First may I say what an honour it is to be asked, and privilege it is to give, a lecture to mark this occasion, though I take it the particular choice of lecturer is more because of my position than merit, I having held for the past quarter of a century the chair that was endowed on Cambridge University for our founder in the name of our first President. I leave it to you to think later whether your committee have established a good tradition by marking the second hundredth meeting by repeating an invitation to the current Emeritus Arthur Balfour Professor, as the first was marked by Professor Punnett in 1949.

I was told I could talk about what I liked, but there was a strong hint that something a little historical would not come amiss. But of course I cannot give you anything historical to match Professor Punnett's marvellous account of the Early Days of Genetics with its highlight in the conflict between Bateson and Wheldon over Ben Battle who was registered as a chestnut but ran as a bay. Illegitimacy was never an acceptable hypothesis in the world of race horses.

But thinking what I might say it occurred to me that the history of Genetics - especially in Britain - is divided into two parts round about 1949. Before then genetics was hardly recognised as an essential part of Biology, certainly not so essential as to be allowed any substantial part of the undergraduate biological curriculum. In most Universities it had almost no part at all. About then and after, University after University took up genetics and made a place for it.

I address myself to why this took so long, what was responsible for the change, and a little to whether we have further still to go and what we need to remember as the essential basis of what gave us success .

Consider what an extraordinary story it is. Take the example of Cambridge. There from 1897 to 1906 genetics was in effect invented. There from 1909 to 1943 there was a department headed by Professor Punnett, and from 1943 to 1957 by Professor Fisher. Yet it was not until 1953 that the department got a formal place in undergraduate teaching with a third year course. And it was not until 1964 that elementary lectures in Genetics became a standard part of the curriculum. And don't think this was just a local peculiarity. The attitude was rather general. Professor Irene Manton once told me that she and Dr Sansome, when on the staff of the department of Botany in Manchester, asked the Professor if they might not give lectures on cytology and genetics. They were told: "Of course, provided you give them outside the timetable." Lectures outside the timetable were what Punnett gave, Fisher gave and I gave till 1964 in Cambridge. They did not even have that in Manchester.

The Jericho of my title therefore is the city of Biology whose walls seem to have been fortified against Genetics. Why so and what led to their fall?

Traditionally the way to capture Jericho is to walk around the walls shouting and blowing your trumpets. But, while we each know someone who behaves as if he thinks that is the right approach, such people forget that this requires the miracle of a stationary sun. Rather do such cities get taken by a combination of scaling ladders, battering rams Trojan horses, spies and moles, and are usually taken piecemeal.

Now you may think that entering Jericho took so long because of particular personalities. Of course there is truth in this. If Bateson had not left Cambridge in 1909 to set up John Innes the history of Genetics would have been different. But I doubt if any gain in Cambridge would have been as great as the John Innes loss. Likewise, if the work Bateson was doing before he left Cambridge had not had to be done in his own garden, the building provided by the Arthur Balfour endowment might not have been largely a Professorial residence, in which of course Mrs Punnet lived and exercised influence.

Mrs Punnet was a very strong character as the following story which I have at first hand shows:-

The late Professor Koller was named Pio as in his part of Hungary the first son of a bourgois family inherited the business or estate, and the second went into the church, and was therefore given a name that might help in that career. In due time Pio became a monk, but in due time became disenchanted with monkery and conceived a wish to be a scientist. In those parts there was a precedent for monks who wished to do science, and the particular science had next been pursued in Cambridge. Pio therefore arranged to come to Cambridge to learn genetical research. Arriving in his robes at the front door of Whittinghame Lodge - the department and also the professorial residence - he rang the bell. Quote: "A gaunt woman opened the door, stared at me and said

'Who are you?'.

'I am Mr Koller.'

'Oh' she said 'You are the young man who thinks he's coming here to do research. You can't do that you know.' and the door was banged in my face.".

This story clearly suggests that Mrs Punnet may have made it difficult for Punnet to develop the department. But I do not think this is the reason why so little was done and Mrs Punnet's influence on the history of Genetics lies in a quite different direction.

His rejection at the door of Whittinghame Lodge led Koller to find a niche studying cells in the Strangeways Laboratory and he later fixed himself to move to John Innes and study chromosomes. Then, interested in Drosophila obscura, he visited the States to look at the American D.obscura, which had just been renamed pseudoobscura. Some say that it was Koller who introduced Sturtevant and Dobzhansky to the idea that Dp would be good material for studying natural population genetics. You will know of course that the third paper in Dobzhznsky's long series has Koller as sole author, and that this paper is the first one that required selection rather than drift. Thus Mrs Punnett's trousers may have profoundly affected Genetic History, through indirect responsibility for Dobzhansky's population genetics.

In later years this question of the role of selection and drift played quite a part in our meetings and round about our 100th meeting I can remember several occasions when our members gave papers about selection in nature with quite emotional sections against the relevance of drift. Nowadays the controversy is still with us in relation to the relevance or otherwise of strictly neutral evolution, though even the proponents of neutral theory readily accept the importance of selection. It is really only those who would like to have an evolutionary clock that keeps time, who tend to be over enthusiastic for neutrality.

But the influence of Mrs Punnett on Koller and hence on Dobzhansky is not the sort of historical factor that concerns me tonight.The important reason why Genetics was neglected is that it just didn't seem relevant to most biologists.

My own experience of this begins quite early during a long holiday in Switzerland the climax of which was a visit to a remote place called Obersteinberg.

Doubtless because I had spent 4 years of childhood in Capetown when the Cape flora was new to my botanical parents,I was interested in flowers. So I toddled up the Alps armed with a vasculum, and exploring a moraine at the top of an extremely isolated valley I found two colour mutants of Alpine toadflax.

The Lauterbrunnen Valley

Photo © JMT

The moraine is just under the Tschingelhorn, the white dome at the head of the valley

I found myself immediately in a problem. My two pink and orange plants where not in the flora. To the question 'Why not?' the answer was that they were not species, they were "only varieties", and this from Botanical parents who had actually been to Bateson's lectures. Of course you will recognise that we have here an example of the effects of isolation and drift, precisely comparable to the findings of Cavalli and others for human populations in alpine valleys. In 1924 I could not expect this explanation, but the "only varieties" answer was most unsatisfactory.

Later I used to go on the excursions organised for vacation courses by the Botany Department at Bangor. Here too I used to find odd things and ask awkward questions. I remember in particular finding a pennywort (it is superficially like a small succulent foxglove), with an extra rosette of leaves on top of the inflorescence. The lecturer brushed it off as just an abnormality. Here lies the core of our problem. Intraspecific variation meant trivial or abnormal departures from the species, departures from the essential, Platonic essence, Goethe's essential forms. Such concepts dominated biology, which had in fact barely been touched by Darwinism, except in as much as it encouraged comparative biology, for in truth the variation on which Darwinism depended was still regarded as trivial and barely relevant.

Thus it was that in three undergraduate years of Zoology and four of Botany time was found for only four lectures on cytology and genetics - one on mitosis and meiosis and one on Mendelism from each department. These lectures were there to "explain" heredity, would soon have been forgotten except that the two department's versions fortunately disagreed, which roused my interest so that in the summer of 1938 I went to the John Innes Summer School.

Hitherto Zoology was all bones, or shells, apart from purely descriptive embryology. Botany was better for we did in plant physiology come across photosynthesis and respiration, and hormone control of growth, but most was comparative anatomy as well.

Then, suddenly, there was Darlington deducing principles with lucidly simple euclidian logic from projections of Mr La Cour's beautiful cytological preparations. And Mr Lawrence told us about what was in those chromosomes - explaining genetic segregation interaction and linkage, largely in terms of methylation, oxidation, glycocylation, single metabolite steps controlled by genes, which at least sometimes determined the presence and absence of enzymes. And he showed us how genetic interaction could be used to reveal pathways of synthesis and even quantitative interactions of separate pathways.

Here was something real, something to catch the imagination, something that seemed to point to ways of understanding how life ticks. Yet nothing of it appeared in the Botanical or Zoological curricula.

So I set to making chromosomes, did so for a while, then spent five years in the wilderness.

When I returned there was much talk of Beadle and Tatum's great breakthrough. This puzzled me for a long time for I saw little of general importance in it different from what had excited me at John Innes seven years before. But I was wrong. Beadle and Tatum's paper is our turning point, and it is so for three reasons each of which is recognised by these authors.

First, its primary concern was phenotype, and it is phenotype that other biologists are interested in.

Second, they deliberately chose important aspects of phenotype, at least important to biochemists: amino acids, vitamins, essential substances that no one could write off as insignificant, as they did flower colour, skin pigment, bristle shape and the like.

Third and most important, these techniques, involved refined and critical study of genotype-environment interaction.

Of course genotype-environment interaction had been considered before, especially in quantitative genetics. Woolly statements were also made such as "phenotype is the result of interaction between genotype and environment", after making which you could go on to study the effects of genotype or of environment, conveniently ignoring their interaction. But B & T used g x e ineraction in a simple and revealing way, which is the basis of much of subsequent molecular genetics,

Take two environments - minimal and complete medium - and seek mutants that will grow on complete but not minimal. Take n further environments - supplemented media - and find out which mutants grow on which. Do a little genetics at one end, determine the dominance, linkage and gene interactions, do some biochemistry at the other defining the phenotypes better, introduce quantitative enzyme assays make it all easier by using Lederberg's powerful replica plating technique, and you have biochemical genetics. Add genetic fine structure analysis, protein sequencing, and at last DNA sequencing and you have molecular genetics. But the more you think about it the more has hinged on the fulcrum of critical study of the specific phenotypic effects of carefully defined environmental differences on simple intra family genetic differences.

Thus it was that B & T opened up the way to modern genetics, but it was their choice of an important set of phenotypes that made the first real break in the walls of Jericho, for thereafter the (quote from B & T) belief that "genes are concerned only with the control of superficial characters" end quote, had to decline, at least in the biochemical quarters of the city.

But it took a long time to die in other quarters. Notably amongst students of development and amongst physiologists who were reluctant to accept that our models of the control of gene action might help explain differentiation and still less morphogenesis. There are still many who, without necessarily recognising it, seem to think of form as an essential cause in itself, not to be modified by genetic variation, except in insignificant ways, such as by D Arcy Thompson transformations. Such thoughts stem again from Plato, Goethe and are strong in such books as Arber's Natural Philosophy of Plant Form. Even Betty Saunders after Bateson left Cambridge took up Plant Form as a more fundamental study, and such thoughts I think are still the origin of views that genetics cannot explain macro-evolutionary change.

Here again however things are changing and the basic source of change again involves the study of genotype environment interactions. Part of the change stemmed from Jacob and Mono. But the direct development came with Curt Stern's powerful use of mosaics. It started with gynandromorphs but is now available for quite general use.

Mosaics in Drosophila give us the opportunity to study the interaction between genetic difference and the internal environmental differences that are both the cause and consequence of differentiation. These techniques are rapidly becoming more powerful with the availability of biochemical markers that can show which cells have and which have not some gene or chromosomal segment under study, and when temperature sensitive mutants can be used, the time at which the gene effect is lost or gained can also be controlled. So we may expect GE to reveal more and more about development especially given the detailed knowledge of G in terms of DNA sequence that recombinant DNA technology is making possible.

Likewise in the study of behaviour the opportunities and rewards are being recognised and we see GXE revealing more and more in psychopharmacological genetics, and in the elegant use of mutants in Drosophila behaviour genetics and neuro-genetics by Benzer's school.

I shall return shortly to behaviour, but first wish to say a little about evolution studies, especially since, it was interest in evolution that first led Bateson to call for the study of variation, and there is little sign in his early book that he in any way thought such study might have understanding of protein synthesis as one of its rewards.

It is easy for us to feel that it is in evolution theory that we have taken over a substantial part of Jericho, for there is no question that the theoretical developments based initially on the work of Fisher, Haldane and Wright are among our great achievements.

A little reflection however might lead to some caution, and may explain some of the recent dissatisfaction with evolution theory. A general biologist might think it all very well to say that the elementary step in evolution is a change in gene frequency and to have a theory that will predict a change in gene frequency or should one say the variance and mean of probable changes in gene frequency provided that you know the population size, breeding system and selective differential. But while a change in gene frequency is a fundamental step in evolution, is it a really interesting change to the general biologist? Does not an interesting step in evolution as the general biologist really conceives involve something else altogether: an integrated change in a developmental system which is related to a change in the environment. The change in the environment may be extrinsic arising from climate or the extinction of competitors, or intrinsic when a change of behaviour or development permits the organism to exploit an environmental opportunity available before but not hitherto used, but the change in organisms has to involve the developmental system.

That we have not yet reached explanations of such steps of evolution is doubtless because developmental genetics has not yet gone far enough but I also think that genotype environmental interaction has to be central. Yet GxE really plays rather little part in evolution theory. Rather do we tend to treat environment as more or less homogeneous in space and time. Even in ecological genetics serious attempts are not always made to measure possibly relevant environmental factors - how many maps of pie charts have we seen that are not accompanied by soil and vegetation surveys. Yet when environmental factors were taken seriously as in melanism Mimicry, in Dobzhansky's group's studies of the effects of temperature and humidity and yeast type on the fate of D.pseudoobscura inversion, or in Cain and Sheppard's classic study of Cepaea, great insight was obtained.

At present, of course, our hope must be that the new techniques for defining genotypes given to us by molecular biology will lead to rapid advances in developmental genetics, behaviour genetics and evolution studies.

But here it seems to me that there is a danger that as these new techniques are taken up there is less interest in intraspecific variation, less interest in the environment, and in G x E interaction on fitness, so that what got us into Jericho is giving place to comparative studies which were what kept us out.

I do not say that comparative studies are not necessary or interesting, but I must suggest that however interesting the comparative anatomy of genes may be,as a means of investigating mechanisms of evolution it must be open to the same criticism that our founder Bateson used of comparative anatomy proper in 1894 in Materials for the Study of Variation, the book that is the beginning of genetics.

However the comparative anatomy of genes does open up a way that will allow us to use G x E approach by a back door that may sometimes avoid tedious or difficult breeding experiments. This is to use genetic engineering techniques to obtain the sequence of a gene and hence to predict the nature of its product, or simply to clone the gene and produce its product. The effects of that product can then be studied in individuals that do not have that gene, or at times or in parts of an individual when or where that gene does not normally act. Thus it is that the control of egg laying behaviour of snails is now being revealed.

But there is another area in which molecular genetics might contribute. An artificial directional selection experiment much produces a change in developmental system in relation to a change of environment. The environmental factor is, of course, differential predation by the experimenter, though he does not actually eat the individuals he prevents from breeding.

The result may be astonishingly rapid change, giving us the opportunity if we will take it of detailed understanding of the developmental changes selection can produce.

Much work has been done to test methods of predicting rates of change, assess the architecture of the genetic systems permitting change, the role of mutation and recombination and so on. But rather little critical developmental genetics has been done to compare the resulting organisms with the populations from which they came, though when it has been done the results have been surprisingly simple.

I believe that a great deal of insight into the potentialities of variance generating systems to modify development and so achieve evolutionary change could come from a new attack on responses to selection which combines molecular techniques with all the others relevant to understanding the response in a carefully designed selection experiment I further believe that until serious achievements have been made in this direction we shall continue to hear doubts whether our theories of evolution will account for macro evolutionary change, because we will not yet have seriously studied significant changes in development that can result from letting more or less extreme deviants reproduce without competition, something that presumably happens in evolution, especially after a major invasion of a new environment, or to the survivors of one of those major extinctions that occur in the fossil record.

These remarks show that we have not yet fully taken over Jericho, but I think we can fairly claim to have entered the City. The walls are down or the gates are open and geneticists are helping in many parts of the city, though perhaps there are yet a few backward slums to be cleared.

But Jericho, I would remind you, is but the gate to the promised land, whose centre is Jerusalem. This in our metaphor must be the city of knowledge as a whole, not only the systematised objective knowledge which is science, but the relation between this knowledge and subjective experience. So I am going to end by looking ahead and suggesting that the study of genotype environment interaction may before the 300th meeting of the society help us on the road to understanding this relation between the objective and the subjective, which of course is to claim that the study of G X E may take us byeond what many philosophers argue is the boundary of science.

For this I give you a little more autobiography. After graduating I went to the Cambridge Botany School and started work on effects of neutrons on chromosomes. I was given a research microscope, so-called because it had a mechanical stage and an oil immersion lens. It was monocular, so that so that I stared down with my left eye for 7 or 8 hours a day at a bright green light. At the end of the day I found that if I shut one eye I saw red, but if I shut the other eye I saw green, an effect that lasted quite a long time.

This was unpleasant, so I had a little revolution and was given a binocular microscope. 7 or 8 hours of this, and when I looked up I would see red for a few moments, and then the colours reverted to normal.

Why did I see green with the non-red tired eye after the monocular, and why did I see green for a much shorter time when both eyes were tired? The less interesting answer is that one must have means of monitoring one's visual state, and correct for this. More interesting point is that, it clearly illustrates that we normalise our subjective observations, we make them fit expectations in some way, we make the facts fit the hypothesis. Bertrand Russell gave an illustration of this, when you see half a horse coming round the corner you may say there is a horse coming round the corner. You do not describe what you see because you would be very surprised if the other half wasn't following the front. This is why, when well done in a pantomime, the half-horse wondering where the rest of it is can be very funny.

Now I would suggest that these observations on our or my normalising of my colour perception might be made quite interesting if we added the genetic to the environmental dimension, trying to determine what people with the various forms of red green colour-blindness experience after monocular and binocular red or green fatigue. Such experiments could not help adding something to our understanding of how it is that we impose correctives upon our subjective experience and hence tell us something about the mysterious relation between it and the objective.

I am now going to show a film. This film shows two things: first that, those who are determined to treat human genetic variation as socially neutral, are not always right. Second and directly in the present context it gives us some insight into a difference between the subjective experience of two kinds of people. I understand the film was monitored by a mosaic woman, one of whose eyes was red green colour blind.

There followed a film (copyright US Navy) showing a woman entering a colourful room first as seen with a normal eye, and then as seen with a red green colour blind eye)

You may think this last suggestion of mine concerning the way to Jerusalem is rather foolish for it is to claim that we might transcend the conventional boundaries of science. However, I am unrepentant and take comfort from an old Bulgarian proverb which says "Many an ass has entered Jerusalem."

But at least I am sure that since our 100th meeting we have largely broken down much of the walls of Jericho and opened up new understanding in branch after branch of biology, and we may do well to remember that it all began with our founder, William Bateson, who had the temerity in 1894 to throw down the challenge to so many great thinkers from Plato onwards, by maintaining that the study of individual differences is at least as important, if not more so, as the study of species, types or essential forms.

The comparative anatomy of nucleic acid sequences may be interesting as confirming or correcting our concepts of phylogeny. But all our genetic understanding stems from studies of close relatives. If we forget that it will be a great loss.

Appendix

There is another, very sad, story about the Punnets which I feel should go on record. It was told to me by the noted mouse geneticist, Hans Gruneberg. It goes a long way to explain why Punnet did so little to develop the Cambridge Genetics Department, between his election as the first Arthur Balfour Professor in 1912 and retirement in 1943.

During the second world war, the University offered older Professors with Life Tenure a pension if they relinquished their Chairs. Punnet accepted this and moved to live in the South West, vacating the Chair for the appointment of R.A.Fisher.

Hans Gruneberg was medically qualified and did war service in the Army Medical force. For his demobilisation leave he chose to tour Devon and Cornwall.

Finding himself near Punnet's house, he decided it would be a kind act to call, which one afternoon he did. Punnet was seated at the bottom of a grand staircase and welcomed him. However, as they chatted Gruneberg felt something was awry as Punnet kept uneasily looking up the stairs. So he said, it seems you must have an appointment or something. Tell me and I will go as soon as suits you.

No, says Punnet, it is not that. It's my wife. She is having her afternoon rest upstairs and she would not like to come down and find me with a Geneticist!

© J M Thoday