The Birth and Evolution of Medical Renal Pathology

April 25, 2022

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April 21, 2022

Yale Pathology Grand Rounds

Michael Kashgarian, MD, FASN

ID7753

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00:00Quantum everyone for the forest.
00:05In person grand wrong
00:07of pathology department.
00:08After two years and then required this.
00:13This is a special marker lectureship for
00:16excellence in search of the apology and,
00:20very fittingly, it goes through the area.
00:24It's so it's pretty because Mike
00:29was the one who actually started
00:33raising funds for this lecture ship
00:36to honor his teacher and mentor,
00:39William Barry.
00:41Listen junior Barry McAllister was
00:45a graduate of the college and of the
00:49Johns Hopkins Medical School and the
00:52Department of Pathology at Johns.
00:55Pockets after this training he
00:57came back as chief of surgical
01:00typology for the memorial dynamic
01:03of the year new in the hospital.
01:07In that position, he said for 25 years,
01:11from 1953 to 1978.
01:15It was during that period that.
01:18Michael was a resident in the topology,
01:21rotated with him, and learned from him.
01:25This too was a consumer diagnostic
01:29apologist and educator whose teachings were
01:32not limited to the science of medicines,
01:36but they also extended to to
01:39the art of living.
01:40She was an extraordinary motor advisor,
01:44friend and confidant to students,
01:48residents, who workers and
01:52physicians from all disciplines.
01:55With that introduction from the department,
02:00we have a 200 gratitude.
02:05Owner Mike,
02:06as well as the listener.
02:12Thank you so much Mike.
02:20Hello, a long time colleague
02:23of mine. When they get short.
02:31OK, thank you, Manju.
02:33And it is a great honour.
02:38For me to introduce today's
02:42McAllister Memorial Lecture, speaker,
02:44Doctor Mike Fisherian Mike came to
02:48Yale 68 years ago to attend medical
02:52school after graduating from NYU.
02:54And he has been associated
02:57with the ever since,
02:59was just short interruption of internship
03:02at Barnes Hospital in Saint Louis
03:06and Research Fellowship in Germany.
03:09Might is known for being one of the
03:12founders of the field of renal pathology.
03:16And he has worked all of his professional
03:18life to move the field forward and
03:21disseminate the knowledge of renal pathology.
03:24But then he was giving the lifetime
03:27achievement award the Robert
03:28Heptinstall Lifetime Achievement
03:30award by the Renal Pathology Society.
03:34Moreover, Mike would say
03:36quintessential physician scientist.
03:38During residency,
03:39he spent a year in the Physiology department
03:43of Cuttington University in Germany,
03:46working with the renowned leaders
03:48of German Physiology that called
03:51Krama Cal Orey had called.
03:53Throughout his professional career as
03:55an academic pathologist here at Yale,
03:58he forged many collaborations with
04:00faculty and Department of Physiology,
04:03Cell biology and Internal Medicine,
04:05which led to over 350 peer
04:09reviewed papers in top journals.
04:12And these collaborations
04:14were very dear to him.
04:17I remember when I started out in
04:20renal pathology at Yale that very
04:23prominent physicians and scientists
04:25would walk in and ask for Mike.
04:28They never asked for Professor Casparian.
04:31They always ask this Mike here.
04:33Can I meet with them?
04:34So he had this very personal relationship
04:38to all these stranded collaborators?
04:41Umm?
04:42So Mike's achievements and the list of his
04:48achievements in the city is sold on all
04:50the leadership positions that he has held.
04:53All of the prices he has won all the
04:56communities that it would take another
04:59hour to go through all of that.
05:01I just want to mention that in addition to
05:05being an exceptional physician and scientist,
05:09Mike is also exceptional human being.
05:12This specific activities over many
05:14years in the Church of Christ,
05:17Yale,
05:17New Haven Symphony Orchestra,
05:19and in the Connecticut Fund for the
05:21Environment show his deep and broad interest,
05:24dedication in the local community,
05:27where he has lived over 65 years.
05:30I think that we are the best would
05:33have Michael Sharian as a leader and
05:35Mayor Thomas and our department,
05:37and especially for the
05:39junior faculty and trainees.
05:41Mikes life achievements are
05:44great template for their all
05:47professional professional life model.
05:50So when it's title is the birth
05:52and growth of renal pathology,
05:55today's Macalister Memorial lecturer
05:57please welcome micro sharing.
06:07Well, it's a particular,
06:10particularly wonderful honor,
06:12but also an interesting
06:13experience to be here in the at
06:17the podium instead of up there.
06:19And I noticed that you that
06:22things have improved around here.
06:24You all have a box ledge instead
06:26of having to go and get pieces
06:28of of of whatever is left.
06:30Over one of the the attractions
06:34of the of the.
06:36Grand rounds at but of pathology
06:38is that it brought in an enormous
06:40number of people because there
06:41were there were good lunches here.
06:48I'd like to make one a couple of
06:52comments about Barry McAllister.
06:54I think he was a consummate
06:58surgical pathologist.
07:00He was he was a general surgical pathologist.
07:03Everything he and everything that
07:05came to him, he would look at.
07:08He would be an expert in the memorial
07:12unit was populated primarily by.
07:17Community physicians and surgeons.
07:20And they actually really look to
07:24him for for help and assistance.
07:27Now it was this very small room
07:30and with the way we did frozen
07:33sections was kind of interesting.
07:36We I would take get the specimen,
07:39take a small piece of it,
07:41put it in a bottle cap with full
07:44formalin and put it over a Bunsen burner.
07:47To cook it,
07:48and once it was cooked then I put it.
07:51I froze it on a freezing microtome
07:54and and and and that made sections
07:58which we stay in primarily with H&amp;E.
08:02But if necessary,
08:03we had the opportunity to use
08:05some special stains as well.
08:07So it was.
08:08It was really an interesting
08:10way of doing things,
08:12but it was one where at least
08:15for residents who worked there,
08:17we there was a broad ordening experience
08:20on how to deal with different surgeons.
08:24And there was one surgeon
08:26that the gynecology,
08:27who thought that he knew it all.
08:30And he would come down.
08:32And it was, if it was a particularly
08:34if it was an ovarian tumor,
08:36he would never take a Barry
08:40diagnosis for granted.
08:41He would have to look at it
08:44himself and finally decide that,
08:45yeah, it was a bit what it,
08:47what,
08:48what Barry was saying is really what it was.
08:50He had been in in Boston.
08:52And so he thought that some
08:54of that Bostonian stuff had
08:56rubbed off of him on him.
09:00And I actually, you know,
09:03we have a student plays.
09:06And I actually was.
09:09Took his part and I sang song
09:13that my name is John McCain.
09:16John McCain.
09:19And and and a marvelous GYN surgeon, am I?
09:25And and that's sadistic
09:28statistic is my characteristic,
09:31and I'm in love with a wonderful guy.
09:35And and but, but he really.
09:38But Barry was able to handle
09:40any anything that came as well.
09:42And it was. It was.
09:44It was a joy to work with him as a.
09:48As a matter of fact,
09:50I started working with him in the summer
09:52and he would always leave at 4:00 o'clock.
09:55The reason he had to leave at 4:00 o'clock
09:57is that was he had to catch the the
09:59the ferry out to his island in the thimbles,
10:02and so I would.
10:03I would be I would be left taking care of
10:06all of these private surgeons all by myself,
10:09and it was quite an experience.
10:13Well. Uh.
10:16It knows surgical pathology is
10:21relatively new as a sort of a discipline.
10:24You know people were
10:25doing autopsies for many,
10:27many years,
10:28but none of them ever really made
10:31a connection with the with the.
10:34With the clinical experience they
10:36just did it mostly for anatomy and
10:39anatomists were the primarily dissectors,
10:41but surgeons would also dissect,
10:44but they they would not really use the
10:48their findings in an academic way until
10:51Giovanni Battista Morgani, who is?
10:54Who we can call the father of modern
10:58anatomic pathology, he wrote this book.
11:00They said it was a crisis mode.
11:02All of them that are in the in the goddess.
11:06In 1917. Sixty one.
11:10And the.
11:11That's translated and I'm not,
11:14and I will somebody else translated for me.
11:16I'm not good at.
11:18At Latin the seats and causes of
11:21disease are as investigated by anatomy.
11:25And in him,
11:26and in his thesis he just says the
11:30description of gross pathology.
11:32Represents the cry of suffering
11:35from the organs,
11:37so the organs sang to him and
11:40and and and he really and his.
11:42His book was really one one of
11:47the only theses that that had
11:50used anatomic pathology.
11:51Anatomic pathology as part
11:53of overall part of medicine.
12:00That's it.
12:05Nephrology in those days was
12:09didn't really exist unless you
12:12wanted to and because most of the
12:15diagnosis was done by **** prophets.
12:20And they juggled the *******
12:23and we have to juggling.
12:25The ******* would come up with a
12:28diagnosis and now that wasn't that
12:30it was not with one single profit,
12:34but the profits used to
12:37help and consultation.
12:39And you could see runners coming going
12:42across the city carrying despots from
12:44one place to another for diagnosis.
12:47Well this was this. Uh.
12:52This treatise here is a criticism of of
12:56of the process and and and and and it,
13:01Brian says the fraudulent use
13:04of uroscopy by by examining the
13:07patients by is by some physicians.
13:12He called them quacks.
13:14And so you're right,
13:18Nephrology was really that
13:21much well developed.
13:28However, Richard Bright.
13:32In English physician.
13:34Decided that he was be that the.
13:38The physicians were seeing
13:41patients with dropsy.
13:44And and where they had.
13:47Albuminuria.
13:50And so they were swollen.
13:52They had the nephrotic syndrome.
13:55And he decided that he should
13:58look at all of the patients with
14:00them and he came across him.
14:02He created a,
14:04a categorization of the diseases
14:07which were associated with dropsy.
14:11And they they covered into
14:15the inflammatory diseases.
14:17And and he talks about acute and
14:20chronic popular in Ireland on Fridays,
14:23lipoid,
14:24nephrosis acute and chronic
14:27pyelonephritis and nephrosclerosis
14:29associated with cardiac hypertrophy.
14:32And that and and that combination
14:34of of nephrosclerosis and
14:36hypertrophy was actually looking
14:38at patients with hypertension.
14:41Umm?
14:42And his categorization of of renal
14:46diseases lasted not because there
14:49was no real nobody else who even
14:52took on the attempt to look at the
14:56cause of dropsy and and and whatnot.
14:59So his.
15:03But on the other hand,
15:05the in the and in the 19th
15:09century there were several.
15:12Anatomists,
15:12who were interested in the
15:14kidney and one was the Alcop,
15:17had Henley.
15:19And he was the one who was
15:23looked at the kidney and saw
15:25that it was made up of tubules.
15:28And the tubules were the organ,
15:31and not the not,
15:33not the the overall organ,
15:35and he I,
15:37I think you probably all remember that
15:41that we talked about the the Henleys loop,
15:45which was is responsible for
15:48maintaining our internal environment
15:50and the concentration of your.
15:53So.
15:55As it turned out,
15:57when I had a fellowship in Germany,
16:00I went to Gottingen which was
16:02the same place that he had been
16:04so kind of a double honor.
16:09And the other person of of of
16:11prominence in the 19th century
16:13was been a glaude bell now.
16:15He described the the million terrier.
16:20He he was saying that the the the,
16:24the fluid that exists in
16:26our bodies surrounding it,
16:28surrounding the cells with very important,
16:32and it had to be kept in relatively.
16:37Close concentration and of ions
16:41and also in terms of its tonicity
16:46and that it had to be stable.
16:50And so the interstitial fluids
16:52had to be actively maintained
16:54around stable settings,
16:56so that and that the stability was
16:59a prerequisite for the development
17:01of a complex nervous system.
17:03Umm?
17:07Uh, so that the fluids where it
17:10being interested were were were of
17:12interest and but we're not really
17:15being investigated very well,
17:17so I'm jumping to the Yale
17:20University to Yale Medical School,
17:22the Internal medicine,
17:25internal Medicine department in the
17:28early 20th century, relatively small.
17:30They had maybe had four or five professors,
17:33and. The giant planet Peters.
17:40There was a case,
17:42and so he established chemical laboratories.
17:45And and he saw almost every patient
17:50in the in the hospital and to
17:53look at at at their electrolyte
17:57balance and and water balance.
18:00And he set up these laboratories and he
18:05became with a with a a chemist colleague.
18:09He wrote this book,
18:10the clinical Chemistry which
18:12established a whole.
18:16Science of clinical chemistry.
18:18So there was interest in looking at the
18:22body's fluids, but not the we weren't.
18:25They weren't really looking at how the
18:28body fluids were being maintained.
18:31Aside story about. Leaders.
18:36Is that during the time when?
18:43People were being examined for
18:46being communists and and whatnot.
18:49He was that he was attacked
18:52and and and his his he.
18:56Famously, his NIH grants were cut off.
19:00Uh, and he went and he. Umm?
19:07He challenged that in the courts.
19:11All the way up to the Supreme Court.
19:15And the Supreme Court upheld his position.
19:18Unfortunately,
19:19he never heard it because he died just
19:23before the Supreme Court made its.
19:26Decision that that and so.
19:31It he's his, his legal.
19:39History is also important.
19:40It's in that it's in the
19:42archives here at the library.
19:49The brides characterization
19:50is the renal disease,
19:51which remain the standard.
19:54Until the 20th century.
19:57And in the early 20th century. 2 Germans.
20:03Full height when far wrote a textbook.
20:07I'm diseases of the kidney. And.
20:13Are made pet plants painstakingly accurate?
20:18Drawings of the Histology of
20:20rights disease and if you look
20:23at at at his drawings you think
20:25that they were microscope.
20:27They were microscopically produced,
20:29but no, he did it by drawing.
20:33Umm? And there's this was
20:36published in the British.
20:40And early in 1914,
20:43so there was beginning interest in.
20:48Renal diseases and their
20:51effects in patients.
20:54It was not until the 1950s that.
20:59There was a lot of valuable
21:01to take biopsies of the
21:04kidney and examine them and.
21:09Robert Clark and Robert Merky at
21:12the University of Illinois decided
21:14that they would try and do it,
21:15so they actually started
21:17to do needle biopsies of.
21:22Of the kidney, and they needed
21:24a pathologist to look at them.
21:29And the chairman of Pathology
21:31there went to the the youngest
21:34pathologist in the in the.
21:38In the department because he didn't
21:40think anything would come of it.
21:42That was that what it was
21:44totally useless to do this.
21:47The pathologist was Conrad Pirani.
21:50Ohh became one of the leaders of retail
21:55pathology in the 20th century. Umm?
22:01In 19 six enough people.
22:03Not very many people were doing.
22:05If I have this other kidney,
22:08but it was in in in in 1961 the Ciba
22:13Foundation hold held a symposium in London.
22:18And 29 physicians and pathologists met.
22:23To discuss what they thought was the
22:26utility of doing needle biopsies of
22:28the kidney and what it would find out.
22:36It was it they came through
22:38some interesting conclusions.
22:40One is they felt that if if
22:41the biopsies were being done,
22:43they should be looked at by people
22:45who were expert in looking at them.
22:49And that.
22:52And that they should be done
22:55in an organized fashion. And.
23:01And they came up with some standards
23:04of Care now this this is a little
23:07bit of expansion of the standards
23:09of care that they came up with,
23:11but the standard of care.
23:13For the medical renal biopsy became
23:16serial thin section paraffin embedded.
23:21Umm? Slides stained with HEPS Jones
23:25silver triple that bottle of water.
23:40Thank you.
23:48Some immunologists were also becoming
23:51interested in in in the renal disease.
23:56And they decided that that some of the
23:58diseases that they were looking at,
24:00like commercial or Fridays,
24:02were immune mediated and so they
24:05started to look at that real biopsies
24:07using fluorescence techniques where
24:10the antibodies were directed against.
24:13Immunoglobulin is kind of
24:15complement components,
24:17and if there if was known of any
24:20specific antibodies to the antigens.
24:23And and, and and and so that fluorescence
24:29examination of the biopsies became also
24:31part of the of the standard of care.
24:38Are they some centers? Also felt that
24:43electron microscopy might be useful and.
24:50But the cell biologist felt that
24:53that was in there first purview,
24:55that that wasn't for pathologists.
24:58They got to be a cell biologist
25:01to look at and Marilyn Farquhar.
25:04Decided that she would look at the
25:07at the kidney and she did look at
25:10the kidney and then actually found
25:12the that that the effacement of
25:15the foot processes in patients with
25:18dropsy or or nephrotic syndrome. Yes.
25:23But that expanded very quickly to
25:27other electronic microscopists and.
25:31I'm I was in. I came back from my my.
25:39My fellowship in Germany in 1962
25:42and I was able to not only establish
25:46my micropuncture laboratory,
25:49but I went and started to do a kidney
25:56biopsies, but I needed a clinician.
25:59Because you can't do it by yourself.
26:03And the nephrology section who
26:07helped me in establishing my my my.
26:12My laboratory also sent me a fellowship,
26:17a fellow.
26:18His name was John Hazlett and he was he.
26:22He was beginning to learn how to
26:24do a micropuncture and we did a
26:27number of studies looking at at
26:29the maintenance of the electrical
26:32potential across proximal 2 views so
26:34that we absorption could occur but
26:37at the same time he ran a clinic.
26:39The clinic for patients with lupus.
26:43And so he he talked to me, and he said,
26:47well, maybe we should biopsy them.
26:49I said, OK, if you can biopsy them,
26:51we can look at them together and
26:53that any any did,
26:54and we we collected and biopsies
26:59from some 200 patients with lupus.
27:05Uh, we we actually.
27:10And engaged a British epidemiologist who
27:13is in the Department of Medicine at that
27:17time to help us in in analyzing what,
27:21what, what we found. And we found some
27:25very interesting things by this time.
27:28By this time I had a small
27:31electron microscope,
27:31so we were doing EM here and one
27:35and we found one of the interesting
27:38thing is that the the patients
27:41with the most severe disease had
27:45subendothelial electron dense deposits
27:47and they had my immunofluorescence.
27:51Multiple immunoglobulins and compliment.
27:55And so we. We were able to look
28:00at these patients overtime.
28:02And and at that time the only
28:04you know therapy was used.
28:09Azathioprine and so.
28:10All of these patients were
28:12treated in exactly the same way,
28:14and we could see what the outcome was.
28:18And we, with the aid of the epidemiologists,
28:22we wrote papers on on what
28:25was what were signs of and of
28:29of progression, and so on.
28:32And he did something really,
28:34really interesting.
28:37He selected, I think it was about
28:4120 nephrologists in in Canada.
28:44And he gave them the history of
28:48those patients. Without the biopsy.
28:53And he asked them to come.
28:55And and the. The agreement between
29:00them was not really great and there
29:03was a lot of questions about it.
29:05He then gave them the results of
29:08the biopsy and everything codified
29:10into the groups of patients that
29:13were existed and one and that the
29:15treatment actually was was useful
29:17in in diminishing the inflammatory
29:20process that was that with lupus and
29:23and so it became that the biopsy
29:27actually became a very useful tool.
29:30In in clinical nephrology.
29:34Umm? So, so the standard of care,
29:39and this is an expansion of that.
29:41Was that the medical renal biopsy
29:43had to be done on biopsy on serial
29:49thin section paraffin embedded
29:51slides so that they were we.
29:54We would have a a bunch of slides.
29:58At and looked at serially so we could
30:01see a a greater number of glomeruli
30:06and and variety of vessels. Umm?
30:10Uh, and and we we we we did as the
30:14immunologists were taught, told us to do.
30:17We look for immunoglobulins.
30:19And indeed we found them.
30:21And one other outcome of the
30:25treatment was that there was a
30:27shift from the acute inflammatory.
30:32Elephantitis of lupus to the membranous
30:35of form of lupus which was not
30:38which had no inflammation at all.
30:41But it had the deposits of
30:44immunoglobulin in the peripheral
30:47basement membrane and and and the
30:51patients all had an abnormal.
30:54Your ends with with a lot of protein in them.
30:58Umm?
31:03Now, so that a renal biopsy has with or
31:10with all of these different parameters.
31:14That you have is is not a
31:18simple means of diagnosis.
31:21You know you're a surgical pathologist.
31:23You look at the slide,
31:24you call it cancer.
31:25Tell the surgeon would take
31:26it out and that's about it.
31:30Here with the renal biopsy that the
31:33nephrologists were more interested in,
31:36the not only the the the disease process,
31:41but what what could be
31:44predicted about the possible.
31:47The possible response to therapy and
31:49those days it was immuno immunosuppressive
31:52therapy was just beginning and
31:55cyclophosphamide and some other
31:58immunosuppressants were were being used
32:00and so they wanted more information.
32:03And so it was necessary to do all three.
32:09Types of microscopy to come up with
32:12an come up with a diagnosis. Now.
32:18The approach for for diagnosing renal
32:23biopsy requires information from
32:25these several different sources to be
32:29integrated into a single interpretation.
32:32The sources included the clinical
32:34data examination by light microscopy,
32:38immunohistology and electron microscopy.
32:41Each of the sources.
32:44Has several individual variables in
32:48terms of which which immunoglobulins
32:50are involved with the local localization
32:53of the immune complex as well and and
32:57and they had to either be included
33:00or dismissed in in in order to
33:03make the final diagnosis.
33:04George boole who was a 19th century.
33:12Pastor, he was a he was at.
33:14He was a clergyman.
33:19And he developed. Umm?
33:23A A branch of algebra.
33:28Which which this this?
33:31Either that variables could
33:34either be included or dismissed.
33:38And that they were either
33:40positive or negative.
33:42And this branch of algebra,
33:46which the value variables or
33:49truths or or or or false.
33:52And then this expanded the range of
33:55applications that had to be handled
33:58from proportion propositions that
34:00only have two potential values
34:03to those that have many and.
34:06And really so that looking at the
34:09kidney biopsy is is is a method.
34:12We're all doing Boolean algebra.
34:17Now.
34:21He wasn't the only clergyman who was
34:25interested in looking at things in
34:28a different way, and Thomas Bayes.
34:32Uh. Decided that that his
34:38statistic using statistics.
34:40It was that one that Bayes theorem
34:44provides a way to revise the findings of.
34:50Of the findings of the biopsy,
34:53both light microscopy and whatnot,
34:55and put them into categories again.
35:01Again. Saying OK,
35:05This is the pattern that we would
35:08see and and then with with with
35:12Bayesian statistical methods.
35:14That's the way AI started.
35:18So AI actually is using Bayesian
35:21statistics to take a large number of
35:24of variables and look at the of the
35:27individual variables as variables
35:29as well as individuals as well as
35:33the variables of themselves and
35:36in the patterns there are, and.
35:38So what what happens is that you
35:41look at the light microscopy and
35:43you have one level of of. Of.
35:46Of information you add on to that a
35:50second level of the immunofluorescence.
35:54And then you add on the third
35:56level of immunofluorescence.
35:57And if you think about what I what
36:00AI does is it looks like it looks
36:03like it looks at the data and at
36:06one level and then looks at the
36:09second level and and decides whether
36:11or not it has a contributory way
36:14of looking at a final result.
36:19And and. AI does does this with with
36:25with large volumes of of of data,
36:29and so you really need to have the
36:33computer backing that to do this with.
36:36Umm?
36:36And so the data of the single
36:39biopsy went are analyzed further
36:41by using our AI and and and within
36:46the background of existing data.
36:48The predictive value of the biopsy
36:51in the sector in the selection of
36:54therapy and outcome is greatly enhanced.
36:56So. You know the.
36:59The application of AI to looking at the
37:04kidney biopsy has become at least somewhat.
37:11Of interest, there's a group in and in Paris,
37:15which is looking at patients with lupus
37:18and and looking at all the data and and
37:21that can be obtained by from the biopsy
37:24and lupus and and and predict. See.
37:29The. There's a group here at at Yale
37:35that is looking at donor donor biopsies.
37:39There's a, there's a problem,
37:41and that we don't have enough
37:43donors and a lot of donor kidneys
37:47that are dismissed without good.
37:50Reason and so they are.
37:53They're working on on and and actually
37:58those of you who have to do the the
38:00the county of the Gloria glomeruli.
38:02And looking at the vessels and donut
38:06donor biopsies should realize that they
38:08that there's a lot of information there.
38:11But you can't just look at it and say OK,
38:15no good because we have too many goals,
38:17sclerotic,
38:17Andreoli or the vessels show arterial.
38:20Sclerosis and so.
38:22The group here is is using
38:26artificial intelligence to look
38:29at the at at digitized images.
38:33Of the of the donor biopsies and coming
38:37up with algorithms to to separate out
38:41those which which is going to be useful
38:44and those that are not so I think.
38:50The the renal biopsy now is is an
38:54experiment in, in and of itself.
38:59You know, when and and and it requires a
39:03lot of data and it's sort of interesting
39:06that when I came back from Germany in
39:121961, nineteen 62. The number
39:16of biopsies that would have
39:17been done here at Yale was 10.
39:22We we now have, what is it over 10,000?
39:28Yeah, but without that thousand
39:31a year so overall for overall,
39:34maybe even more than 10,000.
39:37So we so we have the the data
39:43bank which is necessary to use
39:47artificial intelligence and and
39:50and and come up with new ideas.
39:56And the The thing is that the
39:58what we get from our artificial
40:01intelligence is what the data tells us.
40:04But once put, when they're when they're
40:06put in the context of the clinical situation.
40:10Well, there there are some visual
40:13findings that that that that can be
40:17linked to disease outcomes and that
40:19and that and can be mined to discern
40:23previously unknown molecular mechanisms.
40:26So my advice to all of you in surgical
40:30pathology is when you look at a slide think.
40:36You know when when, when desktop computers
40:40first came out and you at a very high
40:44price IBM would give you this then this
40:48desktop computer at $10,000 and not
40:50very much information on how to use it.
40:53But all also gave you a plaque.
40:56Not the Plackett said think you had
41:00to hang a plaque over the computer
41:02so that it would work. So I think.
41:07Umm? We're now we, we are now.
41:10I guess we have a a something which would
41:15where we can digitize our our our specimens.
41:20And and if we digitize.
41:25Do this over a period of time.
41:27We will get sufficient data so that
41:30we can can come up with new ideas.
41:35Ideas that we didn't without premises.
41:39And I think we're in a new new way,
41:44so my advice to the residents and especially
41:50residents who are in the front lines,
41:55is think how you can use the multi source
41:58data obtained from digital biopsies.
42:01When we begin to apply.
42:05So I'm happy to answer any questions.
42:18Yes.
42:20I was a young president
42:21here. One of the things that impressed
42:24upon me was said, you know, I didn't
42:26know. The rest is true.
42:29Comment on what you say.
42:33Well, it says that in to the
42:37results from immunofluorescence or
42:39have several variables in that are
42:43intrinsic in the preparation so.
42:49The the, the nature and strength
42:51of the antibodies is 1.
42:54The preparation and of the
42:58specimen is another.
43:00The combination of of of
43:03the ability to have good.
43:10Good samples that you can compare,
43:14and so when you're looking at,
43:16you're looking at new antibody with.
43:19For IgG it's a common.
43:23Common antibody you have to look at.
43:27You can't just look at 1 biopsy
43:30and say oh the IGT is in in the
43:33mesangial We haven't know that
43:36when you look at it normal.
43:38Of kidney that with that same
43:41antibody that it shows nothing.
43:44We need the controls and so it's tricky.
43:48You have to really know what you're doing.
43:52You have your selection of bio of of
43:56your 8 reagents is important your your.
43:58Yeah.
43:59Your validation of those
44:01agents is very important.
44:05And I think, but on the other hand,
44:09you know with experience and.
44:14Of using fluorescence and I
44:17know that you've done a lot,
44:19particularly in terms of
44:22quantitative fluorescence,
44:23it all of these things take it are
44:26have to be taken into consideration,
44:29but it was tricky enough for you to do.
44:36What were you ever bored?
44:39Bored, bored? What's that?
44:45No, you know that's that's the thing
44:49that every time you do something,
44:51something else pops up.
44:54And you never sit there and and
44:57try and sit on your laurels.
45:00You have to look at it and and say OK,
45:03what, what, what, what does this mean
45:06and and does it really mean that?
45:08You you really and and the.
45:12The fact that I was constantly
45:15interacting with clinicians,
45:17they never let it be bored or boring.
45:20They never let it.
45:22They would never let me do things
45:24without complete explanation.
45:26I would have to go over
45:29every slide and with them,
45:30and they had to learn as much
45:32pathology as I could teach them.
45:37So I think. So much for
45:41this historical perspective
45:43that I think
45:44you glossed over very
45:46modestly. Thank you, your contributions,
45:50but I'm just struck by a couple of things.
45:53That first of all,
45:55to share that it was also hepatologists
45:59and gastroenterologists who made
46:01ologists look at tiny liver dies and
46:04tiny and discovered the obtained Posa.
46:09Jerry Askin right here in the
46:12liver with Grandmaster and they
46:13sorted that out and sign.
46:15Ruben was one of the fathers of modern.
46:20So that's one comment, and so the
46:24analogy is that our pathologist
46:27had to be pulled along.
46:30And I wonder the analogy being with today,
46:34as you're making this comment that
46:36we are also being asked today to
46:40go along again with with digital
46:44and AI and machine learning.
46:45And so this is another in
46:48the right direction.
46:50So I have to see it instead of the treatment.
46:53Well, you know it always interested
46:56me that the two that two Protestant
47:00clerical clerical clerics in the 19th
47:05century came up with ideas about thought.
47:09And how thought and came out
47:12in terms of of giving answers.
47:16And I said, well, maybe look,
47:19maybe they're looking for a proof of God.
47:24They're looking at what's
47:25what's going on in the world,
47:27and they looking at the statistics
47:30of what they see and so.
47:32But the Boolean algebra and the Bayesian
47:36statistics are really interesting things
47:39that can't come come from clerics.
47:43Who you know you think?
47:46Well, the only thing they
47:47ever do is read the Bible.
47:49And read it over and over and over again.
47:52But you know,
47:53if you read it over and over and over again,
47:55you have a different interpretation
47:56of what you read from the last time.
47:59Yes,
48:00Mike, thanks for this greater lecture,
48:02so I don't know if we use you
48:05remember the first time you
48:07start doing the the real biopsy?
48:13So how do they transform the service?
48:18Well, the first time I had to do
48:21a biopsy on a kidney transplant.
48:24Well, I was my wife and I
48:26were at a cocktail party.
48:30Have you had a cocktail party?
48:33And I got a phone call saying
48:36that I had to come in.
48:38Because I had to look at
48:41some transplants. Now the.
48:45The the electrical surgeon who was
48:47who was also at the cocktail party
48:49so so we we the two of us went
48:53into totally unknown territory.
48:58And we had a we had.
49:02Basically what we were looking at was
49:05to see the viability of the tissues
49:08that we were getting because the our
49:11our patients were a group of Yale
49:14undergraduates who are coming back from
49:17chasing girls up in in in Massachusetts.
49:22Because that's where the girls all the
49:24troops were and they they ran into fog.
49:27Mine on I-91 and it was it terrible
49:33and six or eight of them were killed.
49:37And their parents actually were
49:40the ones who suggested that they
49:44that they that they be selected
49:47for transplant at the donors,
49:50and so that was those were the first ones,
49:53that that way I had to look at.
49:57And then The thing is that we
49:59hadn't got transplants here before.
50:02These were the first transplants.
50:04And it was important to know whether.
50:08That whether they were.
50:10Whether they would they would
50:12bear with rejection or not at all
50:14over the period of time that they
50:16were being observed clinically.
50:18And so again, we had to learn.
50:21Or I had to learn.
50:24And I, but again,
50:26I learned with the clinician.
50:28And and and we we came up
50:32with actually the 1st.
50:35Regret categorization of of of
50:38transplant rejection and it was because.
50:43I I if I did it alone,
50:46it would not have been as as important.
50:49The fact that the that I did it with a
50:53clinician at my side was was very important.
50:57And actually,
50:58when when you talked about that the klatskin,
51:03the first renal biopsies that were
51:05that were being done when I came
51:08back in Doctor Clasko's laboratory.
51:10Because he was.
51:11He's already experienced at
51:13doing liver biopsies,
51:15and his laboratory was experienced
51:17in making the thin sections and
51:21staining them well and limiting the
51:24variabilities and it it gave us.
51:28The opportunity to do it.
51:30The other thing that he did was.
51:33With every biopsy that he did.
51:36He he had,
51:38he created a card with punch holes in them.
51:43You had a card with punch holes in them,
51:45and each of the punch holes meant meant
51:48meant something about the the the.
51:50The laboratory findings that
51:52clinical findings and so on.
51:54So if you wanted to find out something
51:56would stick a needle into the into the
51:59bunch and then pull out the pull out
52:01the the group and and so that was when.
52:09Actually I was working with working
52:12with John Hazlett in the in in the.
52:15In these patients with lupus,
52:18and we essentially did the same thing,
52:20but I didn't.
52:21I didn't have punch cards,
52:22but but it was a matter of
52:25tabulating the data in such a way
52:28that the data was not static.
52:32The data was was was.
52:35Something which was was predictive
52:38and and was and and we didn't even
52:42know it was going to be predicted.
52:45And so without trying we could.
52:48We couldn't do anything.
52:50But but we try and we did.
52:54And and you know, that's.
52:56The opportunities here.
52:59In pathology are enormous.
53:02You just have to.
53:03You just have to decide to think for
53:05them and think about them and do.
53:11And I like doing it if the in in
53:13renal disease and and the fact
53:16that we now have over 10,000,
53:19maybe even more a year, years of experience.
53:24Well, I I produced in Atlas.
53:28Yes, it was actually.
53:30A clinician who wrote a
53:32big tone on nephrology.
53:35Came to me, I think maybe 20 years ago and
53:40said we need an Atlas of the pathology.
53:44To go along with this with this arbeitete,
53:49our big textbook of of of nephrology.
53:53And so I I got I got I.
53:59Wanted to do it by myself.
54:01I know I couldn't.
54:02And I didn't.
54:04I was unhappy about doing
54:06it with a with a committee.
54:09The committees don't get very much done.
54:14And so I was lucky to recruit Agnes Fogel.
54:20And so the two of us.
54:24Put everything that we knew and from
54:27our selections in into that book.
54:30And so the. The 4th edition
54:32just came out just came out.
54:42Well, thank you for listening.