The Birth and Coming of Age of Hepatology with James Boyer

Transcript

• 00:35Good morning and welcome to the
• 00:37Yale Liver Diamond Jubilee event.
• 00:39This session is being recorded. Thank you.
• 00:51Good morning everyone.
• 00:52I'd like to welcome you to our
• 00:5575th anniversary of the liver
• 00:58center and it's my pleasure to
• 01:01introduce Doctor James Boyer.
• 01:03Jim is the enzyme Professor of Medicine
• 01:06Emeritus, director of the Liver
• 01:07Center at Yale School of Medicine.
• 01:09And from 1982 to 1996 he directed
• 01:12the combined Digestive Disease
• 01:14section in the Republic of Medicine.
• 01:17So it's my pleasure to work on them
• 01:19today to for you to give this talk Jim,
• 01:21please go ahead.
• 01:41There we go. Can you hear me alright?
• 01:46Yes I can. Well, it's a pleasure,
• 01:50and indeed a considerable honor to be
• 01:53asked to lead off our celebration of the
• 01:57Jubilee for the liver program at Yale.
• 02:04This is what I'm going to talk to you about.
• 02:06I'm going to talk first,
• 02:08of course, about our founder,
• 02:09which is Gerald Klatskin and the
• 02:12era that he represented and how the
• 02:15liver unit became came into fruition.
• 02:18And I'll talk a little bit
• 02:21about his impact on the field of
• 02:24hepatology and and how some of our
• 02:27organizations like the ASLD have began.
• 02:30And then I'll switch to the buyer here.
• 02:33If you let me do that term and the
• 02:36founding of the NIH Yale Liver Center.
• 02:39And then I'm going to speak a
• 02:41little bit about the impact of our
• 02:44center on International hepatology,
• 02:46and conversely,
• 02:47the impact that our fellows who
• 02:49came from international areas
• 02:51had on the center itself.
• 02:53And then I'll conclude with a
• 02:55very brief perspective of over
• 02:56the 50 year of my career on the
• 03:00enormous scientific progress
• 03:02that has been made in this field.
• 03:07Well, this is the iconic picture of
• 03:11Gerald Klatskin there with his pipe and
• 03:14his microscope and neither of which
• 03:17he was very far away from his career.
• 03:20He came to Yale and actually in 1933.
• 03:23Hepatology, of course,
• 03:25at that time was not especially at all.
• 03:28And he finished his residency here.
• 03:31Even took a time off for a surgical
• 03:33residency up and in Rochester, NY.
• 03:35Came back was in private practice
• 03:37briefly and then on the faculty for a
• 03:40few years and then World War came along.
• 03:43And he ended up in India,
• 03:46in Calcutta and in the army.
• 03:48And there he came into contact
• 03:51with patients who had hepatitis
• 03:53patients with amebiasis human wrote
• 03:55a paper on emotion therapy.
• 03:58Hepatic antibiosis and most
• 04:00importantly in his fourth year in
• 04:04the army he was stationed in Iowa.
• 04:08And Cecil Watson was a consultant
• 04:11from University of Minnesota where he
• 04:15came once a month and he introduced
• 04:18Klatzkin to what he called the Hypnogram
• 04:21or a battery of liver function test.
• 04:24And when clients can realize that
• 04:26he could quantify liver disease,
• 04:28he got hooked and he returned
• 04:30to Yale in 1946.
• 04:32And if you do the calculations,
• 04:35that was 75 years ago and hence the.
• 04:39Jubilee today, so delivery unit.
• 04:44Markets beginning at that time. And.
• 04:49He was ostracized by the metabolism group.
• 04:54Phillip John Phillips threw
• 04:55him off the 2nd floor.
• 04:57I don't know the 1st floor of the LMP.
• 04:59He set up this laboratory and this is
• 05:01the sign that was on the laboratory
• 05:04door and the test that he ran over Billy
• 05:07Ruben Alfalfa protein elective races.
• 05:09Final turbidity and kept flock flocculation.
• 05:14And nobody knew how to interpret those tests.
• 05:16So he received a lot of consults
• 05:20and that's how the program survived
• 05:24financially and he was off and the
• 05:27unit was off and and and running.
• 05:30At one time he had six or seven
• 05:33technicians in this laboratory.
• 05:35Now Glasgow was the first to do
• 05:38a liver biopsy at Yale.
• 05:39He was not the first in the country.
• 05:41I think the first one was done
• 05:43at Mount Sinai in New York.
• 05:45But he did one in October of 47.
• 05:48First two failed, apparently.
• 05:50And then it was a matter of how
• 05:52to read these biopsies,
• 05:54and he sent them over to pathology
• 05:56to be to be looked at.
• 05:58To these be processed and.
• 06:01It happened to go up to to the Newington
• 06:05VA where Ray Yesner pathologist was.
• 06:09He went there weekly as a consultant
• 06:12to the VA and Ray has there is
• 06:15one who really taught class going
• 06:16to have to read biopsy slides.
• 06:18Now his hobby that's hobby was photography.
• 06:21And so he started photographing them.
• 06:24And he hired Hazel Hubble away
• 06:26from Saint Rayfield, where she,
• 06:28although she had originally been a
• 06:31technician for for Doctor Green at at Yale.
• 06:34And.
• 06:35Over his career.
• 06:37He assembled around 50,000 kodachromes from
• 06:40approximately 10,000 that are biopsies.
• 06:44He recorded all this clinical
• 06:46and histological data on a
• 06:49punch card system.
• 06:50From me this is Hazel Howell,
• 06:53his biopsy technician.
• 06:55She was every bit as fastidious
• 06:58and perfectionist as Klatskin was.
• 07:01He was his match for that.
• 07:04Now the class can biopsies slides
• 07:06and code acronyms have been
• 07:08hooked up until recently stored
• 07:10in a in a klatskin library.
• 07:13Here's a picture of it.
• 07:14Here's another with the code of Chromes
• 07:16are every bit as beautiful today as
• 07:19they as they were when they were taken,
• 07:21and the slides here.
• 07:23And then this is a Mcbee as not index card.
• 07:26It's not one of his,
• 07:28I took it off the web,
• 07:29he would have this filled out all
• 07:31the way around here with liver
• 07:33function and and liver biopsy.
• 07:35Get to you and every Saturday he
• 07:37would come into the office and sit
• 07:39down and punch the cards where
• 07:41the for individual patients and
• 07:43the secretary in the next morning
• 07:45with type it up and there would
• 07:47be 3 copies and they were stored
• 07:50in these cases here one copy for
• 07:52the patient's name one.
• 07:53The number and one for the for the disease.
• 07:57Now, unfortunately,
• 07:58the library had to be taken down
• 08:01for one of office space and is
• 08:03now residing in storage in the
• 08:05library waiting for its next home.
• 08:10Our classroom was proudest of the
• 08:12fellows that he trained many of
• 08:14these fellows as a list of them.
• 08:1647 came from other institutions who
• 08:20wanted to train somebody to to be to
• 08:24bring liver information to their program.
• 08:28And. Several of them have Fallon myself.
• 08:32Willis Maddrey and Joseph Bloomer became
• 08:37presidents of our National Association,
• 08:40so this is a a major pride of of his.
• 08:46There he is, lecturing in Parkers Hall.
• 08:52Early on in his career,
• 08:53he was dubbed by John Phillips as a
• 08:56Doctor of rare diseases because if
• 08:58there was an unusual case in the house,
• 09:00he was the one that read up and
• 09:03exhausted all the literature and
• 09:05became almost overnight.
• 09:06The expert in the field and in that case,
• 09:10and he often presented a grand rounds.
• 09:14This is the list of some of his
• 09:16contributions to hepatology that he
• 09:18himself ordered his most important
• 09:21finding he thought,
• 09:22was the association of viral hepatitis and
• 09:25Australia antigen with chronic hepatitis.
• 09:28Discovery that protoporphyrin was
• 09:30by refrigerant and to be make
• 09:33the diagnosis and protocol furia
• 09:36with Cholestasis and the clinical
• 09:38significance paddock granulomas.
• 09:40He probably has the world's largest
• 09:42collection of granulomas in liver biopsies
• 09:45but never really published much on it.
• 09:47He championed the Association of Paddock
• 09:51adenomas with oral contraceptives.
• 09:53Published together with myself
• 09:54on prognostic significance of
• 09:56bridging the padding in the process
• 09:58in viral hepatitis is a predictor
• 10:00of progression to cirrhosis,
• 10:02and the new journal.
• 10:04He showed that that alcohol,
• 10:07when it was drawn.
• 10:09Affected the Natural History of
• 10:11alcoholic liver disease and studies
• 10:13that he did at the VA,
• 10:15and he was his his paper on halothane
• 10:18hepatitis was the hallmark of the
• 10:21Association of that of that disorder.
• 10:26Other contributions and honors
• 10:28he the bifurcation tumor,
• 10:31the claims of carcinoma bears,
• 10:33his name. He didn't.
• 10:35He didn't initially describe it,
• 10:36but he wrote a Seminole publication
• 10:39in American Journal of Medicine,
• 10:42and since that has been
• 10:44called the klatskin tumor,
• 10:45he demonstrated the Association
• 10:48of Fever and alcoholic hepatitis.
• 10:50He designed a special liver biopsy
• 10:53needle known as the Klatskin Needle,
• 10:56Becton, Dickinson Pay.
• 10:58It still available and he is one
• 11:01of several founders of the American
• 11:03Association of the Study of Liver Disease,
• 11:06and this appeared in 1950 in the
• 11:09Hecktown Institute in Chicago.
• 11:10In the library,
• 11:12we're actually in the office
• 11:14initially of Hans Popper,
• 11:16who is about usually regarded as
• 11:18the father of modern hepatology.
• 11:19And the interested people would
• 11:22bring a puzzling case with a.
• 11:25With a biopsy there to be looked
• 11:28at proper would presented and
• 11:30give the results in.
• 11:34Classroom was the first recipient
• 11:36of a T32 training grant.
• 11:39Back in 1959 and Hepatology
• 11:41and I think one of the first in
• 11:43internal medicine in the country.
• 11:46That means that we have had at except for
• 11:48a lapse when two years when he retired.
• 11:51Yale has had a T32 training grant
• 11:55hepatology for over 60 years.
• 11:58And although he was not a member of the HGA.
• 12:03He received the Freedom of medal,
• 12:05their highest honor. Sorry.
• 12:11From the IGA in 1983,
• 12:14here is John Ferrar presenting the
• 12:17medal to Klatskin and Washington DC,
• 12:20where the meeting was held.
• 12:22That is my back.
• 12:23I presented the asked me to
• 12:26present to you award two.
• 12:28In those days the freedom will
• 12:30medal was presented alive.
• 12:31And the life wasn't all struggles and work.
• 12:36This is a party of the liver group.
• 12:39I think it may have been at the time
• 12:41of Gladstone's retired retirement.
• 12:45You may see a young Roberta
• 12:47Grossman and I eat it here.
• 12:49My wife Phoebe and other memorables.
• 12:53I want to say a few words about the ASLD.
• 12:56It was founded as I mentioned in
• 12:581950 and Pepto Institute in Chicago.
• 13:01When I was a fellow in 1969,
• 13:03that was my first meeting.
• 13:05The membership was only around 2:00 or 300.
• 13:08Held in the old chair in Chicago and
• 13:12and and the chairs were all movable.
• 13:17The SLD gave rise to the American
• 13:20Liver Foundation in 1976 and it
• 13:23found it the general hepatology,
• 13:25which is the primary journal
• 13:27for our society in 1980.
• 13:29Today the membership has grown
• 13:31from 2 or 300 to over 6000.
• 13:34And there are 2500 approximately
• 13:37scientific abstracts accepted
• 13:39for the annual meeting from US
• 13:42and international programs.
• 13:44An incredible growth over
• 13:45this period of time.
• 13:49Let me move now to all the board.
• 13:53From 1978 to 2009.
• 13:58Just a brief summary of my my training after.
• 14:04Graduating from Hopkins and internship
• 14:07initially at New York Hospital,
• 14:09I was in a public health
• 14:12service and interestingly,
• 14:13also stationed in Calcutta and that is where
• 14:16I also got interested in liver disease,
• 14:19studying patients with
• 14:21idiopathic portal hypertension,
• 14:23and therefore I wanted to come to Yale
• 14:26training in the field and so at that
• 14:29time I joined the faculty briefly until
• 14:3272 and spent six years then in Chicago.
• 14:35Have a good it back in 1978 to
• 14:38reorganize the liver and GI programs.
• 14:43This is a sound on paper
• 14:45from my work in India which.
• 14:48Initial recognition.
• 14:51And instead of following that field,
• 14:54though, as the verdict,
• 14:56Grossman did.
• 14:57I wanted when I was a fellow to have
• 15:00a little basic science training and
• 15:03I set up an isolated perfused liver
• 15:05with the help of Doctor Robert Shy,
• 15:07who was an associate of flats skins
• 15:09who going to study lipoproteins,
• 15:11but when I saw this perfused
• 15:13liver making bile yellow bile,
• 15:15I said my goodness around
• 15:17the world is that happening?
• 15:19And to find that answer to that
• 15:21which I still work on today,
• 15:23became a became my passion.
• 15:27Hey Mark, landmark paper from our group,
• 15:30which the localization of the
• 15:31sodium pump to the basolateral
• 15:33membrane of the hepatocyte.
• 15:35It's not here at the apricot panel.
• 15:36Acular membrane.
• 15:37And that'll allow the for us to
• 15:41develop the concept of the parasite
• 15:44as a polarized epithelium similar
• 15:46to other classical epithelia
• 15:48where the sodium pump was on the
• 15:51basolateral side and the sodium
• 15:53gradient could be coupled with anions
• 15:56like Mino acids and bile acids,
• 15:58particular to drive them into the pathotype.
• 16:02Sodium pump left the
• 16:04internal potential negative,
• 16:05and we originally thought that
• 16:07bile acids in other mannheims
• 16:09were driven into the canaliculus
• 16:11by the electrical potential and
• 16:14we were dead wrong about that.
• 16:17But I was invited to give a paper
• 16:22review and the physiological reviews,
• 16:25and I think this really launched
• 16:27my career in 1980.
• 16:33Now, as I said earlier that digestive
• 16:35disease programs needed to be reorganized
• 16:37and that was one of the reasons I was
• 16:40quoted back to Yale at the time I came back,
• 16:44there were three different programs.
• 16:45There was overturned at Yale and
• 16:48the Klatskin wanted the DA by how,
• 16:50led by Harold Kahn and a combined
• 16:53GI program directed by Howard Spiro.
• 16:57A year after I got back,
• 16:59we renewed the pathology training grant
• 17:01and it's been running ever since.
• 17:03And now under my maiden since direction.
• 17:07The Howard Spyros program,
• 17:10then in 1984, was combined into a
• 17:14division of digestive diseases.
• 17:17As for domains today.
• 17:20Then in 1984, the Liver Center was awarded.
• 17:25We had a planning grant that we submitted.
• 17:28And that was and there would be
• 17:30rewarded itself was submitted
• 17:31on a day very similar today,
• 17:33here in New Haven it was snowing.
• 17:35I had to shovel out my driveway
• 17:38to get to get in and and the
• 17:42result is positive and we are now,
• 17:46I think in our last 36 a year
• 17:48of of this award.
• 17:50Initially we had six different
• 17:52cores in the library center.
• 17:54These were these were.
• 17:57Core Patricide isolation corps
• 18:00liver perfusion corps liver plasma
• 18:02membrane isolation morphology core,
• 18:04which is entirely electron microscopy
• 18:07at that time and a clinical core
• 18:10which studied at various clinical
• 18:12disorders and liver disease.
• 18:14Research base was made up of a
• 18:17people working on cellular and
• 18:19molecular biology of the parasite.
• 18:21Transport,
• 18:22which in my area hepatic metabolic function.
• 18:26Paddock fibrosis spike thinking
• 18:29about dynamics which was converted
• 18:31Grossman this area and clinical
• 18:34studies of alphabetic panic disorders.
• 18:38But with time and folk and the
• 18:39focus of the senator evolved,
• 18:41they're a major transition from clinical
• 18:44and whole animal physiologic studies
• 18:46to cellular and molecular approaches.
• 18:49The imaging core transition from EM
• 18:52to live cell imaging and confocal
• 18:55fluorescent microscopy, but again,
• 18:57by Mike Nathenson.
• 18:59Transport studies began to be done in
• 19:01membrane vesicles and isolated the
• 19:03parasite templates and bile duct units.
• 19:06And the clinical core became
• 19:08a biorepository for for, for,
• 19:10for blood and tissue help with statistics,
• 19:14and bioinformatics and HPC applications.
• 19:17These are some of the of the
• 19:20developments in the center that
• 19:22received international recognition.
• 19:24The development of the parasite
• 19:27couplet model primary secretory
• 19:30unit of the parasite is fluorescent
• 19:33bile acids needed into the lumen.
• 19:36Also, localized proteins and this is not MRP.
• 19:40Two it's canalicular membrane.
• 19:43You also developed isolated bile
• 19:45duct units here,
• 19:47seeing again in electron microscopy,
• 19:49but in the mountain nomarski optics,
• 19:51these lives to units could be
• 19:55stimulated with force coming.
• 19:56You can see the expansion of the women
• 19:59here and these were very useful in defining.
• 20:04About secretory properties.
• 20:05Now, as I said, Sara's reputation grew.
• 20:08It attracted a wide range of postdoctoral
• 20:11fellows, and visiting faculty,
• 20:13and many came from around the world.
• 20:17Mario Strawser Vasco here as a as
• 20:19a fellow came from Padua, Italy.
• 20:21Peter Meyer, from Zurich,
• 20:24Switzerland,
• 20:24and Peter was doing transport
• 20:26studies and membrane vesicles
• 20:28here, but he went back to
• 20:30Zurich and was the first.
• 20:31His group was the first to clone the
• 20:34bile acid uptake systems, NTCP and OTP.
• 20:38This is your graph from Vienna,
• 20:41and you're trained in electrophysiology
• 20:43and he was able to be the first one
• 20:46in the world to put a microelectrode
• 20:48and illuminate the bowl canaliculus
• 20:50and measure its voltage and
• 20:53resistances fulvic borders.
• 20:54I think we will be here later with
• 20:57us today in the round table showing
• 20:59some time later on the occasion.
• 21:02Great sailor.
• 21:03He studied the effect diversity,
• 21:05actually colic acid and had coined
• 21:08the term the bicarbonate umbrella
• 21:10as a protective agent for biliary
• 21:14disorders is Michael Tranter,
• 21:16who also will be with us later.
• 21:19Later today.
• 21:19Michael was the first one to study
• 21:22nuclear receptors and how they
• 21:25regulated the adaptive response
• 21:27to cholestatic limited series.
• 21:29Satara and he's from Vienna.
• 21:32Man alright is from the Amsterdam,
• 21:34the Netherlands and Shatara was from Japan.
• 21:37He looked at the translate tosis
• 21:40within the couplets system,
• 21:42later became Chairman of medicine
• 21:44at the University of Tokyo.
• 21:46And there were many others that
• 21:49I can't have time to to.
• 21:52So Anthony Benedetti came from Ancona,
• 21:54Italy Dominic Alvera from Rome and
• 21:58Dominic Emma will be with us later.
• 22:00Adrian Rubin from England,
• 22:02Ralphie broke from Israel,
• 22:04Alan Bowen from Ireland coming to attack
• 22:08from Bangkok and many many many others.
• 22:13This is also true at the VA
• 22:15program that Humanic program,
• 22:16that was Roberto,
• 22:18our own Lupita Garcia South from Mexico.
• 22:21Tiny boats will be with us
• 22:23later from Barcelona shift San,
• 22:26who will be with us from Delhi,
• 22:29Emmanuel secular from Israel.
• 22:31Our own Misako you were carried
• 22:34from Japan and Louis Colombatto
• 22:36from Buenos Aires in South America,
• 22:38and again many others too numerous
• 22:41to go into details of the House.
• 22:44So I want to close here with a
• 22:48brief perspective of 50 yard,
• 22:50five year or like 55 year career here.
• 22:55On the scientific progress.
• 22:57That was made in the field
• 23:00during my my tenure.
• 23:02When I was a fellow in 1967,
• 23:04fifty nine,
• 23:05there were very few
• 23:07therapeutic interventions.
• 23:16Steroids though we had steroids
• 23:18for autoimmune hepatitis and and
• 23:21alcoholic hepatitis, although it was
• 23:23very controversial in that time.
• 23:25We had neomycin and enemas
• 23:27but padding concept allopathy.
• 23:29We had a limited number of diuretics.
• 23:34Done for a cities.
• 23:37We had called starmine for peritus,
• 23:39portacaval shunts and Blakemore
• 23:42tubes for Harrisville bleeding.
• 23:45And at that time there were very few
• 23:47experts in the paddock Histology and
• 23:49Klatskin was preeminent in this area
• 23:51and all the fellows were trained to look
• 23:54at liver biopsies and this was a great
• 23:58advantage as they went out into diaspora.
• 24:01College of GI programs.
• 24:05Now, over the next 20 to 30 years
• 24:08we've been remarkable progress.
• 24:10Hepatitis B was identified.
• 24:13Hepatitis A was identified.
• 24:16And hepatitis C was identified originally
• 24:18of course, called 989 B emphasis.
• 24:21Once it was antibodies to these disorders.
• 24:25That was identified in 1989
• 24:28vaccines for advertised B&A,
• 24:30of course followed those discoveries.
• 24:33And then, once the hepatitis C
• 24:35virus was able to be cultured,
• 24:38Charlie Rice at the Rockefeller.
• 24:41Viral therapies could be developed and we
• 24:45now have total cures for hepatitis CA.
• 24:49Remarkable chievement over just
• 24:52the 25 year period.
• 24:54Cyclosporine and I was.
• 24:57Discovered in 1979,
• 24:58this allowed liver transplantation
• 25:01to move from an experimental
• 25:04situation to accepted therapy.
• 25:06Parenthetically,
• 25:07the first transplant at
• 25:09Yale was back in 1983.
• 25:13Over this period of time,
• 25:14beta blockers and tips for portal
• 25:18hypertension refractory societies
• 25:20were developed or city oxalic
• 25:22acid was found to be effective
• 25:25therapy for some patients with PVC.
• 25:28And the most importantly.
• 25:31Particular phase as an elector age,
• 25:33the genome was closed the molecular
• 25:36basis for disorders like hemochromatosis,
• 25:40Wilson disease, progressives,
• 25:42familiar, antipathy, Cholestasis,
• 25:44and other monogenetic disorders
• 25:48was made possible.
• 25:51Well then we come to the new Millennium 1966.
• 25:55Jim Anderson became chief of the
• 25:58tested diseases for a period of
• 26:00six years before he was lured away
• 26:02to University of North Carolina.
• 26:04The head of the Physiology
• 26:07department is now NIH.
• 26:09And Michael Jackson came to
• 26:12be chief a year later.
• 26:14Digestive disease until 2018.
• 26:1710 years as a director of the Liver Center.
• 26:23This is a good segue to pass the
• 26:26baton to Michael and thank you
• 26:29for being here with us today on
• 26:32this on this wonderful journey.
• 26:35Of our Jubilee and hepatology in jail.
• 26:39Thank you very much.
• 26:42So Jim, thank you very much for
• 26:45a very comprehensive and history
• 26:47of our illustrious work at Yale
• 26:50in in liver and GI disease.
• 26:52And I want to remind the audience if
• 26:54they would like to ask a question.
• 26:55We still have some time few minutes for
• 26:57questions and if you want to ask one,
• 26:59you can use the the Q&A function
• 27:03of of zoom to to do that.
• 27:05And and if not,
• 27:07I'm looking forward to meeting you at
• 27:10our next meeting next next talk which
• 27:12will be given by Doctor Nathanson.
• 27:19So Jim, why are we waiting
• 27:20when we have a few minutes?
• 27:22Maybe I can ask you a question,
• 27:24what what would you have hoped
• 27:26to accomplish in those many
• 27:28years and that you haven't done?
• 27:31Sorry to repeat.
• 27:32I want to ask you what you would have
• 27:35liked to accomplish in your many,
• 27:38many years that year and
• 27:39you didn't manage to do it.
• 27:44Well, I guess we would provide
• 27:46some Nobel prizes. Probably
• 27:48I mean you've done so much right exactly.
• 27:54But I've had a marvelous career
• 27:58and it's been an honor and a
• 28:01privilege to have said to be able
• 28:04to help move the class Canaria
• 28:07into to the modern modern era.
• 28:10That that's why. And to combine
• 28:13all of our diversity activities.
• 28:18The car is probably the
• 28:20most important account.
• 28:22Good well thanks again.