Second Part

0:09:07 Robert Hinde has been very encouraging; our research overlapped a little as he has been interested in monkey and human mother-infant and family relationships.  This has interested me at a mechanistic level in terms of how the brain works to regulate that behaviour, and the importance of hormones in regulating maternal behaviour. I am talking about animals here, because what I find interesting about all mammals is that you have two generations developing in one individual - the infant and placenta, which is also foetal.  The placenta actually communicates with the mother to extract resources, but also instructs the mother's brain; it tells mother to eat more food in early pregnancy so it can be stored for later when she can't eat enough to satisfy the foetus; it also primes the brain to be ready for maternal care. What is interesting about human behaviour is that women don't have to go through pregnancy to be perfectly good mothers - it may help, but it is not necessary.  In all other mammals, except large brained animals like primates, pregnancy hormones are deterministic. Primates learn maternal care.   Another point that has interested me about maternal care is the neural mechanisms, in particular the way the hormones act on the brain to prime neuropeptides, notably oyxtocin for maternal care.  It is interesting that this peptide is acting relatively mechanistically in small-brained mammals, but in humans and monkeys these mechanisms form the foundations for social interaction. I first worked on maternal interactions with a relatively small-brained mammal, the ewe, where you get the mother bonding with her lamb; secondly, how living socially with a large brain, most of it developing post-natally, what changes have had to occur in brain evolution to encompass that; it is interesting that the basic mechanism, in sheep for instance, are very much driven by olfactory cues. When you get to higher primates and humans, olfactory mechanisms play much less of a role, but the brain's reward mechanism kicks in; there is the same basic structure in terms of the hypothalamic mechanisms, oxytocins and its receptors, and also the brain's reward mechanisms.  What has happened as the brain has evolved to a larger structure is the reward system now responds to many different inputs from other parts of the brain, and is not just regulated by these neuroendocrine peptide mechanisms.  One thing about the human brain in particular is that it continues to develop until late puberty, from seventeen up to twenty-one.  Indeed, most of the brain development occurs postnatally, and for a large brain this requires careful development in an appropriate environment.  The brain has got larger to such an extent that it is becoming self-regulatory, although in regulating itself it has to go through a very long social learning process. We kind of think of everything we do as being straight-forward and natural but unless you have carefully watched a mother interacting with a young child, as I see with my grandchildren, you do not realise how much effort mothers put into their children - to get them to stand, feed themselves, walk  and the amount of positive reinforcement and encouragement is just obsessional. But it works; you find that kids that have been neglected and brought up in an orphanage don't readily learn to walk or talk; we think of this as an innate process but it is learned.

8:11:11 From seventeen to twenty-one the brain reaches the age of reason, a period when it is less driven by emotions. As the brain learns to control emotions.  it is the pre-frontal cortex that is maturing at this time.  There is a growing concern for modern kids who are now coming into puberty at junior school age.  They are now coming into reproductive maturity long before they have reached rational and emotional maturity. I Insight into this has come from MRI scans; essentially the frontal cortex is undergoing a pruning and rewiring.  This is not growth in the sense of new neurons forming, neurons are in fact dying and the biggest increase in this brain region is in the white matter which is providing interconnections between neurons.   What I find interesting in this context is the conservative nature of biology. Evolution has taken the mechanisms underpinning mother-infant interactions and expanded these to embrace social bonding. The same neural mechanisms have been called into play in terms of social bonding and social cohesion. Moreover it is also the same mechanisms, incidentally, which are  usurped by addiction - smoking, alcohol, drug abuse; what is sad about such drugs is that they also destroy the maternalism.  Heroin addicted mothers, usually within a year of birth, see half of their children taken into care, either by a relative or the State; by the time the child reaches school age it is 90% that are in care.

Another research interest of mine has been trying to figure out how things are put together at a molecular-genetic level; this is an enormous task as there are so many genes that you could pick on. I was lucky in a way, because I knew Azim Surani and he had just discovered genomic imprinting in the context of the placenta.  My interest in gene imprinting is in the context of the brain, although there were no imprinted genes discovered at that stage.  Imprinted genes are normal autosomal genes which are expressed according to parent of origin; there are some of your genes that you have inherited from mum and dad, but only your father's are expressed, and for other genes only your mother's are expressed One can try and figure out what the whole of the imprinted genome is doing by making parthenogenetic or androgenetic animals.  This requires the nucleus from one egg being transferred into another egg producing a diploid organism made up of all the genes which have come from mum. You can do the reciprocal by taking out the female nucleus and putting two male nuclei into the egg.   This procedure is lethal very early in development because of the placenta primarily, but you can make chimeras where you take cells and make them parthenogenetic or androgenetic. Providing they don't exceed 40% of the total cells they will survive.  This has a very big impact on brain growth, its size at birth, and informs as to the whereabouts these cells are influencing the brain. Since these early collaborations with Azim I have been following through the imprinted genes particularly in the context of maternalism, and how important the matrilines have been.   I am particularly interested now in how the brain and placenta have co-adaptively evolved; I am also still interested in olfaction and in small-brained mammals it is the most important sensory system they have.  I have studied how this system adapts according to the environment.   Mouse olfactory and pheromone receptors are continually dying and being replaced, and are thought to be one of the few neurons in the brain which regenerate. The question is that, if they are continually turning over, are they coming up with the same repertoire or is their turnover being selected in such a way that they are better able to respond to the environment in which they find themselves. Both of these issues, olfaction and maternalism, are interesting, not just from a genetic point of view, but from an epigenetic point of view. Genes which are regulated and expressed as a result of environmental influences, can be considered to be epigenetically controlled. Thus evolution is, in part, dependent on environmental selective events, but these may not be just a passive selection, but much more adaptive than we previously thought.

15:28:06 The difference between science and chess is that your only opponent is yourself; it is an intellectual challenge where you don't always come up with the right answer but you are continuously forward progressing.  If you try and think about genes and behaviour, how do you know what time and which part of the brain is crucially important, or which of the genes are the ones that might provide a handle on this very big problem.  How to narrow things down without losing track of the big picture; that is what has really interested me and has undoubtedly been helped by discussions with colleagues, Joe, Azim and Charlie.  Neither Azim nor Charlie know a great deal about the brain, but they have other in-depth knowledge that I would have had to generate myself.   The easiest way to generate knowledge about a completely new scientific area is to talk to somebody who is interested, especially if it is a fellow scientist. You then get the social contact and enthusiasm, and the sowing of seeds that make you want to know more.  It is not just having the thought that something might be interesting and then reading about it, but you need some enthusiastic direction and discussion to progress. Azim is the most modest person you could ever imagine, but has been extremely stimulating in developing my understanding of developmental genetics.

I also learned a huge amount from Gabriel Horn; he has real leadership qualities, and is absolutely brilliant at motivating and encouraging people; I was asked to take over from Pat Bateson. Going back, I did overlap for a few years with Gabriel in Anatomy; I was the first non-medic to be appointed to the department apart from Martin Johnson, and the other medics were not exactly warm and welcoming.  Gabriel not at all like that but was keen on everybody with enthusiasm for research; I was the first person to introduce use of radioactivity into the department and this excited him. He made me feel important whereas nobody else in the department ever spoke to me. Harrison, who had been very welcoming, was busy being head of department and was otherwise detached from newcomers.

19:11:00 The collegiate structure of King's (where both Azim Surani and Charlie Loke are fellows) has made these sorts of discussion easier; I would also say that supervising is a wonderful stimulus because it forces you to keep broad; every year I used to find students would ask me questions in a way that I hadn't really brought together the information in that way before. It is not that I didn't know the answers or the component parts, but I hadn't considered them in quite that format before. Never a year went by when I didn't at some point receive some kind of new stimulating viewpoint.  It is always rewarding to teach and see young minds develop, but also rewarding for yourself. In the college, Sidney Brenner is a person for whom I have enormous admiration.  When I was admitted to my fellowship I sat next to him and came away feeling very small. I now know him well enough to recognise that he is not a very good listener, but with a few prime words you can get a monumental amount of knowledge, information, and ideas from him.  Sidney is just pure crystallized genius; he is the cleverest man I know and I am proud to have been at the same college with him.  I took over at Madingley from Pat Bateson when he came here to become Provost. I came into Madingley to take it in a slightly different direction to Pat.  Since he stopped being Provost he has come back to Madingley and become much more involved with myself and post-graduate students, and we have been doing things together; Pat is now very interested in epigenetics.   He too likes this way of being able to engage the environment in terms of gene-environment interaction in the development of behaviour.

23:52:05 The human brain is different from other mammals because of the long developmental process it undergoes postnatally; in terms of belief systems, we all need them in the sense that we can understand what we mean by guilt, shame, or blame.  We need an internal representation of virtuous self to be able to feel guilty, to understand what you should be and what you are not being, and matching up to the standards that you set for your internal representation of self. Some people put God in that representation slot to set these standards; I don't feel you need any external reference point; I think it is an internal reference point that is needed, but you really do need it.   This is something that you appreciate when you reach maturity, being able to value relationships and what you put into them, and all the things you do in terms of what you expect of yourself. In all of the things that I have achieved, I feel that I have had a lot of influence from other people but I don't thank God for it. I think it has come about, partly through my own direction but especially through being in an environment like Cambridge. Cambridge is just such a wonderful place for anyone who wants to learn and be curious; you could live a thousand years and embrace many different disciplines and still never come to a conclusive end point.  However, you need to be careful about losing focus because there are so many things that are intellectually stimulating.

27:17:21 A crucially important part of my life is my family; my wife is Spanish and I have three children who are now grown up; my two daughters have children.  That has been my secure base for the way I have operated.  The family are always there, always welcoming, always understanding me, allowing me to do the things that might not generate a lot of income.  I could not have done anything without them; I don't force my family to engage with what I do academically, although if they are interested that's great. I did not notice the parent-child interactions so much with my own children; but then one is too involved, too emotional and too close.  You can't stand back and observe; it is much easier to do so with grandchildren and I hope retirement will provide me with more opportunity in the direction. I was made a Fellow of the Royal Society in 1997, an Honorary Foreign Fellow of the American Academy of Arts and Sciences two years after, a Fellow of the Academy of Medical Sciences, and received the Wiersma Honorary Professorship at Caltech, among many other awards.