Dr. Howard L. Weiner's 40th Anniversary Harvard Lecture

all right this is the introduction Harvard and this is our keynote speech at the day too and I was wondering how to begin how do I introduce Howard and I thought let's see what wikipedia says so I took the Wikipedia page and this is exactly what you see that he shares his birthday with Jesus Christ and we can't escape it so if you then go on to see what the public information is and clearly he was born the same day as Jesus his nationality is USA he went a Dartmouth College and he did his MD from University of Colorado Medical School and he had promised Mira that he is going to do internships in Israel after he got married and he kept his promise and his internship in Sheva Medical Center in Israel followed by his residency at the Longwood neurology program he is a faculty appointment at the Brigham when the Harvard Medical School he was a first in command of the Robert all croaky and neurology he is of the director of air CND center he set up the partner Center and he has done I got a number of prizes and just surprises just one of them and there was a chair named after him is called Samuel L washers from chair and in fact it's not named Howard Alwine our chair because as long as you're active faculty member at Harvard and you can't name chair after an active faculty member so he named this chair after his maternal grandfather Samuel L wash is strong and he chose an able person to be the first increment and that happens to be me and in his prizes and in fact I will talk about a little more is he got the NI Directors transform of the award he has set up another biotech company in autoimmune and helos he has been very prolific and he has got 685 papers published six books three movies and there's a book written about him by Susan Quinn in fact I have read it and it's called human trials but that's public information so I wanted to see how people when they know him personally how do they define Howard and in fact the ladies time actually took some of the tundra out of this by giving all these names and I took a little survey and there people think called him a neurologist they also called him an immunologist they call him a writer they define him as a filmmaker a director producer and people who know him closely they know he's a philosopher he's a scholar he's a builder in fact he likes to build nuts and bolts from bottom up actually building CND building a mess Partners Center everything I mean he just builds it meticulously which lost for a long time he is an avid golfer he is a wonderful mentor and partner and fair I'll talk about it a little more and that's what I've heard all these two days what a wonderful mentor he has been to me to David and all of you here okay he has also been a wonderful partner he is very generous in fact every time I go out for lunch at dinner with him actually he never lets me pay and I welcome it every time all right and and this is the best way to define him he is in mansion and I told my brother you know my brother is much smarter than me and he's really genius level and I said you know I have this friend Kali he does all these things his name is hole winner and he said to me you must be kidding he must have a twin brother with the same name and that's how we can accomplish all these things okay he has got this incredible ability to form partnerships in fact I have seen him over the years forming partnerships even with the people it's very difficult to work with he set up the partnership with Dennis not that I'm calling dinner as a difficult yeah he set up autoimmune Inc with Bob Bishop and who was the president of and CEO of autoimmune and obviously he has said of course lifetime partnership with Meera who's sitting here in the audience you can see young Howard and Meera in the left side and you can see hand-in-hand on the right side when they were promoting Emma's partner center part SME center he also is the first increment of the Robert L Crocker this is the chair that was set up by McDonald's Ray Kroc he was one of the youngest two faculty members of our medical school he actually got chair when he was only associate professor and as we well know how difficult these personal chairs are and he was one of the youngest incomes on this chair and he is a wonderful sportsman like not only does he play golf don't play squash he excellent Zoomer and he has got this ability of a sportsmanship hand-eye coordination which is incredible and this is our first celebration in fact I came to the center in 1992-93 and this is our first celebration when the first clinical trial was done for oral columns in MS and you can see there is Howard and there is David there's Scotty and there's me we are actually celebrating positive results with oral tolerance giving myelin to these MS patients unfortunately the oral tolerance actually as a therapy did not succeed in Phase II clinical trials and real metal of a person you really see under difficult situations and this is one time when actually felt what howard is like he picked up the phone and called all of us and I was on that side and he said Vijay I have a bad news that the phase 3 clinical trial data on oral tolerance did not work and to me it looked like this somebody and my family had died but Howard said you know not a problem we'll figure it out we'll find the way to make it work nothing will change let's keep going let's Howard he never ever quits then this is something that if you take a poll from the people who have worked with him these are his catchphrases so if you have a piece of data and he likes it says Oh beautiful they say I love it he said Howard we have to buy a new machine it costs a lot of money and I'm kind of you know talking slowly how much it will cause it's just how much is it I said yeah you know it's probably cost about $600 he says I prove no questions us right and then if he he in the middle of a discussion if he has to say something and joke pops in his mind she says BJ I'm gonna tell you this is a joke and then he'll tell you the joke so that you don't confuse the reality from the joke okay and then if there is something difficult and he I have seen him handling it with poise with dignity and like a statesman and you'll say yeah if he if you're saying something that he doesn't agree you don't agree with you he said just a second let me explain to you what it is he'll say let me say something and if he sees that he is so I mean he he precedes and foresees what you're going to say if you are agitated and he knows there's a problem he says I understand I understand keep going no problem let's work together it's going to be a wonderful place to work okay so Howard not only have you been a friend a guide and mentor to all of us even a scholar and you have written already five books actually six one is in the works and it's called a fire in the brain it's deals with all the six diseases centers dealing with I had the pleasure of reading the book it's not published yet and actually I recommend all of you read the book and while he was a resident and he wrote this neurology for house officers and which has actually become actually a legend and every person in fact doing neurology training reads this book and it has been translated in six different languages not only does he write books he has had movies and people mistake these as two different movies now they are the same it was first called the last poker game and then he changed the name to the Apes and Phil's lost poker game and in fact he also made a movie called what's life and life's big questions and you know I was because I'm I do not know this and I thought in in Hindi they say gentle Janardan actually that means the audience is the one that actually sees what you are making what is your art how do they feel about it so we are so close to Howard we do not know what people are thinking about so I actually did a google search to see what people are thinking about his movies I know about science but I can't judge the movies I mean I am too close to him so here is Cynthia saying just washed it again a beautiful gift to humanity and for the last poker game and imprints an impressive news nuanced drama that tugs at the heartstrings so Howard it's not just the science at the books you have been an amazing storyteller amazing writer and the books and the cinema they equally seem to go with you I don't know how you manage both art and science together he has plain eared actually at least four different fields he has actually published 685 papers and they belong I could categorize them into four different areas immunology and MS and ALS mucosal tolerance Niraj digital diseases microbiome so I'm going to slowly go through all these 685 papers so you can see they keep coming and I do not know how he does it you can see there's from Steve Houser there is from Steve here from David Hoefler and these are all the papers he wrote on the on the MS and in fact there is also one from Fran yeah on the biomarkers and this is the original paper they talk about this immunosuppressive therapies in MS and then this next one that he worked on on oral tolerance and this was studied a long time ago and Yohai actually was the student and a postdoc here and he published many of these papers showing that he could make these clones and he could taller guys they could transfer their tolerance with clones and these were named as th 3 cells and this was a time I came here and in fact worked with Yohai and Howard to characterize these clones and they have become classic and they are called we have only had th 1 cells th two cells and he gave us th 3 cells he also has worked a bit Dennis and in Alzheimer's disease and he would tell me and I will go and talk to him or science and and it's awesome he says you know Howard I'm not a neurologist I mean I can understand inflammation in the brain but how big is this outside mistake what Dennis is doing and he he was said to me he says trust me it's bigger than M s and he worked with Dennis on these and really did an outstanding job in actually how to caller ID by nasal and mucosal tolerance and wrote a series of papers so I will I will not show you all the 685 papers because I will take a couple of more days and this is the last one that his interest in microbiome so I'm going to leave you with with a video which really brings together all the talents of Howard as a scientist as an artist as a director and above all I think it's a dedication to human disease that every time you talk to him ultimately he won't say the answer the disease find treatment for the disease and there is no politics in it it's the science that matters and I'm going to leave you with this movie and in fact it's heart-wrenching [Music] I got my ticket for the long way round two bottles of whiskey for the way and I sure would like some sweet company be me - what'd you say [Music] he playing it [Music] so this was the movie and that was selected out of 725 submissions to NIH directors transformative grasp which Howard and Adina Scott and I could never figure out how could you solve MSR ad by flipping cups maybe I missed a trick or two so Howard I really want to thank you for your friendship for a wisdom for your passion courage curiosity and mentorship so for being part of my life you changed my life and my career I'm blessed to have you in my life thank you [Applause] so BJ thank you so much I I there's really nothing to say there's nothing to sing but I have my talk and I have my title but I wanted to you talk about partnerships and people that you love and you're one of them so I'll start with a few slides of us and here we go so we spend a lot of time together over the years here's some pictures I guess I paid for all these dinners here here we are by the ocean somewhere here we are in Israel when we left this conference from Jerusalem and took a taxi to Tel Aviv and had a nice dinner at the at this manta ray restaurant and then we went to ballet ballet thing here's our families here's Karen and yourself myself and Mira and here's the Biogen Idec professorship that I received and this is monisha lee and i mean i you say that i helped you a lot debt cetera but you're one of the major people in my lives the professorship was given to me by Biogen Idec with a big gift but he couldn't have my name so I chose my maternal grand father his name was Samuel Worcester strim he died in the Holocaust he asked my mother to have his if she had a son to be a doctor and I became that doctor and you bear my grandfather's name it's hard for me to talk about my grandfather without tearing up so every time I try Kenz I can't I cannot do it so let's get into the science so this is my title bringing basic science to the clinic at 30-year Odyssey I don't know where you got the 30 years it's actually 43 years and here we have myself and Ann Romney on television we went onto CNN after she established the and Romney Center i sat there very quietly they asked her all the questions about presidential candidates and elections etc but I was very happy too I took care of her she has MS and we've kept her in good shape by giving her a lot of treatments now she's not on treatment and she said to me she was in the middle of a presidential campaign and it's funny she called me she says you know Mitch running for president Howard we're gonna have to delay this Center a little bit but we finally got it going and she said well you have to have you have to distill what you're doing into words that everybody can understand and so this is the sayings that I came up with but they really distill what Dennis and I have been doing since we started the center and what makes it such a magnificent place and the first thing I call drilling for oil and you know no one will give you money to drill for oil because they'll say well if there's no oil there and so Dennis and I are happy to give people money to drill for oil and every once in a while there's a gusher and then all the money comes in the other point is breaking down silos to do different things and put things together in different ways the final thing in Michael oz marker mentioned a little bit with Dennis's well you need to translate what you're doing is what I call shots on goal and a shot on goal is to treat people and to do some time clinical trial and whether you want to use soccer or hockey you can't score a goal if you don't take a shot on goal and so we have been doing that and that's what I've done all my life so that if you want to talk about bringing basic signs to the clinic its shots on goal so my talk is going to be focused on five shots on goal over my whole career and what I've succeeded what I failed at cetera so I was interested in multiple sclerosis when I first started as a young faculty member and the big question is his MS caused by a virus or is it caused by an autoimmune response now I never really thought it was caused by a virus per se but I took basic training in Boerne fields lab to learn about viruses and interesting where's Mike Lee he worked on real virus and I worked on verifier so his interest in what you're saying but I always thought it was an autoimmune response so but how can you prove that how do you prove that well you have to go to the clinic to prove it and if it is autoimmune then is the immune response humoral or cellular that's a big question now if it's humoral then maybe you can take out antibodies and so in I think this is 1980 we published it so in the 86 or 88 we did a pilot study of plasma exchange in multiple sclerosis to see whether that could do something I did it with Dave Dawson here's a picture of Dave Dawson at those times I won't show all the pictures that David you Steve showed about me getting the plasma exchange but so I was working on plasma exchange and the other way was through cellular mechanisms in that Steve Hauser and there we are in the enders building here he is working on this old trs-80 computer and we carried out what has become a classic trial in multiple sclerosis where we gave intensive immuno suppression in patients with progressive MS that's the title of it was published in the New England Journal and we really saw a dramatic effect and it was so dramatic that I was on the news here's a picture of me I think in Newsweek Here I am on the New York Times and we really found that we had helped a lot of people but life is not always that easy and I've had two major scientific issues that I had to struggle with in my life and this related to cyclophosphamide because the Canadians published in 1991 that they treated people with cyclophosphamide and it didn't work and it was presented as a big national meeting I don't think Marty Sammon is here but he remembers sitting there and these people who couldn't find it were vitriolic and openly attacked me openly attacked me how can you be treating people with this chemotherapy drug you're hurting them you don't know what you're doing they wrote letters in journals that said Harvard shouldn't allow me to continue and many people said to me Howard what are you what are you gonna do I said well there wasn't anything I could do I know we had help people and we just have to understand it better in fact I was coming up for promotion to professor at that time and one of these people wrote a they were asked to write a letter for my promotion anonymously of course but of course I found out about it and I and it was a slanderous letter really slanderous and even though I had all these papers and all these things Harvard would not promote me and in fact Jean Brown Wald who was the who brought Dennis and I there he showed me the letter says Howard we got to fight this we wrote back a letter to to Harvard but they said no we can't promote someone to professor if there's any controversy about what what he's found so this was not an easy thing for me as it turned out the art trial was done without cyclic without MRI scans and Henry McFarland who was that the is their pointer here yeah Henry McFarland who was at the NIH did a study with Paul cyclophosphamide and showed very clearly showed very clearly that the cyclophosphamide did something on MRI we continued to study our patients and found that response to therapy was linked to duration of disease etc but they their study wasn't that bad but it was just different than ours and you really have got to go where the science leads you and you you can't be afraid to try and understand in the fact of the matter both the Canadians and we were right in other words the patients that we had treated we're actually progressing but they had a lot of attacks they were very active inflammatory and that's why the Sauk the foss might just shut everything down they took patients who had been progressive for many years didn't have any inflammation and treated them and that's why they didn't see anything and now we understand more about mechanisms of progressive MS and we don't use strong immunosuppression anymore in progressive MS our approach with the cyclophosphamide has vindicated people in Johns Hopkins were then giving higher doses of cyclophosphamide that we were doing to try and do something for the patients and now a strong therapy to modulate the immune system has become standard for multiple sclerosis we did a double-blind study of true versus sham plasma exchange and found that to be positive Brian wine Shankar at the Mayo Clinic did another study found to be positive and now it is accepted in multiple sclerosis to treat with strong immunomodulatory agents now at the onset of disease and plasma exchange is used in people who have acute attacks and don't recover so those shots on goal turned out to really help people now here we are these are the early days you see Steve Houser and that's Bob Brown he spoke here yesterday couldn't be here today he's holding a pizza I guess I paid for that pizza there's a marked our dough and marine Paul's be in Bob as you heard is very interested in ALS and there was a lot of theory that ALS may have been an immune mediated disease and so we did a trial with Bob where we gave high-dose cyclophosphamide ALS patients and we were hoping you know maybe we'll see something we saw something with ms but we didn't see anything we now are treating Analysts patients with more sophisticated immuno therapy imagine if this had worked how it would have helped the patients but that was a shot on goal that didn't go in at that period of time one of my first fellows was Audrianna Fantana in audriana's here thank you for coming there's a picture of you you haven't changed he has an identical twin so sometimes if you're in zerk you think it's Audrianna but it really isn't the next person that I became very close with is David half ler and here we are at the fafsa meeting we went to these festive meetings in in vermont I actually had a beard the only time I had a beard David doesn't hear but he everyone has it beard he doesn't have a beard depending when you see him but let me just say to the David I don't know yeah but 90 you can turn all the papers we did and David was here for almost a quarter of a century and so David gets credit is a wonderful partner to help build up our Center and build up the whole Emma side so David thank you but we still were trying shots on goals here David has a beard now he's got a big one this is a woman named Lynn Sherman who we were treating and we tried other things one of the things we did was try monoclonal antibodies I think we were the first people to give him on a clonal antibodies for an autoimmune disease and we just went to Schlossman slab and got their antibody and once you're in the parking lot David are you sure we want to do this I mean what's going on here but we did it and we didn't cross state lines that's right that's why we could do it so we treated people with an anti t12 monoclonal we treated people with what does it say there and anti cd4 and anti cd2 when he saw immune responses Larry Simon Nazir is also pioneered and used monoclonal antibodies against t4 cells we did make an observation or David made the observation that when we gave the monoclonal antibody it didn't cross into the blood-brain barrier didn't cross into the spinal fluid but we there were cells that had the antibody on his surface and that proved that you had trafficking of cells into the nervous system so that's shots on goal number one shots on goal number two his oral tolerance this is a paper that I published with Paul Higgins where we suppress ei e by giving myelin basic protein or one of its fragments sorry I just came back from Israel and I'm covering from a cold now one of the the main people who worked on that you just heard him talk is Joe hi Jen and yo I published two classic papers the one in science where he found a regulatory t-cell clones induced by oral tolerance another in nature where he found a peripheral deletion of antigen reactive cells you'll see Vijay's name on one David's name on another after I don't know 50 papers multiple talks started and I started a company raised a hundred and forty million dollars did phase one trials did Phase two trials got the initial trials published in science I think twice in science one we do the face here's the company here's autoimmune I do like to play golf BJ luckily Bob Bishop liked to play well this is a golf outing here's David here's God's anvil and patsy i'm the whole team here's a picture of a model Sabbagh who's here who was preparing bovine myelin and working in autoimmune and so we did fails the phase three trials in ms in rheumatoid arthritis and in type one diabetes and they all failed and vijay spoke a little bit about that i can tell you when when you do a big trial and it's a public company and you go to report it it's done in secret because they don't want this talk market to know and you may have worked for ten years on it you get the answer in 30 seconds the statistician walks in and he says I have bad news we didn't meet our primary endpoint that's it or I've got good news we did meet our primary endpoint so Dennis I can imagine now Sandrock the thirty seconds where they said al I hate to tell you we have to stop the at Academy up trial so this was another major disappointment that I had to deal with it this is a woman Susan Quinn who wrote a book about Marie Curie then she decided to write a book about me and she thought she'd have a great breakthrough but it didn't work and so she published a book human trials which was a double entendre you do human trials but there are a lot of human trials so this was a big disappointment and it was tough but I didn't you know someone asked me how you can do it when it's tough I sometimes think about my grandfather and what he went through and how tough was that then what would he say to his grandson he says Howard I mean forget it just keep going and I think about that I think about that so what next what do we do next well we keep working and I discovered by almost by chance that you can induce oral Tong's by Yukos Lee giving anti cd3 monoclonal antibody how did we do it we found in a t-cell receptor transgenic Mouse you could feed over and you got regulatory cells so then the question was in a wild-type Mouse could you give anti cd3 and mimicked the effective oral OVA in an over t cell receptor transgenic Mouse I remember people in the laboratory were there and I told him I want you to feed this monoclonal antibody and they said Howard you're crazy and I said just do it so I was lucky I could just tell them to do the experiment here's the paper in Nature Medicine oral cd3 specific antibody suppresses the AE by inducing these unique regulatory cells lapped regulatory cells which will play an important role as we go forward so there were a number of animal models that we could treat with oral anti cd3 how does anti cd3 differ orally and IV when you give it IV you you remove cd3 from the surface when you give it orally you don't it's processed in the gut here's taka Oh EDA who was in the laboratory and he did studies with these Lapp positive cells and it also worked in colitis I kept working and we gave anti cd3 nasally think about it giving a monoclonal antibody nasally and there were a number of animal models that worked and they and nasally you can see them here and what happens when you give a monoclonal antibody nasally it doesn't go into the brain it localizes in the cervical lymph nodes and the person who did these experiments is lee or mayo here he is with Chantal Kuhn who works on anti cd3 here's Li or in Israel in his laboratory nothing is more satisfying than to see one of your fellows in their own lab and I've had that joy over and over again so this is a great picture of Li or here's a progressive form of EI E and you can see they have an attack they recover and you can see the nasal anti cd3 works it protects from myelin loss and axonal injury but very important is it decreases inflammatory astrocytes in talking to BJ yesterday he wonders whether inflammatory astrocytes are important in progressive MS and the nasal anti cd3 also affects microglial cells hears changes after giving a nasal anti cd3 in this progressive model and so you have the mechanism of oral versus nasal anti cd3 aneil 10 t reg versus a tgf-beta t reg depending on the dendritic cell that process it this is a beautiful figure made by none other than Scott Danville here's Scott here's VJ and we heard Scott talk today and he reviewed the paper and wrote that beautiful beautiful figure so then the question is can anti cd3 be given orally to people that's what we want to do we want to give it orally to people and I went around to every company and I couldn't get anti cd3 from industry think about it I went to taller I went to Lille I went to GSK when I said it's so easy we just give it already no we're giving an IV we can't do it so what do we do this was very frustrating a solution we just brought ok t3 off the shelf and fed it to humans to try and prepare for shot on goal this is work I did with your own Elan it was in the who's in the audience he's a visiting professor from Israel was last year ten years ago and we gave oral ok t3 to human subjects and found an effect your own did a study of oral anti-skate III and patients with nash and then as luck would have it I get a call from somebody that they just acquired fur alum AB this is ok t3 these are the other mono colors are being used and somebody from Tiziana called me and says we just acquired that for alum AB and we've read all your papers we want do you want to help us develop it so and this took about eight or nine years and so we got access to the fur alum AB which is a fully humanized monoclonal antibody and so we taking up getting ready for a shot on goal and we're actually doing a study now where we're giving nasal anti cd3 at three doses to healthy volunteers Tanuja chitinous is clinically running the study Claire Beecher Allen is doing the immunology people are being dosed as we speak we're almost done the results the results are no toxicity and immunological observed so that sounds pretty good that's nasal anti cd3 and who are we going to treat well we're going to treat progressive MS patients we're ready to do that and I'll tell you it's very interesting nasal anti cd3 this is we're that Oleg and I did with Nargis nasal anti cd3 has an effect in m in ALS because it down regulates microglial cells so I've spoken to merit suit of each at the Mass General and we're gonna treat in patients with ALS with nasal anti cd3 we wonder would it help Alzheimer's disease we don't know it could decrease inflammation and I've been talking to Dennis and Reese about it Dennis has looked at all the data and if possible we may do some nasal anti cd3 and Alzheimer's patients so from that failure of oral tolerance one wonders how can we make it work number one it may be that when someone has an autoimmune disease there's a lot of inflammation in the body and you have to treat him first with something maybe a treated with anti cd20 or course of immunosuppression before you try and taller eyes them you have to decide which way to give it maybe use an adjuvant and to new Jan had an idea the done by Raphael that the anti cd3 orally actually conditions dendritic cells in the gut and when you give anti cd3 plus antigen it works better so we may have a way to treat with combination and finally the microbiome I'll talk a little bit about the microbiome but Raphael and Lori and found that the microbiome is very important for oral tolerance and we've identified bacteria they can make oral tolerance better or worse shots on goal three cancer discovery of a new checkpoint inhibitor for treatment of cancer is an outgrowth of Studies on oral tolerance this was kind of unexpected now in my movie Aben Phil's last poker game there's a guy who wants to be live forever or whatever so he drinks cancer cells he's drinking human cancer cells because he thinks it'll help him live longer and then he's talking to Paul sorvino's talking to the director Nursing omen and he says well what will help my I got cancer you know that can help me he says well it can help old age and it can cure cancer on the side so here I was studying oral tolerance and I may end up having a treatment for cancer just on the side by the way eating cancer cells is the orally is the last thing you want to do for the cancer because it'll shut down the immune response against it so how did we get to this first there's somebody named taka Oh a de who made a monocle antibody against lap and here's a paper that he published because lap is a search for a protein we gave the anti lap antibody in an oral tolerance model induced by anti cd3 and it abrogated oral tone so it worked just like we thought it would anti lap abrogates oral tolerance so then the question is I had this idea as it will wait a minute what if you give anti lap in cancer and so that was a question Galina Gabriella Gabrielle use in the laboratory began doing experiments and it was one of those things where almost every experiment work every cancer we tried or that she tried when you give anti lap had worked we published a paper in science immunology here's all the people who worked on it and it promotes anti-tumor immunity we have good news that came out a few days ago well we started a company that bring him in us we started a company called Telos and then a few days ago we learned we didn't know about it that merck paid seven hundred and seventy three million dollars to Telos to get our anti lap antibody so this is pretty exciting the company was set up in 2016 we got money from the partners Innovation Fund it's based on work by galina and myself at the Brigham and it hold it holds the ability to treat treat different cancers now when people saw that they thought are you gonna retire you know they see 773 million dollars the way it works is you get it in little pieces so initially the hospital gets I don't know 20 million or something there's percentages that we get so we get a few hundred thousand dollars initially they can go to the lab in the department that I can use for travel Galyna can buy a new house but we it's not gonna change our lives but as time goes on there's other milestones and if it goes into phase begin phase two other milestones kick in if it goes into Phase three without even working other milestones kick in and then you're talking about millions of dollars coming in which would be nice if it ultimately becomes a drug that's used a dentist we won't have to raise money for the heir CMD anymore now I guess a good omen was I was getting off the plane and I saw this woman holding up a sign that says lap so I figured that's a good sign for our company and for the future of lap so does anyone want to guess what this stands for this is the Los Angeles Philharmonic she was welcoming the Los Angeles Philharmonic to Boston but I I think it's laughs anyway okay shots on shots on gold so anyway it's interesting all that work in the years and the money and everything on oral tolerance and autoimmunity it all failed and then because of that this kind of clicks in I guess this whole all happened about ten years over ten years shots on goal for the microbiome and we're investigating the gut brain access in five diseases being studied at the end Romney sinner here's the paper that we published on alterations of the human gut microbiome we did a study of probiotic on the microbiome and Hartman talked about what you could do I will I will say that a large portion laboratory is now actively working on the microbiome we're very excited about it we've recruited Lorri Cox who's here who's a microbiologist she's not a neurologist but she's learning neurology and is really helping us set up our whole microbiome in all these diseases so I I I go to the neurology meetings and okay we got to get all the Parkinson's patients we got to get the Alzheimer's patients we got to get the ALS patients I could talk for an hour on all the preliminary data we have we have amazing preliminary data microbiome affecting microglial cells microbiome affecting different diseases etc etc we are planning a fecal microbiome transplanted MS just to try now interesting Steve Houser is doing the same thing or Sergio bernzini and he's set up a big microbiome Center at UCSF now one of the very exciting potential shots on goal is an oral micro RNA now this is something you probably never thought about or it's really crazy if you want to talk about thinking out of the box etc but Charan Lu has been discovered micro rna's micro RNA is in the feces micro rna's and feces no one looks for micro knees and PCs and so then we looked at micro rna's in ms and EA e and shirong discovered a micro RNA called mere 30d and if you from feces of MS patients and EA East subjects and if you feed this micro RNA this is a micro RNA if you feed it it shuts down EA e shuts down type 1 diabetes shuts down type 2 diabetes and it does it by inducing Accra Mencia acumen SIA in Hartman talked a little bit about Akram NC we're not sure we're there Akram NC is good or bad or whatever we filed a patent on it I was talking to Barbara Foxx who just sold Tilos I says Barbara I got another company for you we can give this oral micronet which is easy to synthesize and begin testing it so this is going to be an immediate shot on goal here's the people this is the the opening we had of the last Aven Phil's last poker game at the Coolidge Corner here's Chiron who's made the micro RNA here's Galena here's Lawrie this is Raphael who's the head of our Brazilian mafia because he keeps bringing all these Brazilians in the lab and he's our oral tolerance guru he also I must always announce when I said he had triplets how old are the triplets I think they're about a year old but imagine having triplets how old are they 15 months okay so these are all the people were growing up Chiron Galena Lauri and Rafael are now instructors and so they're on the way to in their academic career so here's the book I wrote curing ms and if I want to write a book I was thinking write a book called MS secured within reach Steve said I think we've got it Howard well how what is a cure for MS you have to halt the progression of the disease reverse neurologic deficit a vaccine to prevent MS I think that's how we're altima lis going to cure it I think progressive MS is our biggest problem and we've started a progressive MS initiative one of our patients whose wife has progressive MS has given a very nice donation and we all meet together we're doing treatment we're doing MRIs we're doing PET imaging we're doing microbiome we're doing microbe biomarkers we're doing clinical things all unprogressive ms the next book is vijay mentioned is called fire in the brain where i talked about the five diseases here at the centre in terms of understanding ms one of our big things is the climb study and these are all the people involved in the climb study here's our latest picture of all the people which is a longitudinal study of ms if you want to understand ms you've got to understand individual patients and how they do Tanuja chitinous is the medical director of the climb study here we are at the Ekrem meeting and then i'll show you two pictures and I'll tell you which one is my favorite but it'll be easy to tell this is a Tanuja and Fran where they both became professors and David remembers they I don't know who says if you can't get the too many people in Harvard right who are professors related to ms or whatever but we just keep having one after another after another and so the nice thing in this it related to the AR C and D so Fran became a professor on the highest level basic work and Tanuja became a professor on the highest level clinical trials and clinical work and that's really amazing and they it happened on the same day this is the picture but this is the one I really like both of their key to have two kids and they came for the professor ceremony before I go on to the shot the last shot on goal I've tried to show pictures of everybody who's coming everything but I want to give special thanks to Steve Miller here's your picture Steve I don't know what's going on here's yo hi but thank you thank you for coming and we look forward to playing golf again Hartman I want to thank you for coming this is an old picture you've seen it before we're drinking beer after a job and here's ayran cone it's in Germany and last but not least my doppelganger Larry Steinman who is just an amazing person Larry thank you so much for coming and helping out so now we go to the last shot on goal and the last shot on goal is Alzheimer's disease and I will say that Alzheimer's disease is our biggest challenge it's our biggest challenge so here's a picture and I won't make you guess but this is Samuel Worcester strim okay for whom my grandfather for whom VJs named and this is my mother in Vienna before the war they got these great little hats this is my aunt of course so there's my mom and my in Sammy Worcester's Truman and here's my mom is a beautiful young woman and here's my mom when she came down with Alzheimer's you can kind of see a blank look in her face I brought her to see Dennis Dennis was as compassionate and helpful as always she knew something was wrong and she's is Howie aren't you a brain doctor can't you do something for me and I said well mom we we don't have anything yet so I've been touched by that and obviously she's she passed away but I actually have begun working on Alzheimer's and I was just at the ADP meeting and it's just kind of amazing Here I am at the ad I'm an MS doctor right I'm at the ad PD conference and I'm giving a symposium talk on Alzheimer's and I'm talking about innate immunity and the role of the microbiome so that's very exciting and here too the people here are too the people that I'll show some of their work this is Danny Franco who's easier this is a little bit of the Israeli mafia this is Danny Franco this is a loan Monson eggo I guess I bought whatever was here one of the things the things that Dani and I do is take picture with his kids it's really interesting I remember when Vijay's son was first born and they we had a one-hour a one-year thing and then time goes on and you see them as young men and young women and so we're gonna keep taking pictures Danny until we go to their wedding together so this is the theory that we're working on the innate immune system looking at monocytes and I'll tell you about that looking at microglial cells this was developed with Oleg boot tufts key and this is a figure related and you heard a little bit about the microglial cells and all the different aspects that we're studying here's Oleg and I actually in an ALS meeting where we were talking and so here's studies that have gone on for a number of years on amyloid and Alzheimer's disease here you see now Dennis's name here's a lone months and they go where we looked at responsive amyloid protein in transgenic mice here we're looking at t-cells again now I get to work with Dennis and this is increased teeth this is very interesting and Dennis we have to go back to this in terms of t-cell reactivity to Alzheimer's increased t-cell reactivity in older patients here's alone here's Victor this is Tanuja husband who did you meet him in the center yes okay so there's a good thing and here's Risa here's Risa and Dennis to myself so and here's another paper by the victors on looking at immunology of Alzheimer's Dennis and I did a trial where we gave this is a great paper I'm first author and Dennis's the last authors I just love that paper where we gave nasal a beta peptide and we actually saw something that was positive we didn't know exactly what the cause was and we were ready to do a shot on goal and go into trials and at the that time six percent of the ad patients who were immunized with a beta gotten meningoencephalitis solo hold trial the whole trial was stopped I remember we bought I think it costs $35,000 we bought the peptide to give to people that was GMP we talked to the FDA they said you're not giving a beta to anybody so we gave this GMP $35,000 a beta peptide to the laboratory to use but I wondered then and Larry Steinman was involved in looking at a lot of this stuff as well well what why did these Alzheimer's patients get this is simple itis and how does it relate to ei II so I did a study to find out whether a PP mice are more susceptible to EEE and could you induce EA e if you gave beta amyloid with pertussis and the answer to both experiments is negative they're not more susceptible to ei E and you couldn't induce EI e however interestingly when we looked at the brain of the animals with EI e it cleared all the amyloid and so then the question is well is it only just antibody is an antibody dependent well we can do this very easily in mice we looked at b-cell deficient mice and it wasn't related to antibody well you can't treat Alzheimer's by giving them ei E or M s so is there a way to do that and after a lot of work in struggle etc we discovered a adjuvant called proudly which is made up of Neisseria and also LPS and found that that itself could treat the treat the animals and this is work done by Danny Franco who's here and this is pretty remarkable these are animals treated with the nasal protal and this is the a beta and this the animals that are the control animals these animals treated with a beta how does it work ollague tusky did some chimeric experiments where we labeled peripheral monocytes and we actually can show that in the animals that are treated there's less a beta and there's more monocytes coming in Danny also in Israel found that you could treat with proton with this zebra vascular and amyloidosis it was based on this work and Oleg's work that we got the NIH transformative award and now the question is where are we can we do a shot on goal and it isn't easy to find the people to make the proton to do this to do that etc but I'm happy to report that just this spring we put together a deal to manufacture nasal proton to treat humans so we're getting ready for a shot on goal it's a collaboration with the Chinese we had a big ceremony this is bio dexterous in Canada this is n hua this is a company called IMAP and how did we do this why did this company agree to put up I mean they're gonna give two million dollars to make the vaccine and then they committed another eight million dollars for the trials why what was the trick to doing it well the trick is in this picture David do you know who that is yeah this is Jing Wu Zhang who was a fellow in David's laboratory and went to GSK who went back to China who set up a company who kept in touch and I called him I said gee we I heard you just started a new company you just work with GSK could we are you would you want to do nasal prodel in in all summers and he said yes he said yes so we had a signing ceremony and I apologize here we are there's people taking pictures there's people from China there's Dennis there's me and here we are signing that so I'm very excited about this and so excited to work together with Dennis on the nasal protal and and we've talked to recent it opens up a lot of potential therapies that we can do together in Alzheimer's disease so I'm coming towards the end here's another question you heard a little bit it's called what is life you know I was a philosopher David as a Kim but you chemistry philosophy you know and so I didn't know how to answer the big questions with what happens when you die is there free will all these different things so I made a movie that's what you do to answer these questions travelled around the world one of my MS patients is on the movie and actually this movie won Los Angeles Film Awards there are the awards I won and this came out in 2011 and in there it says director that's not doctor that's his director I made another movie which was more of a Hollywood movie called Haven Phil's last poker game Vijay do you know why they changed it from the last poker game to haben Phil's last program because they say if you start a film with the letter A when it comes up on all the lists they sell more of the movies so they come up with their name that starts with a so this involved Academy award-winning Martin Lando and Goodfellas Paul Sorvino it's a long story how I got to do the movie but I did it they loved the script interestingly one of the characters has Alzheimer's in the movie and it plays an important role here's the poster with Martin and Paul they've he's a Jewish doctor and Italian womanizer and gambler they become friends they're both impotent which plays a role in terms of losing things when you get older she's a nurse for her biologic parents gets an anonymous note that her father's in this home she meets the two old guys they both want to be her father so it's the story of searching for roots getting old etc and here's a review in the Village Voice Martin Landau made the movie when he was 87 he died when he was 89 he was a Tribeca when it came out but he didn't he wasn't there for the release and somewhere upward says Howard whiner and eminent neurologist etcetera and they said very nice things about it most of the reviews again I think 70 75 percent of users are good some of them really outstanding every once in a while there's a really bad one you know you don't like to read those so you just don't read them but as a as a as a scientist we're used to bad reviews in the California Film Festival that won the Best Featured drama and Martin Landa ones Best Actor here we are at the Tribeca Film Festival where I met all kinds of people here's Robert DeNiro who sent me champagne for the movie everybody wants to know are you gonna make another movie I have two other scripts that are being looked at in Hollywood today whether they get made or not I don't know what is called Subway's which is a existential movie of a doctor goes from midlife crisis in New York in the subways represented subconscious so he goes into subways that represent a subconscious like temptation mother the grass is always greener subway and he comes back up and he tried to get out of the subways love kills is very simple it's a medical thriller opens with a murder in the hospital characters are two young doctors a beautiful nurse and patient who's very sick who gets an experimental medicine and falls obsessively in love with one of the doctors and then it gets very complicated and then one of the doctors gets murdered and the patient dies and you'll have to watch the movie to figure out what happens so now I'm talking about partnerships talking about partnerships and here's the partner a couple partnerships of the utmost importance there's Dennis and Polly and mirror and myself or a little younger here's a picture of us guest last spring or the spring before when we went out to the Romneys had a something in Salt Lake City and we walked around and had a good time and we even got a big donation from that afterwards which was very good my own personal partner who's the most important partner here she is on elliott street dentistry members that's mira our two sons the baby is in a category we academy award-winning emmy an emmy winning comedy writer and the other one is a Wharton graduate that's on Elliott Street and so and here's a very beautiful picture of my partner Mira now Dennis okay so Dennis is I call him my wonderful partner and I mean it immunity is my wonderful partner I didn't have pictures to show then everyone hasn't showed so here's the here's the famous picture of us at the bi and then here's the famous picture of us on the Tokyo Tokyo walk and we hear about all these things and yeah how you did all these things everything so I tried I tried to honestly and I'm not I'm gonna be serious now I tried to honestly figure out how did we do it what are the factors why did Dennis and I succeed at center today so I actually wrote some things down because I don't want to do this extemporaneously to analyze why why it worked so first of all I don't think this is something that happens very often I think it was a perfect storm a unique moment in time you and I in our careers gene brown waldo waking up a thing us having to meet each other and i don't think you could necessarily create something I think it was kind of the stars in the moon becoming a line so I think it was a unique moment and I think that happens in many of our lives and many things I think when we started the center it was actually good that ad in ms were separate and they were pretty separate at the beginning and the reason that was good is it allowed us to grow and develop our own areas without competing or worrying and I think that was very important we could support each other etc so I think that was an important point we were friends we were good friends and I think that was important the other point is I think we were equals okay and I think that's important now you can use any metaphor you want that we could both run as fast jump as fast do you know the intellectual thing I think we're both if one of us was a lot better than the others it wouldn't have worked and I honestly think we are true equals I you know we each have our strengths and weaknesses but we're pretty equal and it related to the science we did the awards we won we both started companies there's almost nothing that we weren't equal in doing and even in the fundraising I mean we turned out to be good fundraisers but he's an even in the fundraising you're creating the fnd with Ned Johnson that was your initiative and brilliance in doing it and then my getting an Romney to set up the center and doing it and that was my and we did it together and then of course I became good friends with MADD you became good friends of Ann so I think that's another thing I think that we were equals and I don't think you could have a partnership like this that is so successful if one is a lot better than the other and I don't think one of us is better than the other I am taller and you are handsomer but you know doesn't bother me doesn't bother me what do I admire most about Dennis I think his intelligence his clear thinking those are the is energy those are the the two things the other thing that helped us to succeed there was always a goodwill there was never a bad will between us I think that's very important we didn't play games and we both love science we never had an argument we really never you can wonder did you ever have an argument we never had an argument sometimes we got stuck okay and something like we had moved to a new building who gets this office who gets that office certain things who gets this who does that did you know what we did when we got to that problem what do you think we flipped a coin we just flipped a coin and then we remembered who won the previous four coins flip so then if you declare it's time for a coin flip then you say well you won that one before it's my turn and we did it we used to rotate coin flips so that was one of the that was the one of the things and then in the end it's kind of you know you talk about a perfect storm of things happening it may very well be that because we happen to come together because you started an Alzheimer's and I started in something else and now we're coming together that the world may have treatments for Alzheimer's that they may not have had because you and I happen to come together and so that's I think a very exciting exciting possibility so that's my analysis I love you very much it's just so wonderful to work together and the emotional intelligence that you have the I know sometimes they Dennis y'all be honest with us I don't understand how to solve this problem I just tell them I don't understand it just say here's what I would do Howard you know so we're very honest with you so anyway again I love you very much and it's just a joy to spend all these you together so here are some slides you've seen them before but these are the I mean we have tons of pictures but these are the ones that I came up with and I think the exuberance and everything is there there's one of them here we're dancing and here we're singing at the top of our lungs and then I'll then leave with this particular slide let's continue to make music together so now in your talk you did give some final advice you said pearls whatever you call them so I got to do the same thing because we're equal right we have to do the same thing okay so here's final here's my final advice slides and I'm gonna start with a quiz so get ready I'm going to ask people to raise their hands it's you can't predict what this cruise is gonna be but here we go here's the quiz which famous politician won a Nobel Prize in Literature okay Church but Kennedy okay so who says Franklin Roosevelt nobody who's his Churchill a lot of people who says Kennedy some people say Kennedy and the answer is which the Churchill's yeah he wrote all that stuff and he it's kind of amazing here's a quiz I don't have any think who want to know about prize that wasn't a writer that everyone was really surprised why in the world are they giving him a Nobel Prize in Literature Bob Dylan know me you know Bob Dylan yeah Bob Dylan he went an overpriced Philip Roth died he never got a Nobel Prize Bob Dylan gets a Nobel Prize okay I've read a lot about Winston Churchill and his biographies and everything and he has a lot of advice some of it we're aware of and so I finished with advice from Winston Churchill okay number one is aim high okay aim high and I've always tried to aim high Dennis says that he likes to write the literature not read the literature so that's kind of a high thing I wrote something that's a little hubris area has a little quits but goes like this I want to be confronted with almost insurmountable odds with little chance of success I want the stakes to be high oh and everybody watching and I want to win so that's aiming high okay so we got a not be afraid to aim high number two you've got to work hard and I put in very I think you've really got to work hard just there's nothing like good hard work so you aim high and your work hard the next is be resilient don't quit and Churchill is famous for a quote never ever ever quit and you refer to that particular quote now if you go on the internet and read all of it says he never really said never ever ever quit he said he gave a famous speech where he he said don't give up or don't whatever but he's that's right he's which never but but I have I have a little thing that put my Destin says never ever ever quit and it's it's attributed to Churchill so don't quit here's an important one for us all don't hold grudges I think that's a very important piece of advice don't hold grudges you shouldn't hold grudges it isn't always possible though they just know as possible and here's a true story about my mother okay so as she got older etc etc before she you know got into her Alzheimer's I wanted to tell her I says mom give me some lessons of life you know give me some less life she says Howard don't hold grudges you know because we were good friends with Charlotte and Max for all these years and then they did something we didn't talk to him for 20 years and now we're back together and you just shouldn't hold grudges and then and then I knew about the story of Uncle Henry and so I said to him what about Uncle Henry mom well he never talked to him what he did to your father that's a true story but you still shouldn't hold grudges but you know what can I say and then the very last thing that you get from Churchill is to enjoy life I think we really have to enjoy life he did painting at the end he did this watercolors and he really enjoyed life so the my final message is aim high worked very hard be resilient don't quit don't hold grudges unless you have to enjoy enjoy life here's a picture of the Ann Romney Center and this is the last slide that I'll show that relates to our patients at servitor which i think is important which we have and that's the word hope and i think there's a great deal of hope to help these people with these illnesses I'm humbled and honored to have had all this here I thank everybody I admire so many people here for everything that they do Vijay they thank you for being here David I thank you for all the things we did together and Dennis we just keep making music thank you very much [Applause]

Channel: Howard Weiner

Views: 500

Rating: 5 out of 5

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Id: U-hV85n98yw

Length: 81min 42sec (4902 seconds)

Published: Fri Sep 27 2019