Genetics as Revolution - 2015 JBS Haldane Lecture with Alison Woollard

Genetics as Revolution – 2015 JBS Haldane Lecture with Alison Woollard

so each branch of science attempts unifying theories physics for example has has thermodynamics to bring together mechanics and heat Einstein's relativity added to the unification of ideas underscoring how fundamental qualities are quantities like matter and energy are just two sides of the same coin we now have wave particle duality and a common framework for understanding special relativity in the context of quantum mechanics yet the ultimate grand unified theory of everything a theory of quantum gravity remains elusive biology on the other hand has its grand unifying theory thanks to Darwin's theory of evolution by natural selection published in 1859 combined with the theory of heredity pioneered by Mendel published a few years later and it's the story of this theory of heredity that this lecture concerns made up as you shall see of a series of revolutionary ideas pioneered by some of the greatest scientists that the world has ever known it's an exciting story basic because it concerns the revolution in our molecular understanding of the very nature of life itself and it is a very exciting time to be telling this story because we're entering a period when we don't just understand the ultimate influence of genetics on on life but we're developing the power to intervene in our genetic destiny now is the time to understand how this has come about what it means and how we should move forward not just the scientists but as a society Darwin's big idea was that the variation among creatures in their natural environment resulted results in the struggle for life in which only the most suitably adapted will survive evolution base Klee oops evolution basically means a gradual change over time and natural selection provides a mechanism for evolution some change will be favored it will make the organism more likely to survive in a particular environment and reproduce producing progeny with the same traits you can see with Darwin's finches so you see ultimately one type of creature can be transformed into something completely different in illustrating his theory of evolution by natural selection Darwin realized that all species are connected indeed they share a common origin he thought of the concept of the Tree of Life that's Darwin's notes on on his idea of the Tree of Life Darwin's tree was a simple one and we now know it to be more complex quite a lot more complex but Darwin was right all species are indeed connected simple life forms evolved four billion years ago and natural selection has sent organisms off in a myriad of different directions to make the extraordinary diversity we have around us today over nine million species and that represents only a tiny minority of species that have ever lived though I mean talk passionately about the grandeur of his view of life with its endless forms most beautiful and most wonderful that he described in his book and Darwin's theory of natural selection works too works works well as a unifying theory and biology works so well in fact that theodosius dobzhansky writing about a hundred years later was prompted to say nothing in biology makes sense except in the light of evolution that's theodosius dobzhansky x' quote there but there was a problem with Darwin's big idea and the problem with Darwin's great idea was that Darwin had no robust mechanism to explain inheritance and this rendered his logic in completes his unifying theory failed in this respect Darwin knew of course that traits run in families otherwise natural selection wouldn't work at all but he had no decent mechanism to explain how inheritance works despite recognizing the supreme importance of heredity this modification by descent in his hypothesis so what were the prevailing theories of heredity in Darwin's time among the earliest known writings on the subject of heredity are those of Hippocrates in 400 BC that's Hippocrates he believed that reproductive material came from all parts of an organism and hence that characters were directly handed down to the progeny as evidence for this hypothesis he referred to a race of mankind called the macro sefa li immediately after a child was born the microcephaly fashioned its head by hand to give it an elongated shape at a later period the elongated later for the elongated head would form naturally without the necessity for molding it soon after birth in much the same way that baldness and blue eyes are inherited if reproductive material came from all parts of an organism then it would come from the molded head 50 years or so later Aristotle had another go at him at a theory of heredity and he questioned Hippocrates his view he couldn't understand how certain characteristics like voice and nails and hair could contribute to the reproductive material because they were so intangible they might even be made up of dead tissue he also observed that children sometimes look more like their grandparents and their present than their parents and he was worried about plants how could parts which might be missing at the time of reproduction like leaves for example how could they be inherited and how could it be how could it be that parents could each contribute something from all of their parts yet their progeny have only one and not two of everything so Aristotle modified Hippocrates his theory by postulating that the reproductive material is made up of substances that have been diverted from various parts to the reproductive path and this was a really important idea he went on to argue however that the contributions to the progeny from the two parents are not equal and held the contribution of the father in somewhat higher regard no surprises there so the father's contribution was shape and form to the embryo as opposed to the mother's contribution of inner material in other words all the dull stuff many variations of these transmission theories were proposed over the subsequent centuries the only theory of heredity that has perhaps rivaled this that the transmission theories is the preformation theory which can be followed back to st. Augustine and this theory held that the creation in the creation of the first woman all the following generations were preformed and the theory gave rise to the idea of a homunculus you can see here in the sixteenth century although Nicholas heartseeker who drew this homunculus in 1695 was definitely a spur missed in his view of heredity transmission theories however did dominate during during Darwin's time and I'll star when writing in 1868 about his theory of pangenesis in this paper here animals and plants under domestication he suggested that all the cells and tissues of an organism throw off minut granules which he called gemmules and he thought that these must be circulated through the organism and multiplied and were passed down to the reproductive cells which thus contained a multitude of components thrown off from each individual part of the organism he also thought generals were capable of transmission in a dormant state to future generations so Darwin had a way of explaining the non expression of of parental characteristics as well as a direct transmission of characteristics from parents to offspring that was so important for his theory of natural selection he felt that pangenesis which he described as a provisional hypothesis in his 1868 work he thought this brought together in his words a multitude of facts which are at present left disconnected by any cause his theory was not however so very different from that of Hippocrates over 2000 years previously and it's remarkable that the Hippocratic view remained essentially unchanged for 23 centuries it's not as though no one did any breeding experiments during this time especially in the 18th and 19th centuries it's more the case that although these experiments did not support the classical view they didn't present any alternative hypothesis until Mendel it's noteworthy however that several decades before Mendel published his work at least two other plant breeders made very similar observations to Mendel night working in England in 1799 crossed unpigmented and pigmented edible peas together and he was surprised to find the only pigmented plants that grew in the following year the first generation the first filial generation but these on self pollination produced both pigmented and unpigmented plants from this he deduced that there was a stronger tendency to produce colored than colorless plants gauss also working in england in 1824 made similar discoveries but he took the analysis slightly further and he was working with yellow and green seeded peas so he pollinated green seeded peas from a yellow seeded variety and he found all yellow seeded plants in the first generation and then when he self those again he got pods with all green or yellow or a mixture of both green and yellow seed plants the following year but then he went for a further generation and he discovered that while the green peas bred true only giving green progeny the yellow yielded a mixture some pods were yellow some with both green and yellow intermixed so I didn't Knight and Gauss discover the theory of heredity what's their problem well their problem was or they didn't count the numbers of the two kinds of peas or if they did count them they failed to see the significance of the numbers and in doing so they both failed to discover the hereditary mechanism which Mendel found forty-two years later in 1866 Mendel had been doing similar experiments tonight and and these are actually some pages from Mendel's notebook his thoroughness in recording the my new shy of his data enabled him by a stroke of genius to detect the underlying mechanism and so to put forward an entirely new hypothesis for heredity the grandeur in Mendel's work is easily obscured by seemingly obscure facts and figures about pea breeding schemes but on the contrary the devil is absolutely in the detail the grandeur is revealed by the seemingly mundane working with the pigmented and unpigmented peas just like Knight Mendel also noted that he only got pigmented plants in the first generation and that when he self pollinated these he got pigmented and on pigmented varieties in the next generation they f2 generation but he counted the numbers of each kind and he found 705 pigmented counts and 224 unpigmented plants among 929 plants in total and he observed that these frequencies were close to 3/4 and 1/4 of the total he called the pigmented characteristic present in all the immediate progeny of the cross and three-quarters of the following generation he called that one dominant and the unpigmented trait recessive in other words inheritance is particulates it's not a case of blending parental characteristics like mixing paint Mendel also worked on the yellow-green seed color characteristic first explored by Gauss and he confirmed that yellow is dominant to green and that both kinds appear in the second generation after crossing but again he countered his peas and out of 8023 plants 6022 were yellow and 2001 were green again a close approximation of 3/4 to 1/4 or a 3 to 1 ratio Mendel confirmed got his observation that the green peas Bet bred true but he went much further he found that of 519 yellow pods 166 bred true whereas 353 did not instead giving yellow and green seeds in the same three-to-one ratio as in the previous Jenner Mendel figured that the 166 pure-breeding to 353 impure breeding was a close fit with a 1 to 2 ratio of the total in other words the f2 ratio of 3 dominant to one recessive was really a ratio of one pure breeding dominant to two impure dominant to one recessive which always breeds true he pursued these plants for several generations and showed that the pure breeding types always remained pure breeding and the impure breeding ones always gave the same 1 to 2 to 1 ratio in each subsequent in each subsequent generation Mendel was very cautious about his data and went on to repeat his experiments with 7 other characteristics one character was always dominant to its alternative he found and the second generation always gave a three-to-one ratio which on closer inspection turned out to be a disguised 1 to 2 to 1 ratio so what does this all mean this is a scary pee slide right and I promise it's the only one Mendel built a hypothesis to account for his data in which he used symbols for his traits he used a capital letter for a dominant trait and a small letter for a lowercase letter for a recessive character so it could be big why in the case of these yellow seeds seedy plants and little why for the green ones and it's clear from this that he was thinking about factors or determinants responsible for the manifestation of the character this is absolutely crucial to Mendel's hypothesis his characters were not transmitted directly from generation to generation according to the classical theory but rather they are discrete particles responsible for the appearance of particular characters furthermore each individual receives one particle from each of its two parents in respects of a particular character and these two particles separate uncontaminated when the reproductive cells are generated so if Big Y if Big Y denotes the particle that determines yellow seeds and little Y green then the parents Big Y Big Y and little Y little Y give rise to the offspring Big Y little Y now these will be yellow because the characters dominance but self-pollination of these will give will give these progeny it'll give little Y little Y Big Y little Y Big Y little Y little Y little Y this is crazy to talk about isn't it when you ie three yellow two one green at the phenotypic ratio but that is really a disguised one to two to one ratio when you consider the factors themselves a further point which didn't escape Mendel's reasoning was that egg cells carrying Big Y were is equally likely to be fertilized by pouring pollen carrying Big Y or little Y in other words fertilization was random between egg cells and pollen cells or egg cells and sperm cells if you were thinking about animals regardless of what factors they carried this later became known as his law of equal segregation Mendel was sitting on a revolution of incalculable proportion but nobody noticed he published his work in 1866 that's two years before Darwin published his pangenesis theory of blending inheritance based on his gem mules made from all parts of the organism it seems extraordinary in these days of instant communication that Darwin never came into contact with Mendel's work absolutely extraordinary what would have happened if Darwin and Mendel had met and discussed Mendel's results Darwin would surely have been perplexed that Mendel's f1 peas weren't yellowish-green but rather zat the mode of inheritance suggested by Mendel's work was most definitely particular I wonder what he would have said as it happened Mendel's work was almost entirely overlooked for 34 years being rediscovered in 1900 coincidentally by three different scientists the Reiss corenz and vaunt ischaemic working on a variety of different plant species Koren's introduced the terms introduced the term Mendel's ragel or Mendel's law for the basic principle namely the segregation of the discrete particulate determinants of alternative characteristics when reproject reproductive cell now call these gametes are formed and their reassociation at fertilization the race is credited with introducing the term mutation to describe suddenly appearing variations which could provide the raw material for natural selection Bateson and Saunders working in 1902 were the first to apply Mendelian law to an animal species they looked at the domestic fowl Gallus domesticus and they found that an extra toe was dominant to the normal foot Bateson and Saunders also applied Mendelian theory to earlier unexplained data and even re-examined Darwin's 1868 work on the Snapdragon anti Rhino majors one form of the Snapdragon the Pearl auric form differs in having a radially symmetrical flower instead of the normal irregular tulip variety Darwin interpreted the results of his cross as it's indicating that the tendency to produce normal flowers prevailed in the f1 generation but the tendency to Pearl or ism appeared to gain strength by the intermission of a generation with Mendel's theory it was only necessary to postulate that the Pearl auric trait was recessive it disappeared in the f1 generation and reappeared in f2 in the 1 to 3 ratio thus the classical and Mendelian theories of heredity can be very clearly teased apart in the classical theory something is transmitted directly from each of the each part of the organism for example the Snapdragon flower to the corresponding part in the progeny whereas in the Mendelian world inheritance is indirect through the agency of particulate determinants it's these determinants that are transmitted from generation to generation and the character of the flower or whatever it is you're looking at that develops is simply the fortuitous combination of the set of determinants that it happens to receive at fertilization the contribution of each parent retains their integrity rather than blending with the contribution of the other parent and crucially the determinant is not is not modified by its presence in the organism thus the inheritance of the reboil maria modeled head in the hip pratik example given in sport of the classical theory is impossible the major problem in biology in the early 1900's they following the rediscovery of Mendel's work was that its relevance to evolution was unclear and hotly debated variation in wild populations looked continuous like the products of blending inheritance it looks much more like a blending inheritance model not the discrete model proposed by Mendel and how did you account for large jumps and new species with this model well crucial to the solving of this problem was the study of populations in the field an area we could we would now call population genetics RA Fisher was the major figure in the development of the so called modern synthesis producing in 1918 his seminal paper the correlation between relatives on the supposition of Mendelian inheritance it sounds really dull but it was far from that what Fisher did crucially in this paper was to show that continuous variation could be the result of the action of many discrete determinants we would now call these genetic low-side therefore Mendelian genetics was in fact completely consistent with the idea of evolution driven by natural selection the application of Mendelian principles to populations was furthered in the 1920s 30s and 40s by Fisher along with JBS Haldane we've heard about from from from Malcolm and Sewell right dobzhansky EB Ford Ernst Mayr and others but time is not going to allow me to give due credit to their crucial work on the maintenance of genetic diversity on genetic polymorphism and the mechanism by which new species become reproductively isolated nevertheless this new work on population genetics is my second revolution in genetics following Mendel's great theory theory of heredity in 1866 and it's rediscovery in 1900 the second revolution resulted in the grand unifying theory of biology the paradigm of evolution by natural selection with an integrated mechanism for heredity that could be applied to populations variation at the genetic level or mutation provides the raw material required for natural selection to sculpt evolution over many generations the third revolution has to be the chromosomal theory it's all well and good talking about factors and particles of inheritance but what are they and where are they well the wear was answered by Thomas Hunt Morgan it's Thomas Hunt Morgan at about the same time that the modern synthesis was being developed the what had to wait a few years bizarrely Thomas Hunt Morgan was born in Kentucky in 1866 the very year that Mendel published his work by the time that Morgan began to began his work on the fruit fly Drosophila in 1910 Mendel's discoveries were codified into two main laws the first rule we've already come across the law of equal segregation the second rule was known as the rule of free combinations we would now call this the law of independent assortment and this states that when new generations arise the different hereditary factors can form new combinations independently of each other Mendel found this out when he did his so-called dihybrid crosses for example if a tall purple flowered plant is crossed with a short white flowered variety the factors purple and white can be inherited independently of the factors tall and short you'll end up with tall white flower plants and so on in precisely predictable ratios but Morgan's particular genius was that he spotted some inconsistencies in the second law and then had the confidence to seek an explanation for them Morgan found the first discrepancy when he crossed flies that had purple eyes and short wings go with me on this one with those that had red eyes and normal wings right the purple the purple eyes are PR and PR plusses the red eyes because plus in genetics means normal right and VG is the short wings and VG plus is the normal wings again because plus means means normal now under Mendel's second law Morgan expected to get purple eyed flies with normal wings out of his crossing scheme at the same frequency as getting his red-eyed normal winged flies back again because the factors should have thought independently from one another but this was not the case at all he got the purple eyed normal wind flies out but only extremely rarely Morgan's Great Leap Forward was to figure that the eye color trait and the wind size traits must be physically connected to one another in some way that's diagrammed out here he called this phenomenon linkage and he found that there were many examples of this in his fly crosses but importantly that the linkage relationships were confined to four combination groups now in parallel to all this work with fly crosses the early cell biologists were busy in the late 19th and early 20th centuries and the importance of their work was not lost on Morgan the mechanism of fertilization had been discovered by her twig in 1875 working on sea urchins and vice Minh took to the microscope in the 1880s having distinguished between the hereditary hereditary material the germ plasm or germline giving rise to the gametes and the rest of the body the soma to propose that the nucleus of the male and female germ cells must be the bearers of hereditary qualities much earlier than this several disciples of the new cell biology had observed thread-like structures in cells named chromosomes chromosome means colored body because that's what they could see down the microscope and this was first noted but in 1888 by heinrich von wild Earhart's this slide here is actually one from a drawing from Walter Fleming in 1885 from the quote the saliva gland of a midge but nobody knew what these things were for on the rediscovery of Mendel's work in the early 1900's Sutton and Bowie independently suggested that chromosomes were good candidates for the exact distribution of hereditary factors at the genesis of a new individual simply because of the proportion of the chromosomes in sells before and after fertilization in the chromosomes factors could be combined or could come apart because they would double the number of chromosomes in the somatic cells compared with the sex cells and I just want to show you a movie at this point one of my favorite movies because it's of my worms C elegans of an embryo of the worm and I want you to look at the bottom one because that's the one that's going to undergo this process of fertilization and what we're going to see are them as the nucleus from the male and the female the male and female pronuclei and they're going to come together and they're going to fuse hopefully and that really is the thing that marks the beginning you see that fusion that's the thing that marks the beginning of a new life and you and then after that the cells will undergo division and and so on and so forth but that that first thing kind of play it back because it's anyway once it's done that then that's really the beginning of life I always find that amazing to watch down the microscope and this this process of so that the the the gametes have half the amount of genetic material from the mother and the father so when they get together they reconstitute the whole again the process of having the number of chromosomes during the generation of these sex cells or gametes is called meiosis it's a reduction or division and sudden and bovary's idea of chromosomes distributing hereditary factors during the formation of gametes had huge resonance with Mendel's first law of equal segregation so the ground was well-prepared for Morgan to link cell biology and heredity the linkage group have connected hereditary factors turned out to be chromosomes and the number of such combination groups or linkage groups turned out to be the same as the number of chromosomes in an organism for in the case of a fly 23 and us Morgan's discovery of linkage completely proved and greatly extended the chromosomal theory of inheritance proposed by Sutton and Bovary just from looking down microscopes Morgan's linkage rule limited to a large extent Mendel's second law as being more applicable to her three factors residing on different chromosomes morgan published his chromosome map with different hereditary factors lined up in chromosomes like beads on a necklace you can see her however there was more morgan found inconsistency in his own linkage theory he found that even when his factors were connected on the same chromosome he could still see what looked like a degree of independent assortment even though it was rare remember the purple ID normal winged flies well he did get some of them and he called this phenomenon crossing over he envisaged the physical exchange of parts between chromosomes occurring at the crossover points or chiasmata as you could see them in certain in certain cells and this is the grasshopper testes i always wonder how people came about you know how they started looking in these weird and wonderful systems but you can see crossing over really really well in the grasshopper testes the theory of crossing over though it was greeted with much skepticism at the time until 1931 when harriet Crichton and Barbara McClintock were able to visualize reciprocal exchange of genetic material at much higher resolution nowadays of course we would call this process of genetic exchange recombination and it's an extremely important mechanism for generating genetic diversity during reproduction so the third revolution is the chromosomal theory of inheritance linking Mendelian ideas of heredity into the physical structure of chromosomes which behave as to obey Mendel's first law but disobey his second at least where factors are linked on the same chromosome Morgan's work was utterly extraordinary who would have thought it would be possible to localize in these chromosomes which are only a micrometer or so long that's one thousandth of a millimeter thousands of hereditary factors accounting for all of the characters that makes every organism what it is and do it all by analyzing the results of fruit fly crosses when Morgan got the Nobel Prize in 1933 his work was likened to the astronomical calculation of solar your body's still unseen but later on found by the telescope but more more so it was said that Morgan's predictions exceeded this by far because they mean something principally knew something that has not been observed before in Morgan's own words that the fundamental aspects of heredity should have turned out to be so extraordinarily simple supports us in the hope that nature may after all be entirely accessible her much advertised inscrutability has once more been found to be an illusion due to our ignorance this is encouraging for if the world in which we live was as complicated as some of our friends would have us believe we might well despair that biology could ever become an exact science the term gene was first coined in 1909 by Johansson to describe physical and functional units of heredity he took the word from from Darwin's word of pangenesis but the role of genes wasn't clarified until the 1940s in a landmark study by George Beadle and Edward Tatum that takes us to the start of our fourth revolution the molecular biology revolution this major revolution actually consists of several sub revolutions some of which seem to get more airtime than others but fin simplicity and in the interests of time I've lumped together about 40 years of really important work and several of these sub revolutions and will now attempt a whistle-stop tour which takes us up to the 1980s Beadle and Tatum too were working on the haploid fungus Neurospora they irradiated Neurospora to induce mutations and then tested cultures for interesting mutant phenotypes they found numerous mutants that had defective nutrition for example in the biosynthetic pathway by which arginine is made in the cell they were able to block the pathway at different steps with different mutants eventually figuring that each gene controlled one specific enzyme in a series of interconnected steps in a biochemical pathway this was the one gene one enzyme hypothesis Beadle and Tatum schwer quiz a significant unifying concept because it provided a bridge between two important research areas genetics and biochemistry so sub revolution number one of revolution four is the one gene one enzyme or one protein hypothesis but what would genes made of what to answer this question we need to start with Frederic Griffiths in 1928 performing experiments on the bacterium streptococcus pneumoniae some strains of the bacterium are lethal when injected into mice while other non virulent strains are not you can see here riff has made the puzzling observation that if he injected the non virulent strain into mice together with a heat-killed virulent strain which on its own would not be lethal the mice died live bacterial cells could be recovered from the dead mice which were virulent when injected into live mice so how did this happen somehow the cell debris of the heat-killed virulent cells had converted the non virulent live cells into virulent ones in other words the cells had become transformed now we fast forward to 1944 when Oswald Avery working with two colleagues MacLeod and McCarty set out to chemically destroy all the major components of the dead cells one by one and test of the extract had lost the ability to transform you can guess what they found can't you DNA not polysaccharides or protein or fact or RNA just DNA clean and simple DNA is the transforming principle and this was the first demonstration that genes are composed of DNA so sub revolution number two DNA is the genetic material contained in genes between you and me this was a bit how could such a low complexity molecule as DNA encode the diversity of all life on the planet DNA was already known you see because it was first isolated in in 1869 by misha he got it from puffs he went to clinics and got puffs because they had lots of these white blood cells and with big nuclei and then he grew them all up and he got got lots of new clay in following my shoes discovery of DNA that russian biochemist levine worked how that DNA was a poly nucleotide in 1919 and he did what biochemists like to do is chop things up he did used hydrolysis in his case and each nucleotide he found was composed of just one of four nucleotide bases a sugar molecule and a phosphate group so that sub revolution number three DNA is composed of four nucleotide bases a sugar molecule and a phosphate group Levine proposed what he called the tetranucleotide structure in which nucleotides were always arranged in the same order gcta gcta gcta but scientists eventually realized that this was over simplistic and that the order of nucleotides is in fact highly variable some revolution number four the order of bases in a DNA molecule is variable perhaps it can act as a code it was char GAF who worked out that the amount of adenine or a is usually similar to the amount of thymine or t and the amount of guanine G usually approximates the amount of cytosine or C char GAF was very inspired by Avery's 1944 paper he wrote Avery gave us the first text of a new language or rather he showed us where to look for it I resolved to search for this text sub Revolution number five egg was T C equals G Shark apps worked together with some crucially important x-ray crystallography work by English researchers rosalind Franklin and Maurice Wilkins paved the way for Watson and Crick's derivation of the three-dimensional double helical model for the structure of DNA in 1953 in their nature paper Watson and Crick began we wish to suggest a structure for the salt of deoxyribose nucleic acid DNA this structure has novel features which are of considerable biological interest no kidding this was no mean feat you could fit 25,000 strands of DNA side-by-side in the width of a single human hair and this is sub revolution number six one of the big E's DNA structure one long molecule spiraling around in a double helix exquisite simple ordered regular two strands each with a strong backbone made of sugar and phosphate with the bases on the inside a pairing with T and C with G Watson and Crick's discovery of the structure of DNA is considered by some to be the most important biological discovery of the 20th century the reason for this is that the double helix structure fulfilled the three requirements for hereditary substance firstly sequence the four bases make up an alphabet of four letters a genetic code to specify the sequence of amino acids in proteins known to be crucial for cellular functions Fred Sanger had determined the first protein amino acid sequence of insulin in 1951 so the amino acid sequence was begging for some kind of genetic code perhaps the genetic code could write information in DNA as a sequence of nucleotides and then translate it into a different language of amino acid sequences in a protein secondly if the base sequence of DNA specifies the amino acid sequence of in proteins then change or mutation is possible by the substitution of one type of base for another at one or more positions and this would give rise to altered proteins and likely altered cellular function this is heavy stuff mutation would account for the genetic variation investigated by a Mendel and the driving force of natural selection in Darwinian evolution no one's a Francis Crick burst into the Eagle pub in Cambridge on February 28 1953 and said we have discovered the secrets of life thirdly copying as what's an incorrect stated in the concluding words of their paper it has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material if you have pairing and free nucleotides in the cell and enzymes then you have DNA replication and here's an extraordinary fact every day we produce around sixty billion new cells each replicating in excess of 100 billion meters of DNA in the process that is the distance to Mars and back so DNA is a code a code that holds all the information to make all living things an instruction manual to make a worm or a cat's or a fly or a human or a dinosaur its regularity and stability make it the perfect system for storing the vast amount of information required for building life the information is passed to every cell of an organism because perfect copies are made prior to each cell division and one copy of everything is distributed to each reproductive cell or gamete according to Mendel's law in the germline and thence passed through the generations sub Revolution number seven is the cracking of the code convincing proof that a code on a sequence of nucleotides that code for one amino acid at codon is in fact three letters long came from extremely elegant experiments in 1961 by Francis Crick Sydney Brenner and co-workers using mutations in viruses that infect bacteria called bacteria phage essentially they found that combinations of three nucleotide additions or three delicious deletions were okay suggesting a triplet code the code was cracked later that same year by Nierenberg matter i and colleagues so that individual amino acids could be associated with particular codons the next thing that exercise the molecular biologist was the business of gene regulation sub revolution number eight the problem was that if DNA codes for proteins that give cells their particular characteristics and all of the cells of an organism of a particular species contain the same DNA sequence because the DNA sequence is of course the thing that defines the particular species then how come some cells can do different things at different times in different parts of the body and so on the breakthrough involved Jacques Monod a young Parisian molecular biologist and Francois Jacob a medical student intent on big a surgeon and they were working in the 1940s after the invasion of France Jacob served as a medic in the Free French forces before he was badly wounded ma nod joined the resistance where he met another molecular biologist Andre Lewis after the liberation of Paris Menard served in the French army and happened upon in a mobile US Army Library Avery's article suggesting that DNA is the hereditary material isn't it extraordinary that soldiers in the field were reading molecular biology papers in their spare time with his interest in genetics rekindled he joined Liu off after the war to work on phage and bacteria as did Jacob whose injuries were too severe to allow him to pursue a career in surgery the cast of three was set and over the next decade one of the most creative and productive collaborations in the history of genetics worked out how genes are turned on and off with a toggle switch in other words the same genetic material in different cells could be interpreted in different ways to give rise to a different set of proteins they could make a protein or not essentially they found that genes govern the formation of proteins that can block the expression of other genes by binding to and acting on the DNA itself their findings were deduced entirely from genetic evidence from studying the effects of mutations in Horace Freeland Judson's wonderful book the eighth day of creation I would really recommend to you describes the ferment of the whole molecular biology revolution jacobim on odds work is described as making things that were utterly dark very simple the concept of the genetics which went far beyond bacterial enzymes and viruses they understood and were able to articulate with exceptional eloquence how their discoveries about gene regulation pertained to the general mysteries of cell differentiation and embryonic development of animals were the problem of the common set of genetic instructions in every cell is particularly acute what is true for e.coli is also true for the elephant equipped manat and that brings us to the end of the molecular biology revolution which culminated in a molecular understanding of the nature of the gene including a copying mechanism for DNA through organisms and through generations that meant that heredity and the flow of genetic information could finally be understood in a much more tangible way involving real molecules behaving in a way that is entirely in keeping with their structure thus the grand unifying theory of genetics and evolution could now be understood at molecular resolution so what next my fifth major revolution is forward genetics and one that is very close to my heart using the genetic approach to understand not just hereditary mechanisms but many other problems in biology it had been discovered by Muller in 1927 well again working on fruit flies that bomb bought bombarding an organism with x-rays or treating it with particular chemicals could induce large numbers of inherited mutations with clear effects on the morphology or the phenotype of an organism of course it's because the mutations caused a change in the DNA sequence stopping the particular proteins encoded by that DNA from working properly and biologists started to use the genetic approach the study of mutants to try to understand how genes influenced other hitherto mysterious bits of biology one of the most important of these being development how does an organism develop from an egg to an adult how does it end up the right size with the right number of cells all in the right place doing the right thing at the right time it seems like a problem of staggering complexity but the problem could be reduced with the use of model organisms like Drosophila and other others newer on the scene like the nematode worm C elegans introduced in the 1970s and you can see the power of this work by looking at the phenotypes of some of the mutants this for example is a fly head looking fairly average for a fly head is awful ahead and here's a mutant in which something goes very wrong so what's happened here is it has legs instead of and now I don't know about you but I think that is quite a big thing to get wrong but what it does is it illustrates the gene that causes the the single mutation in one gene that causes this defect is doing something really important in determining the form of the animal putting the legs in the right place and putting the antenna in the wrong place so by looking at a situation in which that has gone wrong you can illuminate how that process normally works here so here's a great paper that was written in 1980 by Christian Aslam vollhardt and Eric fish house again they were ordered a Nobel Prize eventually and that what they did was to to gather a whole host of interesting Drosophila mutants that illuminated different aspects of the development of that organism and how it works at this molecular level and then C elegans my favorite organism came on the scene pioneered by Sydney Brenner in 1973 we can see here some of the first worm mutants that's a normal worm here this one here and this one is short in fact it's called a dumpy mutation and this one is much longer than it should be and this one again is a bit smaller so that illustrates something very interesting about about how animal size is regulated how is it that different animals will grow to a particular kind of size and again using a mutant in which that goes wrong you can understand how that process normally works so this approach had been used since the 1920s but it took on a new vigor in the 1970s and 1980s firstly because biologists now understood the nature of the gene and could map mutants using Morgan's discovery of linkage and the chromosome theory secondly because techniques became established for working out the sequence of DNA and thirdly because it became possible to make transgenic animals that meant that the precise gene that had gone wrong in the mutants could be pinpointed and also that DNA could be isolated in vitro mucked about with and then introduced into an organism like a fly or a worm or a yeast cell or even a mouse this approach has now blown apart much of biology we now understand for example much of the molecular details of how cell division is controlled house and embryos take on the correct identity how cells and axons migrate to the right destination how gender is determined at the molecular level how some cells undergo programmed cell death the list is extremely long and I could name examples for several hours what's more because of the techniques of transgenesis it was possible to introduce DNA from one species into another Paul nurse pioneered this approach in the 1980s showing that the human counterpart of the yeast cdc2 gene was able to rescue yeast mutants that were unable to grow properly because they had a defect in their cdc2 gene in other words the human genes and yeast genes were very similar their function was said to be conserved this was crucially important because it meant that as had been suspected previously work on simple organisms ultimately informs our knowledge of human biology and disease model organisms became biomedically significant using the genetic approach we've even begun to understand how lifespan is genetically programmed here's a lifespan curve of some worms normal ones and a daf-2 mutant right a mutation in one gene is causing these worms to live much longer than they should so it's showing the age at which worms die it's not extraordinary we can even start to understand how behavior is controlled these are going to some worm mutants normal ones and and mutant ones actually they're not quite mutants they're because they're they're naturally occurring mutations they haven't been they haven't been induced by some sort of chemical but they come from Australia and what they do is they like to gather together in groups and be very social whereas the ones from England kind of a bit they're loners but this illustrates wonderfully how you can use the genetic approach to understand behavior because the only thing that these work that that differentiates these two worms is a mutation in one gene and they're really so the really revolutionary thing about forward genetics is it's approach the investigator observes a bunch of mutants until he or she finds one that displays a defect in the process under investigation thus revealing an important mechanism and one that can be understood at the biochemical level once the sequence of the mutant gene is revealed the work is unbiased because no assumptions are made about the biochemistry of the process under investigation phenotypic analysis leads the geneticists to the important genes a geneticist cannot be fussy about what kinds of genes and what kinds of proteins they want to work on because the genetic because because the genetics can lead them anywhere they're led purely and simply by phenotype the work is still going on of course but we've made massive progress in the last 40 years in using genetics to understand how life works and this extraordinary effort is my fifth major revolution in genetics using mutants to understand anything in biology that is genetically programmed which is pretty much everything in biology my 6th and penultimate revolution in genetics is genome sequencing and genomics this work was started by Fred Sanger in 1977 and Fred Sanger had already developed a method for determining the amino acid sequence of proteins back in the 1950s and then he did it for DNA and that's why he ended up with two Nobel prizes but what's the technique for sequencing small stretches of DNA was worked out but next thing was to scale up and sequence a whole genome assuring in the field of genomics the study of whole genomes the bacterium him off him him off him off Phyllis influenza was the first free living organism to be sequenced in 1995 followed by yeast 1996 the first multicellular animals C elegans in 1998 fruit fly 2000 and the human genome first draft in 2001 completed in 2003 this was an extraordinary achievement involving many hundreds of different workers from all over the world over a period of around 13 years and costing around 2.7 million billion dollars if you typed the whole human genome out at 200 letters per million it would take you 29 years with no brakes and yet we've got that inside every single one of our 40 trillion cells and our enzymatic machines can copy it in a matter of minutes we've now got the point in human history said john sulston shown here who spearheaded the project in the UK and also worked tirelessly to ensure that the data remained in the public domain we've now got to the point in human history where for the first time we're going to hold in our hands the set of instructions to make a human being what's even more extraordinary than this though is what's happened since the technology has developed so fast that it's now possible to sequence the human genome for under a thousand dollars in a matter of hours thousands of different kinds of organisms have had their genome sequenced the tsunami of data is so huge that this is of itself a problem in terms of storage alone let alone analysis it was estimated back in 2013 that's two years ago that biologists around the world churn out 13 petter basis of sequence a year one pet abase is 1 million Giga bases which is a thousand mega bases if this was stored on regular DVDs the resulting stack will be 2.2 miles tall every year and I bet you now we're producing data a much much higher rate than we were in 2030 so this sixth revolution provides challenges as surely as we shall see is also the case for the seventh and last revolution it's easy to be dazzled by the possible uses of genome information sequencing the genome of your cancer cells may allow oncologists to tailor-make your treatment to increase the chances of success the speculation is that healthcare professionals will eventually be able to use genomic information to predict what diseases a person may get in the future and attempt to minimize the risk or even eliminate it altogether through the implementation of personalized preventive medicine that's not at all straightforward though actually because human disease is rarely caused by a mutation in a single gene that can be easily traced such as cystic fibrosis most disease such as heart disease or cancer or mental illness will result from an extremely complex interaction of many different genes with each other and with the environment there's a public misconception that scientists are discovering the genes for disease on a daily basis not to mention the genes for characteristics such as binge drinking or forgetfulness or intelligence or beauty very little in human biology is straightforwardly deterministic at the genetic level genomics is best better understood as probabilistic a whole host of genetic factors contribute to the odds that the outcome is decided by an even greater range of genetic biological and environmental influences thus I do not think that we need to take two gloomy and dystopian of view of medical genomics it's true that there are ethical debates to be had around single gene disorders what about late onset diseases with no cure would you want to know if you decide to no then what about your family doesn't your diagnosis affect them too supposing they don't want to know what are the psychological impacts could there be genetic discrimination but it's simply just not going to be possible to devise simple genetic tests for intelligence or creativity thank goodness or even heart disease diabetes or schizophrenia it's just too complicated I'm sure there'll be an explosion of it of Internet companies offering such tests in the future they should probably be banned not because they might give you devastating information but because they will almost certainly give you misleading information a probabilistic view on the other hand might tell you how best to avoid your own personal risks part of me thinks however that this will probably boil down to eating less fat drinking less alcohol and taking more exercise where have we heard that before I don't want to give you the impression that genomics poses no social or ethical challenges there are questions of ownership privacy and access and certainly need for debates the debate needs to be had between well-informed stakeholders who understand the science not lobby groups with a particular agenda so that is a sixth revolution in genetics the genomic revolution the outcome of this revolution is is yet unclear but one thing that is certain is that genome sequence information brings all of life closer together than it was ever thought possible it's a more modern version of Darwin's tree literally thousands of genome sequences are now available and comparative genomics allows us to interrogate evolutionary relationships between different species with more resolution than ever before DNA is not just an instruction manual for the making of an organism it's also a history book a historical record of all the genetic mutations that have happened by chance to make us what we are and to make everything else what it is we're all related through an unbroken chain of many billions of copying through four billion years imagine how excited Darwin and Mendel would have been if they'd known all this my final revolution in genetics however the seventh revelation also takes us into the future but this revolution unlike the genomics revolution has only just begun its genome editing using what is called the CRISPR caste 9 system geneticists have developed several techniques for genome editing or changing the genetic makeup of organisms by causing targeted change in the nucleotide sequence in the past but the revolutionary thing about CRISPR Castine is that it works with extremely high efficiency and is very versatile so what on earth is it the technique makes use of the natural immune defenses of bacteria which have come up with molecular scissors to remove unwanted DNA for example DNA transferred by an infecting virus these molecular scissors or nucleases the caste 9 can cut out sections of DNA with extreme precision they can be guided to cut the precise bits of DNA to be modified by in experiments by a synthetically made guide RNA that directs the cut through hybridization with its matching genomic sequence when the cell repairs the break errors can occur to generate a knock out of that gene or additional modifications can be introduced this technology therefore has the potential to rewrite the genetic code genetic conditions could therefore be treated by modifying the DNA of affected cells like rubbing out so many typos there's also the possibility of radical new therapies for a range of diseases although single gene disorders are rare if you add them up they affect an awful lot of people so collectively they're not rare genetic Alliance UK estimates that 5.5 percent of the UK population suffer from one of six thousand Mendelian ii' diseases caused by a mutation in just one gene Mendelian diseases by age 25 that's 3.5 million people so the impacts of genome editing in these patients and their families could be enormous human embryos could also be modified such that the disease-causing mutation whoops sorry such that the disease-causing mutation is overridden not just in that individual but in their children their children's children and so on is this a good plan research institutions funders and scientists have called for a renewed debate on the ethics of modifying human embryos before the science gets ahead of public opinion the overwhelming view of scientists at present is that the procedure is too new to know how safe it is and one big concern is that a public backlash could impact on the race to develop new and safe therapies so do we go out bravely to meet this vision as Thucydides would have said glory and danger alike is this playing God it's editing the human germline a line that should never be crossed is it the first step on the road to designer babies whatever we may think about the answer to this question one thing is resoundingly clear talking about it is essential like for genome based diagnosis public debate must be at a high level with all parties understanding the science such that rhetoric doesn't get to replace fact public trust in science depends on openness transparency and effective regulation and this is the approach that must be taken there's no scientific answer to what is the right response to the potential use of technology that answer has to be provided by society the amazing thing for me about the CRISPR Casa 9 system is that once again evolution shows us the way evolution has come up with these remarkable enzymes and we have the privilege of being intelligent enough to make use of them so this brings me full circle from Darwin and his lack of a theory of heredity through Mendel Morgan the DNA folk to genomics and genome editing this has been a whistle-stop tour and I've left out countless important revolutions on the way including Barbara mclintock's work on jumping genes or transpose of our elements showing that genomes are not static at all but highly dynamic changing I've left out technological innovations such as PCR and gene cloning that paved the way for the revolution in genome editing I've left out newish ideas about epigenetics and revolutions in the RNA world in fact genetics is so exciting and revolutionary that it's hardly possible to say anything at all in an hour if I were to sum up what I've said in one sentence it would be to note the extraordinary counterpoint in biology between astonishing variety on the one hand yet astonishing constancy in fundamental mechanisms on the other I'm sure that you will agree with me that the revolutions are if anything gaining in momentum so we're in for exciting times if you were to ask JBS Haldane about the future of biology he would say the following in forecasting the future of scientific research there is one quite general law to be noted the unexpected always happens so one can be quite sure that the future will make any detailed predictions look silly yeah an actual research worker can perhaps see a little further than the intelligent onlooker even so it may seem presumptuous for any one man woman in this case especially one who is almost completely ignorant of botany to attempt to cover however in adequately the whole field of biological investigation I hope you will forgive me my terrible over science if I end with another quote from Haldane my own suspicion is that the universe is not only queerer than we suppose but queerer than we can suppose thank you you

21 thoughts on “Genetics as Revolution – 2015 JBS Haldane Lecture with Alison Woollard”

  1. Beautiful survey! Too bad the theory of evolution is nowhere mentioned in the one true source of eternal knowledge: Dianetics, the book of Scientology. Praise Xenu

  2. On the shoulders of giants seems to be how the biggest discoveries continues to rocket science and technology and our species to either great heights of brilliance or the lowest depths of despair.

  3. Watching vids like this at british science institutions like the royal society, i wonder why they havent they produced anything of note since the industrial revolution 300 years ago?

    And judging by the comments, science seems to be more entertainment these days to birts than anything worth pursuing and achieving at.

  4. I am deeply concerned about eugenics. But if we must have it we would be better off editing genomes than we would be killing people like the Nazis, though.

  5. So it all just evolved like that. Billions of different animals and organism just evolved. No hand of design. No Creator. No master plan. Look at the beauty of it all. How it all works together in harmony, in purpose. How can you bypass the question. WHO MADE IT ALL? Your theory of evolution without design, without a designer cannot sell. Because it is impossible. There is a Creator, A designer, A maker, A planner, THERE IS GOD. He is in all that you are discussing. All that you see and don't see. He is even in you. He hold's you together and make you live. Science all point to the fact that there is a force that holds all things together, that holds the atom together. How blind can you be? How fool can you be to think it all just evolved without a super intelligent being that made it all possible. That holds it all together. That planned it all. That designed it all. Open your eye and see. Seek Him and you will find Him. When you do, you will have true knowledge. You will understand. But with all your knowledge, right now you don't. But I do hope one day soon you will see, know and understand.

  6. Thumbs up for a lady who is clearly as knowledgeable in her field as she is passionate about it – as opposed to another teeth-sucking lady (only to eager to delve into pseudo-science) who seemed WAY out of her depth talking to an actual audience.

  7. Human effort to search for knowledge is breathtakingly beautiful way, and calls for a remarkable comparison, between two branches, mathematics and evolution, with origins deep into our past.
    Socrates discovered how mathematics was the 'mind of God', and shared by all human, including Meno's illiterate slave, for which he was declared as the 'wisest man on earth' by the Oracle of Delphi, almost 2500 years ago, and proving God and man compliment each other, with deep significance we still ignore, and fail to recognize and appreciate.
    On evolution the story is even more unbelievable.
    We are familiar with Darwin and his father, as the beginning of evolution, yet Indian history pays undue importance (and little understood) to the similarity between man and monkey (hanuman), discovered, and recently dated to 11,000 years ago when in Sanatan religion Krishna preached how God Vishnu is the cause of the evolution of the world.
    God without man or man without God is meaningless. They are related.
    The universe is queerer than we suppose.

  8. Darwin's theory of evolution is just that, a theory. A theory that has no proof, only blind followers who will force everything into the Darwin paradigm.

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