个人简介
I, as many, liked the world of ideas from when I was small. I read some philosophical books in my early teens, mainly by Bertrand Russell, but came to the belief that studying physics could provide better opportunities to appreciate and come close to beauty in nature.
I studied physics whilst at Gonville and Caius, College, Cambridge, from 1961-1964, as an undergraduate. I found the experience frustrating as there was not enough time for me to understand and appreciate the vast amount of material. I felt I could not do justice to my aspirations or the subject.
I knew I wanted to be in a field where I could try to make some significant conceptual contributions and hopefully do some related experiments. I had little confidence I could achieve this in physics. I was very interested in theory. The particular field did not seem so important to me, but rather the approach one took in an attempt to make progress. I was very fortunate. My brother, Mark, who had trained as an organic chemist, was doing his PhD under the guidance of Sydney Brenner and Francis Crick in the area of protein synthesis and the genetic code, in the Laboratory of Molecular Biology, in Cambridge, England . I was accepted to do graduate studies at the same laboratory with John Kendrew, who already had his Nobel Prize for the structure of myoglobin. My graduate studies were to be in the field of protein Xray crystallography.
To have been at The Laboratory of Molecular Biology at this time was a unique privilege and allowed one to witness history. I taught myself some genetics and took an interest in many things. Crick and Brenner were interested, among very many things, in the origin of the genes coding for antibody chains. I thought the model by Brenner and Milstein on this topic, published in Nature, implausible, and brought my considerations to Sydney Brenner, who was very open to discussion. There were several hours of discussion every Saturday over coffee in the second floor laboratory “kitchens”, on scientific or other matters, with Sydney being very prominent. This was the time of the acridine mutant work using T4 phage that gave rise to the experiments on the general nature of the genetic code, of experiments on co-linearity of gene and polypeptide, of elucidation of the genetic code and of the proposal for the Wobble Hypothesis and of allostery.
We had visitors I am unlikely to forget: Monod, Benzer, Stahl, Gowans, and Jim Watson, for example.
One day, doing some experiments, I was wearing plastic gloves as I was dealing with a nasty chemical, bromo acetic acid. I felt a throb in a finger as I fell asleep that night. The next morning one fingertip was quite white and without feeling. It was in time surgically removed and skin grafted to the end of what remained of my finger. However, the first morning after the accident, I saw a sharp line developing that demarked the healthy from unhealthy tissue. I interpreted this as reflecting immunological self-nonself discrimination. I was already somewhat interested in immunology. Cesar Milstein had suggested I read some Burnet, but after reading a bit I gave up and started speculating. I talked to Crick about several ideas. He suggested I see Avrion Mitchison, for a potential postdoc position, which I did. However, Crick suggested, as I talked to him more about my ideas, that I would find Mel Cohn of the Salk Institute a very compatible individual to do a postdoc with, given our common love of speculation. Crick was a Visiting Fellow at the Salk Institute at that time. A series of circumstances led me to realize during my PhD studies, and then find evidence in the literature that I could use to support the idea, that antigen interacting with a single lymphocyte might inactivate it, and that activation might require the antigen-mediated cooperation of lymphocytes. I realised that these rules provided a potential explanation of immunological self-nonself discrimination.
Mel Cohn went to a Brooke Lodge meeting only a few (two or three?) weeks after I arrived at the Salk Institute, California. He talked about the ideas on the induction and paralysis of immune responses, as the processes of activation and inactivation of lymphocytes were then called. We decided that we had better publish our ideas quickly. I am not sure this was the wisest decision, but we thought a formal presentation was better than leaving the point of view we had open to misconception. I wrote a covering letter explaining the situation to Nature. I seem to recall that Nature accepted the publication one day after they received it. Never anything remotely like this has ever happened again in my life! There were some aspects of this first exposition that troubled me. Resolution of these aspects led us to formulate the two signal model of lymphocyte activation, published in Science in 1970.
To have been at the Salk Institute at this time was also a great privilege. Neurophysiologists from Harvard came every summer and gave mind bending lectures. Various visiting Fellows also came a few weeks every year, including Crick and Monod. I got to know Jacques Monod quite well as he was always interested in new ideas in immunology. Monod and I also had some considerable, good natured, philosophical arguments. The diversity of lectures at the Salk Institute was probably unique. Some of the most interesting and speculative lectures were on the origin of life, because one of the Fellows, Leslie Orgel, was a prominent individual in this field. Some of the most beautiful were on phage lambda. Dulbecco, whose laboratory was devoted to understanding the biology of the oncogenic viruses, polyoma and SV40, felt that lambda’s tricks might be relevant to understanding the tricks oncogenic viruses got up to. We had seminars on philosophical subjects and on animal behaviour, and an attempted lecture on race and IQ. This lecture never took off the ground as it was disrupted. These were Vietnam days.
The individuals in Mel’s laboratory for the most part had two properties in common: most (though not all) worked on immunological subjects and, of all that I knew, none had a background in immunology. The real sign of experimental sophistication in these days was if you could inject mice intravenously! I remember one individual with a background in phage genetics becoming very distraught on finding a mouse that he had killed had had two spleen. He was distraught as one cannot do genetics with dead mice (anyway, not then). He wasn’t really all that relieved when someone pointed out to him that he had been removing kidneys. It is unbelievable, in retrospect, how we lived. There was very little pressure from Mel to do experiments if you were a postdoc, and in some sense rather little guidance, unless you consider a lot of enthusiasm and more suggestions about what was important than anyone could digest. I also think Mel was fortunate in some of the young people he had. David Schubert, Sidhartha Sarkar, Alan Harris, Alan Sher, Bob Coffman, Chuck Kimmel, Alan Harris, Jim Watson, Mario Caesari, and Martin Weigert were all contemporaries of mine, and I overlapped with Michael Bevan a bit.
Besides my interests in the two signal model of lymphocyte activation, I did theoretical work on autoimmunity and immune class regulation. Bob Coffman was one of the individuals who kindly read and gave me comments on the manuscript describing my theory of immune class regulation. I did not publish anything from my experimental work. This was not for want of trying. I was inexperienced and Mel’s lab was in its early days. I was also a bit foolish. I developed one series of experiments testing whether a circumstance, under which lymphocytes should be inactivated according to our two signal ideas, did indeed lead to inactivation, and got the kind of result I anticipated. However, the results were not as clear cut as I had expected. I took this to mean that my understanding of the phenomenon was inadequate, and so I thought I should not publish. Similar but even less clear work along the same lines was later published and was regarded as pretty significant. I have learnt from this to better accept that my understanding is limited, and to therefore be in a sense both more realistic and more humble.
Another aspect of our intellectual life was its freedom, unbelievable in this modern day of urgency and competitiveness, illustrated by two endeavours. Many people around were interested in neurophysiology. It was hard not to be. I spent some time studying David Marr’s Theory of the Cerebellum, and gave a few talks on it as understanding the theory needed alot of digestion. Sidhartha Sarkar and I decided to try to learn some neurophysiology together. We got a self-teaching book on neuroanatomy, and a brain we were going to dissect. The point of these tasks we had set ourselves, after a few attempts at a bit of cramming, became questionable. We decided we would only need to know neuroanatomy once we had some interesting ideas that would propel our learning all that stuff. We never of course did develop those interesting ideas and therefore never learnt a significant amount of neuroanatomy.
The second endeavour had more long term consequences. A group of us felt we should be studying a subject that might be more relevant to the relief of human suffering. We decided to study together schistosomiasis, a disease that caused much suffering world wide. Donato Cioli, Paul Knopf and Alan Sher were all in this group, and all took the plunge of going into immunoparasitology. I decided to keep my interest in the subject but to remain in basic immunology for the present. I hoped that my contributions in basic science might also help in some way to relieve human suffering in the longer term.
I returned to Cambridge, England, to the Babraham Institute of Animal Physiology in 1972. I knew hardly any immunologists in England, so my options were limited, but I did know Cambridge well. After rather less than a year, I saw an advert for a job at The Australian National University (ANU) in an area suspiciously close to my interests. This was too good to be true. Moreover, the Head of the Department of the position advertised was a well known immunologist, Gordon Ada, whom I had met on his way through the Salk Institute. I applied with some anticipation. However, the job had been ear-marked for Chris Parish. Chris had actually done a lot of very interesting experiments, and these had in part stimulated my Theory of Immune Class Regulation. No wonder the job description made me think the fit with my interests was too good to be true!
Although I did not get the job advertised, Gordon Ada made other arrangements so that I could go to his department at the ANU. I was very interested in doing so, because I knew that the department really was a laboratory of professional microbiologists and immunologists, not exactly the description one would provide for Mel’s lab, and I really wanted to develop my experimental skills. Moreover, I had some clear ideas on what type of experimental approach should be explored to test some of my proposals underlying immune class regulation.
Chris had a graduate student, named Ian Ramshaw, who got interested in the theory. I think his other experiments had not been going so well. We discussed different approaches as to how to test various ideas. It was a very nice journey we took together. I remember Ian coming up with a paper describing an experimental system that he thought might be useful. It was. At one stage, I decided to do a job tour that took some weeks. When I returned, I found Ian had made tremendous progress. We felt we had really accomplished something significant. The experiments seemed to fit the predictions beautifully.
The John Curtin School for Medical Research, of the Australian National University, was another special place, set up, as was The Salk Institute, with a generosity of spirit. In our department of Microbiology, Alastair Cunningham, who kindly gave me some space in his laboratory, was exploring with Linda Pilarski whether genes encoding immunoglobulin chains hypermutate following antigen stimulation of the B cell carrying them. A few months before I arrived, Peter Doherty and Rolf Zinkernagel, working together in Bob Blanden’s lab with the type of systems Bob had established, had made the first observations demonstrating the MHC-restriction of cytotoxic lymphocytes, for which they received the Nobel prize some years later. Here too there was an unusual freedom for intellectual exploration. It is this kind of enthusiastic environment that leads to significant and bold ideas. Alastair Cunningham had been Kevin Lafferty’s first graduate student. Kevin was interested in transplantation and overcoming the transplantation barrier. This had led him and Alastair to try to understand some phenomena related to activation of T cells. They related some of their work to our two signal model of lymphocyte activation. So I came into a very interesting and very interested environment.
Australia was incredibly beautiful, and I very much liked the people. I was asked very informally if I might like to be considered for a better kind of job at the ANU. I decided that Australia was too far away from family. I often subsequently wondered whether I had been too hasty.
I had made a tour whilst at ANU looking for possibilities for my next step. Linda Pilarski, who had done her postdoc with Alastair Cunningham, was at the University of Alberta, Canada, so I had visited the Department of Immunolgy there. The Head was Erwin Diener, who had also been in Australia at the Walter Eliza Hall Institute. I decided to go there.
I arrived at the University of Alberta in 1978, about nine years after my PhD in protein Xray crystallography. I had done some publishable and published experimental work whilst at the ANU, but I wished to develop myself further in this respect. I was successful in this whilst at the University of Alberta. Both Ian Ramshaw and I had decided that the next critical step would be to obtain an in vitro system in which antigen could induce primary cell-mediated (DTH) and humoral responses. In this way, we could examine what circumstance favoured the generation of one response over the other. No one had managed to generate primary cell-mediated responses in vitro, with the exception of those to MHC antigens, which we felt were a special case. We kept in frequent touch. We used somewhat different approaches. Ian developed his system much faster than I did. He refrained from submitting his work until I had caught up, which took quite some time. Who under today’s pressures could and would show such kindness and generosity?
I made successful efforts to do experiments. I felt I was now in a position where I could give students guidance, so I had took on my first graduate student, Jane Tucker. Also, I had help in the laboratory from someone I came to greatly respect, Mohamed Dhalla. After some years, Tim Mosmann joined the department. We were both part of a small MRC group, that included Bhagi Singh. I also met Calliopi Havele, also an immunologist, who became my spouse.
In 1987, I moved to the Department of Microbiology and Immunology at the University of Saskatchewan. One advantage of the move was that the Department of Immunology at the University of Alberta had no microbiologists, in contrast to the Department at Saskatoon, and I really think this affects the way people think. I got a small grant shortly after arriving. This was given to new Faculty, on application, to start up a new area of investigation. I knew what to do. I had wanted to work on infection and immunity, in the mouse model of human cutaneous leishmaniasis, for some time, but regarded this as too risky an undertaking on my own MRC grant. Juthika Menon did her PhD developing the low dose vaccination strategy in this model.
We established, during the 1990s to early 2000s , a number of different systems, investigating issues relevant to preventing and treating this class of infectious diseaes. This class of diseases is defined by the ability of a strong cell-mediated response, in contrast to antibody to contain the pathogen, and includes the leishmaniases, tuberculosis and AIDS. The ability to develop new areas of investigation was only possible because of support in the laboratory from Goujian Wei, whose efforts, under my guidance, have opened up one new experimental system after another. This has allowed me to provide guidance to more graduate students. In addition, Juthika and I started working on human disease, mainly on tuberculosis and on visceral leishmaniasis. We developed collaborative research in Ethiopia. The Saskatchewan Lung Association, formerly the Anti-Tuberculosis League, has supported our tuberculosis research in a particularly helpful way. We have studied immunity to intracellular pathogens that cause chronic disease, such as tuberculosis and the leishmaniases, in mouse models. The way these studies appear to shed light on human disease, and in some cases appear to dovetail with our human studies, is a bit overwhelming. I hope I can contribute to and witness some real progress in prevention and treatment of these devastating tropical diseases. I felt and feel we understand enough about how the immune response is regulated that we are probably able to develop effective vaccination against TB and AIDS, and treat early stages of AIDS. It has been an incredible to go into new fields and obtain clear and striking results consistent with one’s expectations However, my hope is somewhat dented by my losing all research funding from national granting agencies in the field of infection and immunity despite my greatest efforts.
I have had a strong interest in tumor immunology since the late 1960s. When funding for our research on immunity to infections became problematical, I tried to get money for doing studies on immunity against tumors. I had a simple hypothesis as to why the immune system often fails against cancer. We initiated these studies on tumor immunology in the early part of the 2000s. Duane Hamilton was a graduate student who asked me whether he could take the studies over after some initial and interesting findings had been made by Guojian Wei. Duane’s findings were to me and to him very striking and were expected on our hypothesis. They seem to open up new ways of guiding immunotherapy should our mouse studies reflect parallel situations to those that occur in human cancer patients. However, I have found it problematical to obtain funding for this research.
I had a heart attack in August 2006, when Calliopi Havele, my wife, and I were visiting our daughter’s family and our first grandchild in Toronto. This attack led to emergency bypass surgery. I was 63. I had two or three days in intensive care, where the situation I faced, and perhaps the morphine I was given, made me reflect on my past, and how I might still achieve unfulfilled aspirations that had formed in my youth. These aspirations were to interact and communicate with my fellow human beings about how one could understand and become close to or part of nature. I had envisaged that these aspirations could be realised through doing scientific research collectively. However, I had found that doing science, the way it is practised today, is overall a lonely process and seemed not to be a way of realising my dreams. A solution seemed obvious. I had always felt that basic ideas were communicable to most of my fellow human beings. I had never tried to ride scientific bandwagons. It seemed to me that I might have a fresh start of realizing my aspirations by writing a book for the non-specialist on what scientific culture meant to me and illustrating this by the story of my involvement in immunology. I started writing this book within a couple of days of leaving hospital. It is now three quarters complete. At the same time, I have modest funds that allow me to have two or three graduate students. We talk science almost every day and I am particularly happy with our research efforts.
近期论文
查看导师最新文章
（温馨提示：请注意重名现象，建议点开原文通过作者单位确认）
A1. Bretscher, P.A. and M. Cohn. 1968. Minimal Model for the Mechanism of Antibody Induction and Paralysis by Antigen. Nature. 220:444-8. Synopsis: It was proposed that lymphocyte activation by an antigen A requires the antigen-mediated cooperation between the resting lymphocyte to be activated and other A-specific lymphocytes, and that the interaction of the resting lymphocyte with A alone results in inactivation (paralysis in then current terms). It was argued that these proposals incorporate a mechanism by which the immune system can respond to foreign antigens and normally remain unresponsive or “tolerant” towards self antigens, see A2 below under Explanation ofSelf-Nonself Discrimination.
A2. Bretscher, P.A. and M. Cohn. 1970. A Theory of Self-Nonself Discrimination. Science. 169:1042-49.Synopsis: Develops the grounds for the two signal model of lymphocyte activation. This model represents a more correct formulation of the potentially valid ideas of the 1968 paper (A1 above). It is proposed that an interaction of antigen with a resting lymphocyte, through its antigen-specific receptors, leads to the generation of signal 1, which, when generated alone, leads in time to the inactivation of the lymphocyte, rendering it refractory to activation.
A3. Bretscher, P.A. 1972. The Control of Humoral and Associative Antibody Synthesis. In G. Moller (ed.), Lymphocyte Activation by Mitogens, Transplantation Reviews, 11:217-267. Synopsis: A general analysis of possible models of lymphocyte activation/inactivation in the context of achieving self-nonself discrimination is outlined. This conceptual analysis, together with references to pertinent observations, favours the two signal model of lymphocyte activation. The antigen-recognition molecule made by T helper cells is here referred to not as the T cell receptor (TcR), as in current usage, or as “carrier antibody” (as in A2), but as “associative antibody”. The paper also includes a simple quantitative formulation of the two signal model, i.e. considers how the generation of signal 1 and signal 2 might depend on a variety of variables, such as antigen dose and the number/density of specific helper T cells. This quantitative formulation was invaluable in developing A Theory of Immune Class Regulation, see B1 below.
A4. Bretscher, P.A. 1975. The Two Signal Model for B Cell Induction. In G. Moller (ed.), Concepts of B Lymphocyte Activation, Transplantation Reviews, 23:37-48.This volume represents the then current views of different investigators as to the requirements for B cell activation. I attempt to critically examine the quality of the evidence, then available, for the two signal model, as it applies to B cells.
A5. Tucker, M.J. and P.A. Bretscher. 1982. The T Cells Cooperating in the Induction of Delayed-type Hypersensitivity act via the Linked Recognition of Antigenic Determinants. Journal of Experimental Medicine. 155:1037-49.
Synopsis: Tests of a critical prediction of the two signal model of lymphocyte activation as it pertains to T cells. This paper shows that the generation of (CD4+) T cells, able to mediate DTH and specific for an antigen A, could be helped by (CD4+) T cells specific for a non-crossreacting antigen B in the presence of the conjugate A-B, but not when A and B are present but unconjugated. This form of recognition between interacting lymphocytes is referred to as recognition of linked epitopes.
A6. Bretscher, P.A. 1986. The Primary Induction of Helper T Cells Involves the Linked Recognition of Antigenic Determinants. Journal of Immunology. 137:2726-2733.
Synopsis: This paper demonstrates the existence of a cascade of T cell/T cell interactions in the generation of helper T cells. Each step in the cascade involves the antigen-mediated interaction of T cells with other T cells. Each of these interactions occurs via the recognition of linked epitopes by the interacting T cells. See synopsis of A5 above for an operational definition of recognition of linked epitopes, and A8 below for a possible mechanism by which such an operational recognition could be realised.
A7. Bretscher. P.A. 1992. The Two-signal Model of Lymphocyte Activation Twenty-one Years Later. Immunology Today 13:74-76.
Synopsis: Much evidence supports the two signal model, in that CD4 T helper cells are required to facilitate the antigen-dependent activation of most B cells and at least some CD8 T cells. In the absence of such CD4 T helper cells, antigen can inactivate the B cells and CD8 T cells, via the generation of signal 1 alone. These findings are consistent with the envisaged role of CD4 T helper cells as the guardian over the activation/ inactivation of other lymphocytes. The requirements for the activation/inactivation of CD4 T helper cells thus seems ever more central.
Evidence is reviewed showing that the activation of CD4 T cells most probably requires two signals. Signal 1 is generated when the T cell receptor (TcR) binds a peptide/MHC class II molecule complex on the antigen presenting cell (APC). The CD4 T cell is operationally inactivated when this signal is generated alone. Evidence supports the suggestion that CD4 T cell activation requires the T cell to receive a second signal, generated when a receptor on its surface binds to a “costimulatory molecule” on the APC. Both the costimulatory molecule and the T cell receptor recognising it are envisaged to be constitutively present on mature APC and on CD4 T cells respectively. According to some other models, the costimulatory model on the APC is inducible under some circumstances (discussed under A8 and A9). This model is therefore conveniently referred to as the Constitutive Model, see Figure 2.
京公网安备 11010802027423号