Recent talk given to Weill-Cornell’s Clinical & Translational Science Center (CTSC) covering my life and career to date, as well as my new book, The Interleukin Revolution.
You can grab your own copy by clicking this link…
https://tinyurl.com/TheInterleukinRevolution
Further reading:
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Okay good afternoon everyone and Welcome to our continuing ctsc series lecture series and today it is my great pleasure to introduce Dr Kendall Smith uh a colleague of ours at the ctsc a great mentor to our students and a friend Dr Smith earned his degree at Dennison
University he graduated suum lad from uh Ohio State and then was recruited to Dartmouth after his fellowships where he rose from assistant professor to full Professor after that we recruited him to while Cornell which was Cornell Medical School at that time as professor of medicine and Immunology and he remained with us until
His retirement and he’s now professor emeritus at Cornell and still works with the ctsc uh Kendall has embarked on a Gene uh not Gene yet but uh focused on cancer uh immunology and consequently made seminal discoveries and transformed the field of Immunology he is a scientist a physician
An educator and a writer and his revolutionary Discovery involved classifying and understanding the function of interlukin 2 interlukin 2 has the ability to to manipulate the growth and proliferation of te lymphocytes he demonstrated how this hormone receptor system regulates the immune response and further research revealed how it determines the All or
Nothing molecular responses and regulates issues via negative feedback loops this led to the understanding of mutations in genes encoding the molecules of the immature of the of the immune system system and are responsible for leukemias lymphomas congen congenital micro imuno deficiencies and autoimmune disorders and this also led to the
Development of new immunoinhibitory therapies for organ transplants autoimmune disorders allergies and Autos stimulatory therapies for cancer Kendall has published over 237 articles Arles and has authored three books and his latest book is the title of this talk the interlan revolution which was published this year and it highlights his early years
In this field and so it is with great enthusiasm that we look forward to your lecture Kendall you’re on my introduction more I want to thank you Julian um for such a nice introduction and it’s a uh really a pleasure to be back at Cornell even
Though I’m not at Cornell at the present time um I wanted to take this opportunity that Julianne offered to me to to describe my new book which is a um um let me put this let gonna get rid of that it’s a memoir that I’ve written about the first 20 years of my
Um career that took place evolved all at Dartmouth medical school in New Hampshire a little bit before that as well I just preface my remarks by saying that the cover of this book on the left side of your screen is one one of my self-portraits and all of the pictures
In the book are my paintings um I took up that about 15 years ago when I thought I was going to after retire and so I’ve been doing this for I’ve got at least 100 paintings um accumulated at this stage of the game um I wanted to I wanted to tell you
That this um Memoir was stimulated by um a thought that I had that I really needed to reach out to the new to the the new generation of people coming up um and there’s a really nice quote from one of the Darwin uh books that I read Darwin was was um complaining to
His mentor that none of his buddies liked his theories and um The MENTOR said Charles don’t try to convince your peers the next generation will believe believe you and so that’s what that’s what this is all about the Memoir is meant for the general population and especially those
People who have yet to decide to come into science um and I wanted to try to make them understand what a wonderful thing it is to do science because after all science is I think the most creative thing you can possibly do uh because you’re trying to create new
Knowledge and so this is a summary and the in this Slide the introduction is also a summary of what it’s all about um and in four or five bullet points here Incan is a name we made up late one night in the bar after a meeting to describe what we were talking about
Amongst one another there weren’t too many of us at the time just half a dozen and we came up with this inter Lucan inter meaning between and Lucan meaning lucaites and the idea is that the these These are molecules that are hormones and a hormone is this kind of a molecule
That binds to receptors and provokes a response that’s really the endocrinological um definition of what a hormone really is and now there’s more than 40 inter lucans that have been discovered in the last 40 odd years since 1980 what these molecules do is that they regulate the immune
Response and this U presentation is a story of the beginnings of our um understanding of this whole complex system that regulates immunity um so I started on this um for way back when I was in junior high school and I decided I was going to be a doctor and I
Wanted to be a doctor because when I was a caddy at the country club in my neighborhood on the weekends the doctors would come and the doctors would come and bring their wives and they’d have these mixed forom and I looked and I watched these people interact and so forth and I
Said to myself so here they are they both have they have two Cadillacs one for her one for him they belong to the country club and the doctors had the best looking wives so I said I’m going to want to be one of those things one of
Those guys and so I studied really hard and and ultimately went to medical school um and at those days the the the school was divided into the first two years which was class work from 8 to five and the second two years was in the hospital work going on different
Rotations and learning sort of the The Craft um and the good news was is that in um 1965 after my first year I was awarded the most outstanding first year student award and the other thing the good thing that happened in 1965 was I then married my high school girlfriend Lyn um
And here we are leaving the reception leaving the the church on our way to the reception um and so I was really happy because I at least I got I got a good-look wife at this stage of the game now the the clinical years in my
Third year I happen to have when I was on medicine I had a very unusual patient come in to in extremist into the emergency room um and it turns out that this person had only four grams of hemoglobin and um almost died in the emergency room
But we were able to get him up to the floor and get samples from them transfuse them and so forth and ultimately um we admitted him to The Clinical Research Unit and for three months and studied this person because it turns out that he had a very unusual pancreatic ins sufficiency that caused
The vitamin B12 deficiency anemia and that was my first clinical uh report that that came out in the archives of uh internal medicine and as a consequence of that whole process I I got to be to meet n Dr Norton greenberger who had just been recruited
To come to Ohio State from Mass General and he was the head of GI and at one time I was talking to him in the lab and he he said well what kind of a doctor where you what kind of a specialist are you going to go into and I said well I
Had no idea what do you think and he said if I were you I’d go into Immunology that’s where it’s going to be happening in the next two decades and I said to myself H well that’s interesting coming from the head of GI but I and I
Didn’t forget that advice the next thing that happened was I was walking across the quad one day and I ran into a fourthe student who um asked asked me what where I was going to he was all excited about applying for internships and he asked me where I was
Going to go and I I said I don’t even know what kind of a doctor I want to be let alone where I want to go for my internship but I know where I don’t want to go and that’s Vietnam and so he said well there’s only one person here at the
Ohio state that can get you close to getting into the you you should go to the NIH and I said what’s the NIH and he in educated me that it was the National Institute of Health and he said there’s only one person in Ohio state that can get you that’s and
That’s Chuck mingle and he had just been uh recruited from dup to be the head of the hon division so he said if you go talk to Dingle and tell him don’t tell him you don’t know what you want to do tell him you want to be an academic medicine you
Want to get a really good internship and you want to go to the NIH so that’s what I did and and um I went to talk to mangle and he said so Smith what do you want to do do you want to do rectals in Georgia or you want to
Go to the NIH and do research and so that’s that was a no-brainer he said but if you’re going to do that you’re going to have to spend your entire fourth year in in the in my laboratory and I was shocked at that and I said to myself I
Said to him um what about clinical training i’ I’ve only had a few I only have the third year and he said that’s he said it’ll be a piece of cake six six the first six weeks will be difficult but then you’ll get the hang of it and that was true
Actually so then in 1968 I graduated from medical school and it turns out the good news was is that I graduated sumacum laah with highest honors and there were only three people in my class of 150 who graduated sumuk Kum Ladi and one of the other guys was
My very best friend from from high school days Jeffrey wardwell and here’s this painting is a picture of Jeffrey in the glasses and me standing next to him and you know since there were only three people we we all wanted to know the three of us wanted to know who was first
Second or third and they wouldn’t tell us that but of course jeffre knew who was going to who was number one and I also knew who was going to be number one then what happened was I went to uh Yale new hmon hospital um for 2 years 68
To 70 and then on to the NCI uh from 1970 to 72 so the first year at the NCI um I I took care of um chemotherapy patients and they were all on trials and the second year then we I joined a lab and I joined a lab that was studying um Immunology
Now by default I’d already become a a hematologist and so forth and I thought to myself well and and at this point in time I was trying to decide what to do with my life and so forth and I thought well maybe I can study leukemia if I’m a
Hematologist but then the more I studied it and and thought about it and I I I realized that nobody had a clue what was wrong with a cancer cell and um I figured that I concluded that if in order to understand cancer we going to have to understand normal cells
And what makes them decide to divide so in the laboratory I went into they were already culturing lymphocytes it was a technique that evolved in the last 10 years from 1960 and I started to study um immunological memory to viruses by uh culturing lymphocytes in the test tube
With vaccines from Ms measles or rebella and it was able to show essentially that if there was a prior history of a vaccination Andor infection that you could detect the response by a proliferation of the lymphocytes funny thing was is that it took him about a week to have a peak
Prolifer response and I always thought that that was a little bit strange it took so long and it turns out that that that observation was going to take me for the rest of my career to to really understand properly now my labmate uh my benchmate
At in the lab was Leonard Chess who had come from Colombia and he was interested he was studying um adents immunological adents any substance that would boost up the immune response and of course a lot there was a lot of interest in in adant because then
They you could um uh use them for vaccinations and other kinds of things and so he was studying double stranded polyal nucleotides polyic and poly auau and he’d already shown that these um these substances would markedly potentiate the prery responses of um lymphocytes in vitro and because there were lymphocytes
In there and also macrophases we wondered whether or not which cell was really being influenced by these agitant and so um I separated the macras from the lymphocytes and then we treated them with the the substances and then put them back together again and to make a
Long story short the effect was on the macras and that turned out to be important for me as I moved Along on this whole Saga so after I left the NCI I applied for posts across the country and was accepted to a post-doctoral fellowship at Dartmouth medical school in New Hampshire hover New
Hampshire and um matriculated there in 1972 and on July 1 I went to um talk to my new mentor and presented myself and he said well there’s good news and there’s bad news and I saidwell give me the bad news first and he said well my my fundamental research grant
That I had was not refunded so there’s no money for basic research and I said okay so what’s the good news and he said well I still have your salary on a clinical study I’m doing and what we’re doing is that we’re using polyic as an interferon inducer and I’m
Doing phase one trials and so what happened subsequently was is that I was plugged into these phase one polyic trials and we I administered the polyic to the patients and followed them thereafter with blood draws and and clinically as well and it turns out there was a characteristic fever curve
That would was induced by the polyic with a Peak at about 18 hours after the administration which was a pretty brisk intervenience and fusion and simultaneously um looking at the plasma interferon levels in these patients they exact exactly coincided with the fever curve and also at the same time we were
Able to show uh that the there was decreased lymphoid proliferation at the same time that the interferon was was very high so that stimulated me to then to add interfer on to uh look to see what happened to the lymy proliferation in vitro and was able to show that that
Also decreased the lymy proliferation now the thing about this was is that there was hopes back in the early 70s that that interferon could be used as an anti-cancer agent but this these kinds of data uh threw a monkey wrench into that because it looks like it was inhibiting the immune system as
Well well the first thing I did when I got to to Dartmouth was I and I found out there was no money for basic researches I sat right down and wrote letters all over the world to see if I could get another post do as soon as
Possible and it turns out that I was able to get another postto the very next year in 1973 with Professor George mate from The Institute of cancerology and Imogen in Paris now George mate and this is a portrait that that I did of him when he
Was at his Heights he was around 50 something at that time and of course I was around 30 something um he had already hit the big time in his career at this stage because in in 1959 just as he was coming off his post-doctoral Fellowship um they he did the first bone
Marrow transplant uh in a in uh humans and described gbh disease as well as G GB graph versus leukemia dis U effects and 10 years later in 1969 he had a paper in the Lan where he described a new immunotherapy for leukemia acute lymphoblastic leukemia that consisted of
BCG and pools of allergenic leukemia cells now the BCG is stands for basilis Cal Guin and uh it is a live TB vaccine and had been known for years to be an immunological adant among other also other bacterial things as well as the poly robobin nucleotides and so forth
That he’s stuck on he stuck with BCG and he then pulled uh leukemia cells from Frozen from other patients with the hopes and it was essentially a hope at that time that there were leukemia antigens on those cells and so that he called that specific immunotherapy whereas the BCG was
Non-specific immunotherapy and he was able to show a significant prolongation of remission after chemotherapy in these all patients and that qu caused quite a stir in the whole um uh oncology community at that stage the and of course everyone else was really uh were budding uh chemotherapist
And so there was it was very controversial whether this immunotherapy by this flamboyan Frenchman he he reminded me a lot of um um Maurice chavalier because he had a little touch of a French accent and he was very Charming now I couldn’t find uh any laboratory in the at the
ICI that would allow me to look at um fundamental aspects of of how adents um stimulated the immune response but I felt that that was probably the most important question at that time and it turns out that and so I I was sort of floating for a while but
Then I met another American to Frederickson who was on sabatical from the University of Connecticut and he was interested he was already a world world class Mouse H hematopathologist and so we started having coffee together in the morning and then that led to lunches and so forth and we shared
Stories and he um educated me about arthr leukemia and RNA tumor viruses causing arth leukemia and arthr potin or EO so we decided to put together an invitro assay for arthr potin previously that had only been done assays for arthop poan had been done in Vivo in
Mice and they were very time consuming and not very quantitative and and they weren’t very good assays and so we put together a a microtiter assay that only required culture overnight using Mouse fetal liver cells taking 10 days of gestation when when primarily the liver the fetal
Liver is um almost entirely Red Bread cell red blood cell precursors once we had that assay that assay turns out it’s important for what happens next in my life once we had that aset we we got together with two renowned interferon um investigators the jacn and um jacan and Edward
Deer who were studying interferon and we used some of their very purified interferent preparations and we were able to show that not only lymphocytes were inhibited and cancer cells were inhibited but the red blood cells were inhibited well um mat it turns out was also having money problems and so I
Decided after only a year there and I intended to stay longer that I should probably come back to Hanover and so which we did um in 1974 but that’s foray that one year in Paris with Mee was um Revolution AR to our to my family and to
Our family we had two little boys at the time three and four years old this is a picture of my wife when she got back to Hanover she decided uh to open a French cooking school the Parisian kitchen and this is a uh this was a uh a photo of
Her in the process of teaching her class she did that for six years in Handover and really taught everybody in the whole Community um that wanted to learn about French cooking she she’s the one that taught them now I after three years as a postto I decided um that I should become an
Assistant professor so I negotiated that with my mentor there and it turns out the Dartmouth um was was a little bit unusual place to for us to land but because the the Dartmouth College motto is way up there in the woods in in New Hampshire the college motto is Vox clus
In deserto which means a voice crying in the wilderness because there were no other immunologists there my mentor was really not an immunologist but rather he was established as a hematologist so the very first thing I did when we when we got back from Paris
Was as I sat down and I wrote my own grants um and I I wrote two grants one had to do with the purifying arthri poetin and the other one had to do with tumor immunity I wanted to see whether or not I could develop the system so
That I could generate cytotoxic T lymphocytes that would kill cancer cells now it turns out the arith poin Grant was not funed because they didn’t like my really slick initro assay um and you know science especially science funded by by research grants they say it’s it’s sort of like
Bid game hunting you eat what you kill and so tumor Immunology became my discipline rather than um red blood cells and and aru poan so the very first thing we did was we set up a system that I had started over in in Paris of of trying to activate uh te-
Cells in vitro through mixed tumor lymphoid cultures or mtc’s and what we did was it was a takeoff on mat’s allergenic uh pooled um leukemia cells that he was um injecting their patients with I just wanted to do it using normal lymph normal te- cells in
Vro and and with with the hope that if we can find allogeneic leukemia cells to activate them perhaps they might kill um syic leukemia specific cells and they did and so we we were able to generate and generate really good data that was published in the exper Journal of experimental medicine back in
Um um 1977 that was one of the first papers out of the lab that that we set up um and it turns out that the the grant that I was funded on for tumor Immunology plus uh Ross’s Grant the my mentors Grant at at Dartmouth was enough to be able to
Generate um um a bigger laboratory so I hired um two or three technicians as well as a new graduate student and a postto from Tor frederickson’s lab and together we all worked on this whole system of the mtc’s and it turns out that another lab Doris Morgan and Frank retti and Bob
Gallow down at the NCI had had stumbled on a situation where if they used uh conditioned medium from activated lymphocytes they could get cells to grow long term in this in this medium but they didn’t look like they were trying to grow leukemia cells they didn’t look
Like leukemia cells but they looked like tea cells and so we started to collaborate because they wanted to know whether these cells could make something like interferon and since we had interferon assays that was sort of a a natural turns out um that I wanted to
Find out whether or not you could we could generate these uh leukemia specific saot toxic tea cells but we couldn’t grow them more than a few days and so it was what we did was we put them in this condition medium and it turns out that we were
Able to get long-term cultures of cytotoxic t-lymphoid lines we sent that off to Nature because we we thought it was Earth shaking we not only could we get antigen specific cells to to be maintained in in vitro but they would also continue to kill over
Months and um so we sent it off to Nature and we got it back in the very next week which which I knew they had not never sent it out for review and so after I got over my my anchor I decided that they just didn’t understand you know and I needed to
Educate them a little bit so I sat down and I wrote them a one-page letter and made an argument as succinctly as possible as to why they should send this out for review and they did send it out for review and they the reviewers agreed with me and they accepted that paper and
It was published on July 14th in 1977 and I figured I figured that was a good omen because as you know July 14th is bastile day and was the beginning of the French Revolution and I figured this was going to be a revolution in te- cells and it turns out today certainly
Was well the first thing we did was we needed to we needed to find out how much of this um we we assumed that there was some sort of a growth factor in this medium and we we coined the term t- cell growth factor or tcgf and the assay that we generated was
Just like the EPO assay that that we’ already tgan had already done back in um um in Paris so once we had those two things the long-term T Cell lines and the assay so that we could generate a lot of um really good conditioned medium we tried
To clone these cells and which um derive them which would mean that we would were able to derive cells from a single cell and it turns out that those experiments worked like a charm very rapidly as well and we reported that in January of 1979 and this this was really
A Eureka moment because because this this is what enabled us to transition from working on cells to working on the molecules that were making the cells behave whichever way they they wanted that was number one number two this using monoclonal cells and we could show that they were clones and so forth
That proved mon Burnett’s clonal selection theory for te- cells it had already been shown that that individual uh plasma plasmacytoma cells would only have one antibody and that so that was that was considered a proof of Burnett’s clonal selection Theory but it meant was is that what the in in the clonal selection
Theory what antigen does is select the Clones that are going to be reactive because they have a T Cell receptor that responds to that but it’s the tcgf that drives the clonal expansion and that was that was a revelation really that’s that’s the kind of thought
Pattern that says okay this is the key to therapy because if you want to immunosuppress it’s obvious what you do is you decrease the production action of this growth factor or if you want to stimulate the immune response you increase the production or action uh of the factor
So the next that set the stage for the understanding that interl what interlukin are and how they work in the in the body is that they’re hormones and it turns out you know it’s interesting how people come into your life just when they when you need them
And Allan monk was a professor of of physiology at darmouth who lab was just upstairs on the fourth floor we were on the third and as soon as I got back from from Paris I started I met him and we started talking about things and he had described the first um assay for
Glucocorticoid receptors in 1968 and he I told him about the glucocorticoid effects on leukemia cells as well as on on normal cells and he said well what we should do is we should look for receptors in human lymph asde he’d done all of his experiments on rat
Thyoides and so so we did a series of experiments that we published in 1979 that that showed unequivocally that glucocorticoids suppressed the tcgf production to 100% And they also decreased tcgf action uh to a certain extent and this was the really the first molecular uh explanation for that accounted for the glucocorticoid effects
On on lymphocytes and it also led us to the the sort of the obvious um speculation that there must be tcgf receptors so the very next thing that happened was that in that meeting that I described earlier on when we we came up with the interlan nomenclature that that arose out of
Experiments that we did when we started looking at other factors lymy activating Factor was a was a a uh factor that had been described to be to be stimulate proliferation of lymphocytes way back in 1972 and so the the acronym for that is laugh and when we put that into our
Tcgfsa it didn’t have any activity whatsoever that was when we started saying it in the lab that laugh was a joke but we went on and we did further experiments and we were able to show that what laugh did do it did enhance proliferation of T lymphocytes but it
Did so by causing the te- cells to make more t- cell growth factor so because the laugh seemed to precede uh interlan 2 or precede tcgf in the whole process it came away with the name of interlan one and t- cell growth factor became interlan two and then later on after we
Had the problem with this was is that we hadn’t pure ified either one of these molecules yet presumed molecules but when we finally did we purified interlukin two a year before those the other guys got look one and I went home and told my my kids who were about 10 or
11 at this stage of the game that um I discovered the first inter Lucan molecule and they said yeah sure D that’s why it’s number two so it was clear that what we needed to do next was develop is a look for the I2 for the tcgf or I2
Receptor we did a series of experiments that we published in uh 1981 where we showed essentially that the I2 receptor had all of the characteristics of a classic hormone receptor one of which and one of the most important was it had a very high Affinity of interaction of the the Lian
And the receptor the equilibrium dissociation constant uh was 10 the minus 11th moles per liter or 10 pomar now most antibodies are in the range of 10 Theus 6 to 10 10 Theus 9 so you can see what’s going on here this is really a high Affinity which means that you don’t need
Very much of the hormone you need low concentrations of the hormone will drive the response Now by this time we’ve done a series of biochemical experiments and we knew that the molecular size of this uh of the protein was a small protein about 15 a half thousand Daltons and together with a avagadro’s
Constant which is the number of molecules in a mole 6.02 * 10 23rd molecules a lot of molecules in a mole we can use all those things and we can calculate the protein concentration in in the number of grams or turns out it was p ofrs in a
Ler and we found them for the first time that we were going to need at least a thousand liters to purify just one milligram of I2 protein to homogeneity and that was impossible we we couldn’t generate a th000 liters and even if we had we couldn’t we didn’t have the means to purify
That now the next thing that happened though was is that leukemia cell line was found by others that made aund times as much interlan Tu as we could get from normal tea cells now of course you do the math all we needed then were 10 liters rather than a thousand liters in
Order to purify interl homogeneity and we went on then and used biochemical methods to purify enough lcan 2 to make to immunize mice and make monoclonal antibodies which then we used to purify huge quantities of of I2 now simultaneously while we were doing those experiments a group from the
MCI Tom wolman’s group um reported about uh a monoc antibody that they had made um and it was made by tekashi uchiyama who was a postdoc from Kyoto in Tom’s lab that only reacted with activated te- cells to the surface of activated te- cells you could you would not bind to resting
Lymphocytes and then we went on in collaborative experiments to show that this would block I2 binding as well as block I2 promoted proliferation so this was really the first inkling of a cell surface protein that could be the interlan 2 receptor now just at this the same time
A new postto came into the lab Daren Cantrell who was from the University of Nottingham in the UK and she had done her whole uh graduate years um using the floyer to study natural killer cells and so when she came into the lab we could use this new monoclone antibody that we had
Through through the collaboration with waldman’s group and we could go on the flow cytometer and for the first time we could look at the number of receptor sites on individual cells and what to boil down a whole series of experiments we found that the the cells with the highest density of
Receptors grew faster than cells with lower density of receptors and this led then to The Logical speculation that there was a critical number of receptors that had to be occupied by the ligan before you got to an all or none or a quantel response of the decision to replicate
DNA and divide of course when you think about it you don’t want to mess that up that mechanism it’s either it’s got to it’s got to work and it has to work all or none and so the other thing about this um finding was is that we went back
Through the literature and going back to 1930 all cells that have been studied in terms of their growth characteristics behave the same way from bacteria to UK carots yeast as well as Aven and all mamalian cells so there was a very tight control over this decision to
Divide which led us to speculate then if you lose that that tight control uh that could lead to cancer and it also could lead to autoimmunity so he published that uh in science it’s a major article in 1984 and Beyond a doubt um this is the best paper
That ever came out of our laboratory so right Sim simultaneously everything was happening at once um Ellis Reinhardt who became a good friend was a young investigator down in Boston at Dana Farber cancer center and he did a series of experiments um and he really discovered the t- cell receptor and in
19882 they reported a a series of antigen specific both CD4 positive and cd8 positive human uh cytotoxic tmpy clones and it’s very important that they were human because he could use those human te- cell clones to immunize mice and he made monoclonal antibodies then that would react to the human t- cell
Clones and they were clone specific and he was able to then use them and do biochemical experiments and very next year 1983 he had a series of exper of of papers that that nailed the whole deal it was a there was a 90 KD heterodimer
On the surf on the surface of te- cells that were identified by these antibodies the very next year Steve Hedrick and and Mark Davis um cloned a cdna uh that was re that was um coding for one of the chains the beta chain of the t- Cel receptor and so Ellis and I
Decid I’m actually I I thought first time I met Ellis and saw him at a meeting and present I said to myself I was sitting in the audience after I’d already spoken I said to myself this guy’s really smart he’s he’s almost as smart as me I better I better not
Compete with him I think I’ll make him my friend well that’s what I did and so we got together and he had a corner on all the reagents both cellular and molecular re for the t- cell receptor and I had the same in the I2 re I2 story
So we did a series of experiments um that we published in 1984 that showed that the t- cell receptor triggers interlan 2 and interlan 2 receptor expression whereas the i 2 triggers tsel proliferation and we and we pinned that down um the t- cell receptor people
There a whole bunch of them they didn’t really like that story all that much but for me I F I fig this is the key to immune regulation on the one hand and also why why vaccin how vaccination works so that what brings us to 1983
And this slide shows a a picture of U my wife’s restaurant Cafe La fres that that she started in 1983 and had for 10 years to ’93 and she what she she found was an Old Colonial House that was only one block from the center of
Town um from 1826 that she she bought and and renovated into a French restaurant and the picture on the right there is the dining room manager and her husband um Roger who is the was the chef to and my wife then um she was the chef
For the first five years and then took over the both the front of the house in the back of the house and you can see she’s still beautiful then she’s around 40 something at this stage now this was very very important um and the reason I
Put it in the book and also in in this part of the slide or the talk is because because you know there’s all these pressures on a on a marriage and and with children and with the career and so forth it it as they say it ain’t
Easy but uh and what I’ve decided after um being married to my high school sweetheart through our entire lives now that you have to be you you can’t have you have to have a duet going on you can’t have a lead singer in a backup that’s not going to lead to a a
Long-term marriage um and so this restaurant opening the restaurant was was instrumental in solidifying our marriage and making sure it didn’t break up because now she’s just as busy if not busier than me that was the good thing um I used to ride my bicycle and stop at the
Restaurant on it was halfway between our house and the lab for a cup of espresso and then in the Quant in the morning and we talk over our day and so so forth so from the mid to to to the end of the 80s we move we moved then again
Following our noses really we need we knew that we really needed to understand the structure of interlan 2 and we needed to understand the structure of in 2 receptor and that would then allow us to see how the the structures led to the activities um uh um of this whole system
And so in our laboratory kesy tesara who is a postdoc from Kyoto Jinger Yo La he did a series of experiments over over a few years that um pinned down the fact that the the um original I2 receptor which came to be called the alpha chain was not the total
Story that there was at least a second chain involved that was called some we called the beta chain and at the same time there was a grandad student in the lab a Dartmouth grad student qu May Wong who from Taiwan and she she did a series
Of very um uh very nice experiments that were helped by Alan for example and she did both kinetic binding experiments with our binding essay a receptor essay as well as equilibrium binding experiments and she was able to show that what happened was in order to create the very high Affinity of the
Receptor is that the alpha chain would bind a to very very fast so fast it was difficult to measure it and then once it got on to the alpha chain the beta chain glommed on and and held on to the to the Lian so it was fast on and slow off and
That’s how you create high affinity and um the cell biologist asked me to write AEV RW article on the I2 I2 receptor story about this time and I was very proud of that because I think it was the very first time that this kind of of structure activity relationship uh
Kind of thing had been realized molecularly and while all this was going on um I had to reapply for refund my grant and um the uh the grant Review Committee decided that to be to be fair I I wrote a very complicated Grant because there were so
Many things I think I felt that we needed to do but they didn’t want to fund it right away they they decided they were going to do a site visit now they they would always site visit program project grants but they didn’t site visit individual grants and so I
Thought this was very strange so they came up to Dartmouth and we um we gave them a a resounding uh presentation I thought everybody contributed keski tesar way may Wan and so forth um and we uh we walked away with the money that was the good thing but but it caused a
Lot of Anguish I think from bio for all of us so the lesson there for the next generation is you can’t give up if you think you’re right you just hold until for dear life like a pitbull so by this time by the mid to end of the 80s we had
We had we needed to go further we had we needed to get inside the cell and as we did that over the next four or five years it led us to a fork in the road so in 1986 we published a paper in science because we discovered the first uh
Interl looking two specific induced Gene which was an Ana Gene CID U and on the basis of that then we got to we got together with art Pare who taught us new cloning methods to look for only is to induced Genes and Carol beling was a grad student from Reed College uh where she had studied um amphibian you looking to and she came to the lab and and did a series of experiments for her whole entire graduate u career um cloning using art par method sakon sakon response
Gen and that led us then it was clear that there were a whole bunch of things we could do with signal transduction looking at the biochemistry of the first seconds and minutes and then hours after the signal was being transmitted inside the cell and the
Other end of things would be the the the gene the genes that were activated by this signal transduction so that and that led us to I had to make another decision in this whole thing I knew many people were working already working on the signal transduction but there
Weren’t very many people working on the molecular genetics and so that’s what we should do now um all this time we were dealing with these very fundamental is fundamental issues inan 2 immunotherapy came into being with 1985 Steph Rosenberg who was the head of the surgery branch of the NCI uh called a
Press conference where he said that if he used Incan 2 for cancer patients that he could cause almost a 50% response rate in Pati patients with melanoma and reell carcoma hello hello hendle we can hear you I I think that must just be background noise oh
Okay so um the the thing about this this I decided this I was not going to get involved with this whole thing because of the fact that I didn’t understand why he used such very high he used very high doses and he did an V uh push in Pion
Every eight hours for five days and he basically um pushed these all of the patients into severe septic shock and I didn’t understand why that was uh but I there was obvious that it was unacceptable cytotoxic or toxicity so at the end of the 80s I happened to
Be reading in my little study in hanor um the Journal of experimental medicine and I came across a a an article from xan Cohen’s lab from the Rockefeller where he was studying um interl two injections into humans just inter deral injections and he showed that that causes a delay type hypers
Sensitivity reaction I didn’t know that because i’ never injected it into people um and subsequently I went down and I visited them and I thought found out what they were doing and so forth and they invited me to go on a field trip to Nepal and so that was in the summertime
And in the fall in November actually we went off to Nepal and for two weeks we injected interlukin 2 at a very low dose 10 micrograms twice daily intradermally uh for two weeks into these patients and what we found was that there was no systemic toxicity that
Allaha Rosenberg as long as the dose was is low enough there was a swelling of the lymph nodes in the a in the armpit axillary adenopathy there was an accelerated and an increased um delay type hypers sensitivity to inter lugan 2 as time went on and I did Flo citometry um
Experiments and found that the natural killer cells that increased sixfold and the te- cells had increased two-fold over this two two we time period in these patients and then after we came back from Nepal um xan or um had organized so that they do skin biopsies on these patients
After two months and he found that there was a or they found that there was a fivefold decrease in lepos lepr leprosy basili and so I after all of this business I said to myself well one of the things that we could do if we wanted
To is is that we could get involved in using in look to in the clinic but I thought that you know going to Nepal to do the clinical trials was a little bit much and so um I definitely decided I didn’t want to do it in a
Leprosy um and just about the same time I got a call from Jerry Ritz who was an old friend and a good friend of Ellis reinhard’s in Boston at the Dana Farber and he said he he’s been he’s a bone transplanter and he wanted to see if he
Could boost up the immune system of his bone marrow transplant recipients because he was a lot of them were becoming infected before they had a chance for their bone marrows to recover from the transplant so I said well first we better look at the natural killer cells
Now that we know that there’s a beta chain and so forth and so we did a series of experiments and Michael caju from postto in Jerry’s lab and anona janof grad student from my lab did these experiments and we found that natural killer cells only 5% of them had the I2
Receptor Alpha chain but almost all of them had the beta chain and that’s when the light bulb went on because we said well yeah because and they would bind I to but with a hundredfold lower Affinity t- cells activated te- cells so that to me explained rosenberg’s high2
Dose toxicity if you raise it high enough then you saturate those natural killer cells and they start to make pro-inflammatory pyocin like tnf and Isle one and Isis six and then and then you have so-called what we call today cyto kind storm uh and that explains the high dose
High I2 dose toxicity well Jerry uh and and our our lab my lab and caju went on to do dose finding safety studies and cancer patients and they they hooked these people up to indwelling um intervenous lines in their in their um on their arms and he gave a to continuously for three
Months which I thought was I I never would have thought to do that but as long as he kept the dose low enough they had no toxicity that was very important to me anyway so that that’s the is the end of the book because I decided that well the new
Direction that I wanted to take the lab into in addition to looking at the molecular biology of of cell proliferation I wanted to use a a lowdose Isle to in the clinic to try to boost the immune system for HIV positive individuals so I went to the dean at
Dartmouth and I told him what I wanted to do and and he looked at me and he said he said no no no I wanted to see how we could get more patients we didn’t have any HIV positive patients up there in the Northeast Kingdom as they called
It he said we don’t want those people here those those HIV positive patients they’re they you know they’re undesirables they’re homosexuals they’re IV drug abusers and so forth and that did it for me um because the very next year I went on sabatical with an at the Rockefeller for a year and
While I was there I was recruited to come to Dartmouth or to Cornell Medical School and as they say the rest is history so um ah check out Amazon and this is my website and this is my Twitter feed and oh wait I didn’t want to do that again
One more slide so if you’re interested I’m trying to to establish a community where people can text me with this number Immunology uh I’ve made multiple videos U short ones as well as long ones um summarizing different aspects of the book so as you’re reading along you can
Just check check out a video or two and um um that should I’m hoping hoping to stimulate a lot of interest in the Next Generation and I will stop there Kendall can you hear me yes yes Julian that that was an EXC excellent uh discussion of your discoveries but most
Of all about your Innovation and your creativity and your desire to push forward no matter what and I think for the students that are on on the call it just it it brings up an important point that if you want to do something you have to understand that there will be
Highs and lows and that you have to keep going and EV eventually you will get to the goalpost and you showed that I mean in many ways that you just kept going you kept meeting interesting people you kept thinking of how you could do things and
Get it done and you got it done and you didn’t give up so you have to have a certain amount of intelligence which you have you have a certain amount of Crea creativity which you have but more than that you have to have the determination to succeed and this is a beautiful story
A really beautiful story of your life up to that point and it sort of reminds me of something very trite you know that Frank Catra song I did it my way yeah exactly that’s exactly fits what who you are you did it your way and you did it the right way
And for research that is the right way and it was fantastic research and I think everybody must have enjoyed it I I was absolutely thrilled to hear it I never did hear you speak about your research in total from the beginning so I want to thank you and congratulate you really amazing work
Amazing is there anyone else who has a question uh kall yes that was an outstanding talk it’s like a Sermon on the Mount so to speak yeah um you know in our transplant patients when we use calcin Orin Inhibitors we’re able to block il2 at least even even at the MRNA
Level they still experience allograph rejection in your hierarchy of cyto kindes after the I2 is suppressed what other cyto kindes do you think play a critical role in pushing adaptive Tel immunity well um the you know there’s there’s a little redundancy build in the system particular certain inter look War for example
Is also t-a growth factor and um as well as influencing indirectly the B cells then you know the the other thing and this has sort of come to come to um come into the four as a consequence of the pandemic the pro-inflammatory sides that are ultimately released when
You whether you stimulate macras with LPS or you stimulate NK cells with high doses of I2 for example you get the same result you get septic shock or cyto kind storm and my feeling is that the that the pandemic has brought right into the Forefront the fact that the
Symptoms of an infection are not caused by the bug they sometimes they are like deia Toxin and techos toxin but for the most part the symptoms are in inflammation and inflammation is caused by the immune system and it’s and it’s caused by the cyto in too and and you know the the
Sequence of events after interlan 2 activates say either t- cells or ink cells is that they make G interferon interferon further activates them and you get a circular circular thing going on and the Persistence of those of the inflam inflammatory symptoms like that occur in
In things like um uh you know long covid for example and chronic fatigue syndrome and um um chronic lyme disease my feeling is is that that’s then one of the things I didn’t have really time to talk about was there’s got to be negative feedback regulation in this kind of a
Hormonal system otherwise once you set it off it just keep on going and I think that in in these situations where you have Persistence of inflammatory symptoms that that’s due to the fact that you haven’t turned the system off it’s not you’ve gotten rid of the bug but you still have the
Symptoms and so in in transplants the the in inflammatory reaction I think is is another aspect that you that you know leads to Ultimate rejection of The graft and and things bad things happen I guess you know you know more about that Sudan than I
Do thank you so much it a fantastic talk thank you anyone else any further questions you know Kendall in the old days before we had cortisol measurements we used to look at the lymphocytes now for anything well it’s used for bladder cancer I think still and they they
Infuse it into the bladder and I you know I I don’t know that that they really know it works um and it’s relatively benign by comparison to you know chemotherapy and so forth um as long as the is the cancer is localized to the bladder the I guess it sets up an
Inflammatory reaction that ultimately gets rid of the cancer um uh but it it’s you know it hasn’t hasn’t been used uh in the in the clinic for for cancer therapy as far as I know and poor M even though he described the first um bone marrow transplant he didn’t win the
Nobel Prize for that they gave it to e Donal Thomas from Seattle and I’ve always felt that was a that was a very bad mistake and he should have gotten them together with Don Thomas but um because Thomas just popularized um and you know and he also Al furthered along
To hold the technology but matate was first at a time when all the chemotherapist and everybody say the guy’s crazy you know and because he was he was different and he didn’t go to Harvard so that’s bad although nowadays that’s good but uh one of the strange things is
When I was doing a fellowship short Fellowship in female reproduction Endocrinology at that time we had to pass physical and everyone had to get a BCG shot and I was injected with BCG and they said that now I would always have a positive reaction to uhpd yeah yeah but
I don’t I don’t have any reaction so I don’t know what what did you ever did you ever no no okay maybe so I as a non-reactor I don’t know what that means or they didn’t give me the right injection yeah but everyone got it and
But I did have a huge no I must have got something had huge allergic reaction my whole arm swelled up well then you did you did react to it so I yeah but I don’t react to the P I’m negative yeah PPD well you know everybody in Europe’s
Been getting it and U I think they still do I’m not sure about that but um um you know I recount what happened to mat in my book in the book so I this is another commercial the book there’s an awful lot of stuff that I left out of
This talk that’s in the book that you might enjoy and um you know the the chemotherapy people did not want to believe that this immunotherapy was worthwhile and so they repeated his experiments but they didn’t use the same BCG or if they did they didn’t use the
Same dose uh and then they left out the allergenic leukemia cells the and and so forth so that was back in the day when things were you know was before they had rigorous control Trials of anything really in cancer so interesting it’s fantastic uh story it’s amazing it’s an amazing number of
Discoveries really and what you’ve contributed it I am sure everyone listening is kind of overwhelmed by it so anyway thank you and I also thank you for still you know for those of you who work at the ctsc Kendall reviews a lot of the the research that comes through for awards
And his reviews are usually the most thorough so I I wish to thank you for that and I wish to tell you that you can’t retire from that so don’t send me a letter or an email no I have no intention of doing that I’m I’m there for the duration okay
All right you signed on okay anyone else before we say uh thank you and and uh have a nice weekends or week not only Tuesday see something in the chat room just a thank you Dr Smith okay thank you Dr Smith okay bye bye bye bye thank you thank you thank
You thank you so much bye thank you you good to see you Kendall bye yes again good to see you too take care welcome