what is natural selection it's based on the facts that populations of a species of a living organism exhibit variations and if these are caused by inheritable genetic changes which can be caused if when the DNA is not copy precisely or if DNA is damaged by external causes if these variants then influence characteristics that can make these organisms more successful then in principle they will reproduce more and that particular genetic variant will spread through the population over time such variations will accumulate and lead to sufficient changes in that population such that the individuals will no longer be able to breed with examples from the original population leading to a new species accounting for the title of his book the Origin of Species Darwin concluded this in part by his studies of finches in the Galapagos for those and I'd like to think I didn't invent this I'm afraid I stole it but it's a great metaphor denis so some some finches had evolved to crack nuts others to seek insects under bark and what we have here are pliers that basically have the same structure but are designed to do different things like strip wires or you know wrench things and these were intelligently designed and these were designed by natural selection this was the this the fact that these are intelligently designed and these of course a design without an intelligent designer is the reason why darwin is still contentious because it removes the need for a divine creator now i'm going to push this a little further for natural selection to take place three things are needed reproduction a heredity system and a heredity system which exhibits variability upon which selection can work let me show you how this can work on the ideas of simply the cell and the gene imagine a single-celled life form with a brown coat imagine the brown coat is encoded by the DNA imagine there's a mutation which results in the brown coat becoming a red coat and imagine the red coat does better than ones with brown coats perhaps they can't be eaten so easily then what you can see is by combining the idea of the gene and the idea of the cell you automatically get evolution by natural selection these three ideas are all closely linked and can give rise to the variety of life this is an important idea so much so that the 20th century geneticists Hermann Muller use it to define life and that's going to be the starting point for the principles that are now going to draw together he defined life as living things have properties which allow them to undergo natural selection and therefore to evolve so he simply took Darwin's definition and turned it into a definition of life and this definition is one I'm going to use in the final part talking about the principles but first I want to say goodbye to Darwin when he was an old man you have to this is the last sentence in the Origin of Species whilst this planet has gone cycling on according to the fixed law of gravity from so simple a beginning endless forms most beautiful and most wonderful have been and armed evolved I wish I could write papers right at the Edison so of course would scrap it out and said far you know it superfluous superfluous also note that he's linking himself to Isaac Newton and that biology can have laws just like physics I'm going to turn to call principal's but I want to have two minutes on viruses because viruses are always troubling when well actually that very troubling at the moment but viruses are also troubling conceptually in what and by thinking about them I think it will clarify us how we should think about life now viruses this is a bacteriophage which infects bacteria actually have a nucleic acid genome DNA or RNA they have genes important for the virus they undergo evolution by natural selection which is why influenza changes each year so past mullahs test but they can only reproduce when they're inside the cells of other hosts living organisms and they do so by hijacking the cells molecular machinery to copy itself this means a virus cannot operate separately from its host the cellular environment of its host is completely dependent upon another living entity so the question is are they alive or are they not alive now in thinking about this I think it's important to remember that other forms of life are also to a greater or lesser extent completely dependent also on other living beings which is something in this debate that we don't often consider many parasites live on or inside the cells of bodies or animals plants or fungi although their dependency is less total than for a virus ourselves we can't make certain amino acids we must obtain them from other living organisms even free living microbes like yeast are dependent upon molecules usually made by other low living organisms all be albeit simple ones like glucose ammonia plants are more independent they use the energy of the Sun to make biomolecules but even plants rely on bacteria found in their roots to capture nitrogen from the atmosphere perhaps the most free living organisms are the cyanobacteria single-celled microbes that can capture both carbon and nitrogen from the atmosphere and work on the energy from light now I mention all of this so you can see that's a graded spectrum of living organisms from the viruses through to plants with a wide range in before in between and these all have very dependencies on other life-forms in the case of the virus the dependency is very strong whilst in other organisms that dependency can be weak but I argue that these different life forms are all alive because they all can evolved by natural selection if you don't like that explanation I'll give you another one for viruses they're dead when they're outside the cell and there are alive when they're inside the cell so that's another solution to the conundrum now the conclusion I want to draw from this is that life on Earth is fundamentally connected both through being related as a result of evolution the tree of life and also through these deep relationships and interdependencies and interactions that I've just very briefly summarized now with this in hand a big breath I'm about to finish we're going to have a few principles which reflect what we've said now I said that explaining these ideas will help us establish principles let me summarize where I think we've got to I'll start by reminding you what living organisms do they maintain themselves they grow they self organize they reproduce they have heredity so the this is what they do school will we just talk what they do but we're going to try and go a bit further from that this is all brought about by evolution natural selection central principle for life that I think is important is the one by mullah that I just explained to you living things are entities that can undergo evolution by natural selection once you have that then you can evolve diversity and you devolve purpose you get things at work they acquire purpose they are entities that build maintain and reproduce themselves living things evolve because they have the following attributes they are also bounded separate physical entities based on the cell is the basic structural and functional unit of life they have a heredity system which determines how the entity functions that is copied every time the entity reproduces the copying is precise but exhibits variation variation that natural selection can work on if it was absolutely precise and DNA was never damaged we'd have no evolution so it's a balanced life is based on polymer carbon polymer chemistry this is the basis of the lipid membranes that surround cells that can generate order and organization the carbon polymers that make up DNA and RNA the proteins that make enzymes and all the chemistry we need for life polymer base chemistry gives rise to digital information devices storing information in linear chains that can be translated into chemical and physical devices and machines integrating all these functions requires the management of information inputs are gathered from within and from outside the cell process stored and then instruct cells and organisms behave in ways that allow them to maintain themselves grow and to reproduce now should we ever encounter life elsewhere in this universe I suspect it will be based on rather similar principles the details may be different it could involve different chemistry's perhaps not based on carbon however in my opinion for it to readily serve the need for both long-term information storage and diverse chemistry I think polymers are likely to be involved life forms will require energy sources this energy could come from the nuclear reactions within stars light and heat or geothermal energy within planets circling stars but to return to our planet this is the only corner of the universe where we know for certain life exists the life that we are part of is extraordinary on earth it surprises us they have the wildering diversity scientists are making sense of it and that understanding makes a fundamental contribution to our culture and to our civilization I want to emphasize that it contributes to our civilization biology shows that all life including ourselves is related to each other it's deeply connected to all other life we share much with this yellow brimstone butterfly now as far as we know we are the only life forms who can see this deep connectivity and can reflect upon what it might mean in my view this means that us human have a special responsibility for life on this planet made up as it is by our relatives some clothes some more distant we need to care about it we need to care for it and to do that we need to understand it and that's what I'm trying to do in this lecture so thank you [Applause] so let me begin by thanking Paul for a really stimulating lecture we now have a little bit of time for Question and Answer I need to remind you that we're being filmed so if you're not meant to be here then perhaps don't ask a question when you do ask a question if you could wait for the microphone to get you so you can go into the recording and I'm really sorry the people in the upper gallery we won't be able to get a microphone to you and so if you can begin to wave and perhaps the first person can go there while we're doing that I'm gonna take prerogative Chairman's prerogative and ask the first question and Paulie you talked about the the language of the jeans as it's written in four letters and of course we're just coming to the threshold where we're going to be able to change that if we want to increase the the Cadbury in the sense and to do things within synthetic biology I wanted to ask you the degree to which you're excited about that nervous about that and what it might be able to do in terms of new science and producing new things and also whether it might give any insights into the questions that you so clearly outlined in your talk well I think the people doing this are absolutely brilliant I mean for those and maybe not familiar with it it's the ability to construct what are called orthogonal codes which actually allow living devices to be made that don't depend on the details it's the same principles as we talked about here but the same details and so this may have the potential to broaden the ability of living things to do different sorts of things in particular different chemistry's which is where synthetic biology has been discussed that producing organisms that might do more useful things I have a feeling is not going to be quite as useful as it's sometimes argued and that just may mean I'm just too old and white-haired and not imaginative enough I think it's brilliant working we should do it and it may work to produce new things I think it will produce some new things but I think we have yet to explore the extraordinary diversity that might is capable of simply by manipulating what we have already so I I don't see yet as the big shift that some do but I think it will add something to that and what is absolutely short certain it's the people who have done it are absolutely brilliant at doing wonderful work which I couldn't have imagined 20 years ago thank you do we have a question go ahead thank you in your view can information be stored exterior to DNA but within the organism and secondly briefly if I may are you satisfied that we can define easily precisely what the organism itself is thank you what was the second part again can we define satisfactorily exactly what the organism itself is well and I think you could imagine information being stored in different sorts of ways indeed many around 1950 thought that it was encoded in protein structure for example and in a sense there is information that is stored there I personally think and I argue quite strongly that for versatility and for ease of operation that it's stored it'll be stored most readily in linear form and and we see that everywhere you know as I said I'm speaking in linear form but you could design and indeed the synthetic biology approach is to design different different ways of doing it so I could conceive of it being different than DNA you we have story in RNA for example it's still in nucleic acid but it's a different molecule we have information stored outside the nucleus which is not what you were saying but we have that in the mitochondrion which was probably a captured microbe from 1500 million years ago that persisted so we do have different hereditary systems now the second question I still didn't quite catch which I think was to do with definition of an organism well the way I tried to define an organism was not a dictionary style of definition it was to share principles that I think we should think about that approach isn't quite the same as the way that we define organisms at school which I hinted that is to say what organisms do it was to try and dig deeper as to what the principles are I think Muller's definition of evolution by natural selection is a very unifying one I think you have to deliver that program that gets you into chemistry and information and I think that you need something to do it in which gets us into cells I think once we've sort of taken all that on board I think we have a reasonable a reasonable basis for thinking about what organisms are but I agree it's not a dictionary definition the Oxford English Dictionary would have a page on it if if we had to take this on thank you I think someone has a microphone up there yeah hello wait I can't see you right up there hello hi so all of the properties that you ascribed to life one could imagine a computer program being written that displayed all those properties like you can you can make evolving computer programs fairly easily would you consider computer programs that have all those properties to be a form of life or do you think that the subject like the physical substrate matters or is it more of like a structural yeah property well you're quite right we have programs that evolved by natural selection so some people have argued that in some sense this might represent life I did sort of anticipating the question I did sort of stress at several stages that we needed a physical entity that could do it itself now in the tense of a computer program it is also reliant on another life form just to go back to the interdependency in this case a human being that creates the computer program but also creates the hardware in which it works so the way I sort of push a computer program to one side although fully acknowledging that it has some of the characteristics that I described is it is not a physical independent entity which is doing it itself it is working within a medium as you fully I know you fully understand and within that medium it is it's evolving in terms of its language is evolving but it is not a physical independent entity I would argue but that's certainly the point you make is is made and cogently and we have to think about that just like we have to think about viruses but I for me me I'm including viruses of the live computer programs are dead thank you question here hand up I loved your repeated use of purposeful and purpose and that's a very rich concept that that can be used to mean sort of downward causation as opposed to a bottom-up reductionism yep albeit with the need to address the challenge of over determination yep all the way through to sort of purposes that one can find and choose and determine and I wondered how you were using it and how you see a continuum all the way through to us who who certainly feel as if we're biological beings who can choose purposes yeah so that's an insightful question we think we behave with purpose all the time sometimes our purposes seem utterly trivial and that should not divert us in some ways from the sort of purpose I'm talking here mono jack mono who I mentioned coined a term for it he call you gave it a fancy term so we didn't get confused with purpose he called it tealy anomic which is purpose in the sphere of biology rather than human behavior so that's to make some distinction there but I want to explore a bit more of what you were saying about levels because purpose is occurs at different levels and purpose that is behavior of the system as a whole lifts you from chemistry into biology and a chemical reaction is not life a replication of DNA that we can do in a test tube isn't life but the purposeful behavior of a cell is and somewhere in there is a transition from chemistry to biology and I think that's something that is worth thinking about because I'm not quite sure where that transition occurs but there's something else to do with these different levels which I think's interesting I mentioned life as information now at different levels of life from molecular assemblies to cells to organs to organism to populations to ecosystems are all complex systems subject to similar laws when they are reduced to the management of information and what I happen to think is that what we may learn in terms of the management of information at the level of molecules will turn out to be relevant in an ecosystem and what we learn in an ecosystem will be relevant to the behavior of molecules which is why I think we have to focus on biology as a whole system when we teach it and not have molecular biologists and botanist and zoologists or whatever which we we're reversing a bit now but was a real problem so I think the unifying way of thinking about this is the management of information at different levels isn't quite the question you asked but I'm glad to be able to make that point - thank you thank you lady in there strike Jersey hello it feels like yesterday but it was actually a few years ago you gave a wonderful lecture in this room I think it was the remains lecture ah yes and it was called you correct me if I'm wrong for great ideas of biology the cell DNA telling me I gave the same you remind [Applause] anyone and I think there's a fair and most of what you were talking about today was a fifth so it was the fifth but I wonder if you could just summarize what four people at me who the fifth part was all completely knew what the key factors are that weren't there in your remains lectures information and the linearity and the folding well I I'm embarrassed you were present at the Romana's lecture because I was rather hoping nobody would be here so that it wouldn't look as if I was very good I had to come again the you're quite right that it was that was a precursor to this but it evolved by natural selection to to take on a more important problem I was interested then in just identifying some of the ideas of biology in a way to generalize about phenomena which which as I said at the very beginning of biologists are rather reluctant to do but what I realized over the years in thinking about it is that this is a way of thinking about what life is and it also made me think more carefully about the things that you brought up you know going you know the the the linear code the turning it into three-dimensional action you know chemical inertness but storing information to chemical activity none of that was their information there I didn't have mullahs definition there because I didn't haven't read it then so but you're right he was built on that I'm writing a book on it actually a simple book I mean well I think it's simple and it will come out so you'll it's all laid out there and I say more things and I said tonight but I still have a brimstone yellow in it question net poorly the embodiment of urban Schrodinger knocks of today is Tim Palmer the physicist is going to ask the next question train betray my ignorance here but probably the last I think the last time I read a book about DNA popular book I'd say was was about twenty years ago and I remember the phrase junk DNA 98% or something Sydney Brenner was the only Pony I just wonder what I knew often struck me that was an odd thing to happen that so much of our structure was somehow irrelevant what's the thinking today is it is it still this junked DNA or does every piece play a vital role well you're quite right junk DNA was I think invented by Sydney if I remember right me who had a witty way with words he which meant that in this case it was probably slightly exaggerated but what he was pointing out was that we had genes that encoded things the proteins and then in organisms like ourselves we have big gaps in between and they didn't seem to do anything now in yeast which you may remember is what I devoted my life to poor pathetic person that I am you we don't have big chunks of DNA in between genes it's very gene rich in more complex organisms like ourselves there's lots of DNA in between and that DNA is increasingly being revealed as having roles primarily in regulating the genes that are found embedded within it and that it has the potential to give a richer set behaviors then if you don't have it now I'll say something else for which I had no evidence but that might be relevant to it that if you have an organism like yeast which is trying to divide as rapidly as possible then it doesn't want to be replicating lots and lots of DNA that isn't doing very much and so it's managed to get along fine by getting rid of that DNA and I think Sydney therefore called it junk we are rather more complicated than the yeast believe it or not and we can exploit everything about DNA and the stuff in between because we don't care too much about how fast our cells divide so we haven't got a copy all that DNA and so on so having all that junk DNA definitely increases the ability to regulate it in more complex and interesting ways and I think it will be fair to say that we don't yet understand it well enough to have a whole picture of it but to understand how all this works we need to think about the junk as well as the genes because it isn't junk thank you there's a question in the back there the chat with the blue t-shirt yeah so the the image you put up there of the butterfly together with your discussion about information and biological systems kind of brings up the the idea of chaos theory and I was wondering do you think that there are intrinsically bits to how much biology we can understand that is put in place by deterministic laws but laws that are of a complexity that lead to chaotic systems that a certain level of detail we cannot possibly yeah hope to understand well I ponder on this actually and I'm beginning to think I'm too old I'm not going to see it through because I think you're right and how can i how can I put this um I'll put it like this if we look at physics pre 1900 Newtonian physics not completely divided in that way it is a common-sense world for the operation of balls hitting each other and so on then we have Einstein's relativity 1905 and it's a bit strange you know if you go to black holes and there will be quite a few popular books on relativity and you buy them least I buy them I read them you understand it you close the book and then it drifts away and it drifts away because it isn't really part of a completely common sense world it's beautiful very beautiful but it's not part of a common sense well and if you get over that you end up with Schrodinger a tower and so on and Heisenberg and and so on with the structure of matter and you're in an Alice in Wonderland world you know where um you know things can be alive and dead at the same time you know cats can be shouting as cat is alive n dead simultaneously and so this is a very strange world now why do I use that as a metaphor well that may be due to the fact that in physics you're looking at the very small and you're looking at the very big and that it sort of moves it out of our common sense world now biology is infinitely complex it's very very complicated you know people go on I'm going to sidetrack forgive me but I you know people worry about reproducibility in biology and then the next thing that the newspapers say it's all fraudulent they don't realize how bloody difficult it is how varied biological material is and how difficult it is to get experiments to work of the time and that is because we're dealing with great complexity and we don't understand that complexity and I sometimes wonder whether the complexity is going to take us into a different world of the sort you were just not describing but on the edge of where our normal common sense principles let's call it don't actually apply and that and that we're gonna need help from scientists who thinking more abstract ways like the physicist to work our way through it and when I said I'd like to see that time because I think that will come but I have a feeling it's going to be beyond my lifetime so I think we're going to go into a strange a strange world in biology now you asked the question is there a limit I sort of think we're going to understand how cells work I'm not so sure that we're going to understand how consciousness works certainly not in a straightforward way as a cell so there may be a limit there that I struggle with and for sure we're going to need the help with the humanities and all sorts of other areas to be able to deal with it but I think will understand a cell but it may take us to a strange world I think you want to reply is that right you looked as if you were I think that's a very satisfying answer thank you well on that note I think we have to bring proceedings to a close call when you said biology and doing experiments is bloody difficult I could see all the experiment this in the audience when a Nobel Prize winner says that it makes all the rest of us feel so much better this has been such a fun evening thanks so much for coming along and please everyone join me in thanking Paul for his superb [Applause]

Channel: Oxford Martin School

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Length: 86min 5sec (5165 seconds)

Published: Fri Mar 06 2020