Yale Psychiatry Grand Rounds: January 28, 2022

January 28, 2022

Information

Robert Malison Lecture: "A Celebration of the Life and Science of Robert Malison, MD: The Biology and Treatment of Substance Use Disorders"

Richard Carson, PhD, Professor of Radiology and Biomedical Imaging and of Biomedical Engineering, Yale School of Medicine

Joel Gelernter, MD, Foundations Fund Professor of Psychiatry and Professor of Genetics and Neuroscience, Yale School of Medicine

ID7383

To CiteDCA Citation Guide

00:00It has been a a really remarkable and
00:04heartbreaking year of losses for our
00:06department and we're here today to
00:08remember and celebrate one of them.
00:11One of the Giants personal friend
00:13of mine and a mentor of mine as
00:16well as so many of us Bob Malice.
00:18Bob, known to to most of you,
00:21I think, was a central figure in the
00:24department in residency training.
00:25He ran the Neuroscience Research
00:28training program and and mentored a
00:30generation of physician scientists
00:31and was one of the most generous
00:34giving people that I've ever met.
00:37In addition to being an extraordinary
00:39scientist and A and a pillar
00:41of our community.
00:42We had hoped he died unexpectedly.
00:45As you all know, in the summer of 2020.
00:49At home.
00:50And we had hoped to gather in person,
00:54and we've delayed this memorial a bit in the
00:56hope that we'd be able to gather in person.
00:58But as it's become clear that
00:59we don't know when that will,
01:01when that will be possible,
01:02it's really.
01:03A heartbreaking joy to be here together
01:05and gathering his memory today.
01:10We're joined, I believe, by Bob's
01:12wife Jean, daughters Katie and Emily.
01:14Jean sent me and Sean this picture yesterday,
01:17which I think captures much about Bob.
01:23This is Bob on the CNRU and the
01:26Connecticut Mental Health Center,
01:27a place he loved holding
01:28two people that he loved.
01:30Katie and Emily and with the
01:31smile that we all loved.
01:35Two things I want to bring to
01:36people's attention before before
01:38moving on with the program.
01:40The first is that immediately
01:42after this grand rounds,
01:45we normally have our neuroscience research,
01:47training program,
01:48seminar and that is open to
01:50everyone today and we're going
01:51to be sharing memories of Bob.
01:53We have several of his men tease from
01:55over the years going back 20 years,
01:58joining us to speak briefly,
01:59and there'll be space for others to
02:00share thoughts and memories as well.
02:02I will paste this zoom link into the chat.
02:05And anyone who who has any
02:06difficulty with it is welcome to
02:08email me and I can send it to you.
02:10That's at 11:45.
02:13We also recently learned we are,
02:14not surprisingly not the only ones
02:16who are who are heartbroken by
02:19Bob's passing and remembering him.
02:20His medical school class.
02:22Bob was a Yale Medical School class of 1987.
02:26That's where he met Gene and they
02:28have set up a student Research
02:30fellowship fund that's collecting
02:32funds in his honor that will continue
02:35his dedication to training and
02:37mentorship by supporting research
02:39for medical students going forward.
02:41If you contact the Yale Medical School.
02:44Alumni office they'll be able to
02:46give you information about this fund.
02:47It is open for donations from anyone
02:49that's set up by the medical school.
02:54So with that I wanna turn the turn the.
02:56I guess that's not really a podium but turn
02:58the zoom over to John for further comments.
03:11John, you're muted.
03:14OK. Sorry, thank you. I.
03:19Thank you Chris and and thank
03:21you everyone for joining us
03:23today to celebrate Bob's life.
03:26I particularly want to
03:27thank Jean Katie Emily.
03:29For an Emily for joining us,
03:31it's bittersweet to be here together
03:34to reflect on Bob's life. He
03:36was such a special guy.
03:39And his early and unexpected
03:41death was was really tragic.
03:46But I think there's so much
03:49to celebrate that that.
03:50We will be kind of heartened by the
03:54discussion that follows his death.
03:57Still seems unnatural to me.
03:59Scientific generation span
04:00about three to five years,
04:03and by this criterion I'm one
04:06generation older than pop.
04:07He's been my friend,
04:09or was my friend for almost 40 years.
04:12I was his psych 101 section
04:16Coleader his psychiatry resident.
04:19His attending his unit chief
04:21and then his chair.
04:25As Eric Nestler,
04:26one of his first mentor said,
04:28we always thought of him as the kid.
04:30And the kid has died.
04:32While we're here together today.
04:35And the unfairness of all
04:37that is still painful,
04:39I don't want to take
04:40up too much time today,
04:41but I'd like to share some
04:43reflections about Bob that I
04:45prepared initially for his funeral.
04:491st. Bob was his own man.
04:53He was a brain scientist who worked
04:55to alleviate human suffering.
04:57And the scope of his accomplishments
04:59surprised many, including his family.
05:01And this was a consequence of his
05:04deep humility and focus on others.
05:06At the time of his death,
05:07Bob was professor of psychiatry,
05:09the head of the Clinical Neuroscience
05:11Research unit of the Connecticut Mental
05:13Health Center and the leader of three
05:16separate research training programs.
05:18Remarkably, he had five other grants.
05:22Despite all this,
05:23he made time for cello, guitar,
05:25outdoor activities in tennis.
05:30Bob was also one of the most
05:32remarkable mentors in teachers
05:34in the history of our department.
05:36In this he takes after his mentor,
05:38George Heninger.
05:39He was passionate about psychiatry, research,
05:42training and a fierce advocate for the C&RU.
05:45After his death, his trainees commented that
05:48they often came to Yale because of him.
05:52They thrived at Yale because
05:54of his caring support,
05:55and they discovered their own potential
05:58because Bob listened openly to their ideas.
06:01They improved because of his incisive
06:04feedback and they got through rough patches
06:07because of Bob's infectious optimism,
06:09good humor and faith in their potential.
06:12Each one of our trainees was special to him.
06:15He was thrilled by their triumphs.
06:18And graduate students sought him
06:20out at national meetings for a
06:22booster dose of the Mallison magic.
06:24It's not surprising that he received
06:26the Outstanding Teacher award from
06:28the psychiatry residents in 2010.
06:32Bob was also a brilliant scientist.
06:34He was a Phi Beta Kappa graduate of
06:37Williams College and Alpha Omega Alpha,
06:39graduate of Yale Medical School and AP,
06:42a leadership fellow during his
06:45residency and received many honors.
06:47He had the vision and courage to focus his
06:50efforts on important scientific question.
06:52To invest years in learning or even
06:56developing scientific methods from SPECT
06:58and genetics as we're going to hear today.
07:02And these approaches would enable him
07:05to pursue these important questions.
07:08He also had the discipline to see these
07:10projects through to successful completion.
07:13His projects were jewels,
07:14he did not waste his time.
07:18And and you're going to hear a lot
07:21today about the important findings
07:23that he generated in his research.
07:27Bob was insatiably curious.
07:29His trainees described his
07:31openness to their ideas and his
07:34passion for learning with them.
07:36Bob not only led his laboratory seminar,
07:39but he was a long standing attendee at
07:42the Molecular Psychiatry Lab meeting,
07:44and more recently,
07:46the Anteater Vigner Imaging Lab
07:48Lab meeting Alan and Teach eviction
07:51assistant professor at the time said,
07:53I wonder what he was doing here.
07:55The head of the CNR.
07:56You was attending.
07:57My lab meeting was I being audited.
08:00It took me 10 weeks to realize that he
08:03was simply curious and eager to learn.
08:05Like Socrates, Bob preferred to explore
08:08challenging questions through dialogue.
08:10To put it another way,
08:12Bob loved to chat.
08:13Jane Taylor noted every week Bob met
08:16with Ron Duman for about an hour.
08:19I could hear them talk next door
08:21when he was done with Rob Ron,
08:23he would stop by my office and we would
08:26chat for science for another 45 minutes.
08:28I treasured those discussions.
08:32And what about that laugh?
08:34Bob enjoyed a good laugh.
08:36His ubiquitous laugh was a
08:38celebration of the ironies of life.
08:40An invitation to join him
08:42in humble self reflection,
08:44a supportive connection that cut tension,
08:46and an expression of his
08:49infectious personal optimism.
08:50We could really use that laugh today.
08:53For Bob, Family came first.
08:56Bob and Gene are two of the finest
08:58people that I've ever met and
09:00they were a remarkable couple.
09:01I think of Bob and Gene as together forever.
09:05Bob and I were also members
09:07of the fathers of Twins club.
09:09When Gene was pregnant,
09:11Bob asked me for the truth about
09:13being the father of newborn twins.
09:16I told him you can't handle the truth.
09:19But of course he could.
09:21I was most impressed that Bob reduced
09:23his academic effort to spend more time
09:25at home when the twins were in high school.
09:28Bob had a special bond
09:29with Katie and with Emily,
09:31and he was incredibly proud of them.
09:33I periodically saw Bob shopping with
09:36Katie or Emily and I thought grown
09:39children agreeing to shop with their father.
09:42Wow.
09:43That said a lot to me.
09:46We are a better department because of bye.
09:49Bob and Bob and bodied and expressed
09:52characteristics and value that
09:53continued to make us a better
09:55and more resilient community,
09:56including integrity, compassion,
10:00curiosity, generosity, dedication,
10:04professionalism, creativity,
10:06collegiality, humility,
10:09and of course,
10:10a good sense of humor.
10:12I'm thrilled that we're
10:14celebrating Bob today,
10:15and I look forward to hearing
10:17from our speakers.
10:18So at this point Chris I I.
10:22Turn the virtual podium back to you.
10:27Thank you John so much
10:30for this for those words.
10:32We're joined now by by two of Bob's friends
10:37and longtime collaborators here at Yale,
10:39who will share reflections on their
10:41their time with him as friends
10:44and colleagues and and also as as
10:47scientists working together first
10:50please to introduce Doctor Rich Carson.
10:53Doctor Carson is professor of radiology,
10:56and lots of other things here at Yale and
11:00longtime director of the Yale Pet Center,
11:02where he's LED an extraordinary
11:04innovative program of of research
11:07probing the the the living human
11:09brain in ways that others cannot.
11:11And it was a longtime
11:13collaboration of Bobs for decades,
11:14and we'll hear about some of that.
11:16Some of that journey today.
11:18Rich, thank you for being with us.
11:21Thanks so much Chris.
11:23This is a D Bonner and a privilege and
11:27what I wish I really didn't have to have.
11:30I think that's true with all of us.
11:31We really wish we weren't here
11:33today to talk about the talk about
11:35our dear colleague and friend.
11:37And you know I started this with a very
11:38formal slide Doctor Robert Malesan,
11:40but this he's Bob.
11:41He was Bob to everybody.
11:43He was a normal human being and I think
11:45we're going to be a little redundant
11:47today about the the joys of working with Bob.
11:50You heard a little bit about
11:51the resume I just wanted.
11:52Just to remind it,
11:53it'll come in handy in terms
11:55of the topic will raise today.
11:57These are real Yeley.
11:58That's why I put that background
12:00in my screen today it is empty
12:02here is residence here.
12:03Did a brief sojourn down
12:05I-95 at in Philadelphia Penn,
12:07but rest the rest of the time he was
12:09here and what an impact that he had here.
12:12Now the aspect of Bob's career
12:14that I'm going to talk about is
12:16going to be related to imaging.
12:17No surprise,
12:18and the parts we want to talk about
12:21are the two technologies that Bob use.
12:23Throughout his career here to
12:26really do molecular imaging within
12:28the brain using SPECT and PET and
12:30and just set the stage for those
12:32of you who this might be new when
12:34we're looking at how to measure how
12:36to image something in the brain,
12:38we're going to choose some relevant
12:40molecular target or receptor or transporter.
12:42We'll develop a molecule,
12:44a radioactive molecule like tracer.
12:46A radiopharmaceutical will get
12:47approval for human use,
12:49will inject it into the patients,
12:50or maybe we're doing animals.
12:52We collect images with a scanner.
12:54We measure uptake overtime,
12:55and we analyze the data.
12:57That's our bread and butter that
12:58we do every day really dependent
13:00on the novel chemistry.
13:01Looking at a selective target in
13:04the brain and what's really great
13:06is when we have targets that look
13:08at specific brain proteins,
13:09receptors and transporters and enzymes.
13:12And if we do our math right,
13:14if we can do our imaging right,
13:15we can make images of the receptors
13:18and what's really interesting here is
13:20it's the total receptor minus what's
13:23already occupied by the endogenous.
13:25Dopamine,
13:25serotonin,
13:26what have you and obviously we've had
13:28great success in applying that in a
13:31myriad of neuro psychiatric disorders.
13:33We could also try to take apart this
13:36combination of receptors and occupancy.
13:38Because the occupied receptors,
13:40whether that be with the
13:42endogenous log in or with a drug,
13:44we don't see them and that gives
13:46us a measure of that that we
13:48can look at drug occupancies
13:49as well as their transmitters.
13:51And here's the cartoon,
13:52and it's actually cartoon that comes
13:54out of work done done here at ylvis.
13:55If you imagine a little receptor
13:57there D2 receptor and you imagine
13:59the dopamine molecule sitting
14:00in the synapse and
14:01we had a tracer, here's a pet
14:03tracer carbon 11 raclopride.
14:05If we altered that by changing the doping
14:07concentration here by giving amphetamine
14:10to generate more dopamine release,
14:12it would alter our signal.
14:13So a great tool, a little complicated
14:16tool sensitive to the total amount
14:18of our target protein but also
14:20the endogenous activity that's
14:22going on makes it interesting.
14:25And challenging.
14:27Now when we compare these two technologies,
14:29SPECT and PET, let's just get a little
14:32background for what we're talking about.
14:34Inspect a single photon tomography.
14:37We use the isotopes that just give
14:39off 1 gamma ray at a time in Pat.
14:42We're using isotopes to give off positrons.
14:44That's antimatter positive electrons inspect.
14:48The isotopes tend to have half light,
14:50use atoms like iodine and technetium,
14:53kind of bigger atoms a little harder
14:55to fit into biological molecules.
14:57In Petra Lucky we can use fluorine and carbon
15:00easier to add into biological molecules.
15:03Specht things work a little longer,
15:05half lives and hours.
15:06Pet moves a little quicker here.
15:0820 minutes to two hours.
15:11Respect you can actually buy the
15:12isotope so they are a little pricey
15:14and you can make do the chemistry.
15:16And here we need an on site cyclotron.
15:17There's our cyclotron right there and
15:19because you have these long half-life,
15:22SPECT can take a little while.
15:23You could have the kinetics that
15:25take a little while pets got
15:27to work a little bit quicker.
15:28Now, in the imaging device side,
15:30the scanners that we use inspector often.
15:32These clinically useful rotating camera
15:34cameras for a number of different indications
15:37of heavily used in cardiology for pet.
15:39We need these dedicated systems
15:42definitely more expensive.
15:43Respect well, the image resolution
15:44is not as good as we might like.
15:46It's getting better all the time,
15:48but we're certainly at the 1 centimeter
15:50stage pets really push that further along.
15:52Specht has not the greatest sensitivity.
15:54It's got collimators,
15:55pets doing a little bit better and SPECT the
15:59quantification getting the numbers right.
16:01It's pretty hard pet.
16:02Just by the nature of having two gamma rays,
16:05tends to make it easy there.
16:07Nevertheless.
16:09Yale has a fabulous history of
16:11both SPECT and PET in the brain.
16:14I'm very happy staying in the 1990s.
16:15You remember that's when Bob
16:16was just coming at, you know,
16:18coming out into his fellowship,
16:19etc.
16:19The best place in the world
16:21to do quantitative brain SPECT
16:22in the world was yeah,
16:24OK and it was over at the
16:25VA but scientifically.
16:26Based in psychiatry and led by a number
16:28of the names we've heard already today,
16:31also including Bob Dennis,
16:32now PEP began to move into.
16:34Yeah in the late 1990s at the VA,
16:36but our pet center opened a few years later
16:38and one of the reasons we have a pet center.
16:40And one other big reasons why I'm here today
16:43is because of the demand from psychiatry.
16:45'cause of the great 1990s
16:48experience of being able to work
16:51in quantitative molecular imaging.
16:52First respect and Bob was absolutely
16:54key to that growth of that of both
16:57because of his experience of Spectat
16:59yelling so many applications that
17:01I'll try to detail how we have pet.
17:03And you know, perhaps not being
17:05a little self serving here,
17:07but thanks to psychiatry and thanks to Bob,
17:09maybe we might be the.
17:10Arguably the best place to do
17:13brain pet nowadays to go on with
17:15the great history of SPECT.
17:17Alright, so let's talk about
17:18some of his accomplishments.
17:19I'd like to kind of walk through
17:20some of his Seminole papers.
17:22First on the spec side,
17:23going back into into the 1990s.
17:26So here's a classic paper that he
17:28did with Bob Ennis on looking at and
17:31this was one of the first papers
17:32that demonstrated that cartoon.
17:33I showed that if we give a drug that
17:36alters the the neurotransmitters,
17:38we can see that with our molecular
17:40imaging here, done in nonhuman primates.
17:42So here's the example.
17:43Here's what some of the images look like.
17:46Image through a baboon.
17:47Brain he's seen the uptake into the
17:49striatum and the data are collected overtime.
17:52Here's what the time course looks
17:53like here in a control baboon.
17:55And then they do exactly the kind
17:57of validations you need to do.
17:58You need to say, OK,
17:59let's validate that we're measuring
18:01the particular occupancy here.
18:03The D2 receptors give haloperidol
18:04the compete,
18:05and we got a beautiful displacement,
18:07and then the more interesting part,
18:09and indirect activity give a
18:10drug that doesn't bind directly,
18:12but increases the competitor dope mean.
18:14We also get a very long lived displacement.
18:17And this really opened the doors 1992
18:20for being able to do these dynamic
18:22measurements of neurotransmitter changes.
18:25Inspect and a pet which got to
18:27humans about five years later.
18:30Bob was involved in so many
18:32different aspects of using SPECT
18:34imaging in the 1990s hearing.
18:36Yeah,
18:36here's an example of just knowing the basics.
18:39How do you evaluate a new molecule?
18:41And here's some images.
18:42Again, in this case,
18:44in a cynomolgus monkey and the process
18:46that you do to develop a nutrition that
18:48you can look at these time courses.
18:50Looking that in the target
18:51regions here in the striatum for a
18:53different dopamine transporter or a
18:55background region in the cerebellum.
18:57And again the validations not only
18:58giving the drugs that should displace it.
19:00But also checking the selectivity,
19:02checking that if you're selected for
19:04dope mean the proxy team is oxy teen
19:07is not going to produce those kind
19:09of specific challenges and that's the
19:11great part of Bob's intellectual curiosity.
19:13As John mentioned,
19:14was not just applying these tools
19:16in clinical populations,
19:18but understanding the basics.
19:20Recognizing how you can
19:22use these technologies.
19:24Here's another paper now starting to
19:26move this into human into cocaine.
19:28People with cocaine use disorder.
19:30I thought we didn't call it that.
19:31Back then and now looking at how how
19:33you when you give a particular drug.
19:35In this case,
19:36giving cocaine how that
19:38directly is measurable
19:39in the images that we can obtain.
19:41So here's the example again.
19:42Using spec, things are a little slow,
19:44but you're collecting data
19:46and watching overtime. How?
19:47When you give a different
19:49doses here of cocaine,
19:50how you can see reductions in the activity,
19:53measurements and measuring
19:54and they're not big signals,
19:56so you've got to be doing things right.
19:57In this case 5 or 16% at doses of
20:0020 or 40 milligrams of cocaine.
20:03Getting an initial dose response
20:04curve demonstrating that, yes,
20:06you're measuring this target
20:08exactly where cocaine is hitting
20:11in live human subjects in 1995.
20:13Or here's an example looking at another
20:17potential drug that might be useful here.
20:19Opening the door for what has become very
20:21common in the Pharmaceutical industry
20:23to assess drug occupancy directly,
20:25will those drugs work?
20:26And here again,
20:27looking for a very different
20:29mount using a molecule beta CIT
20:31labeled with I 123 that.
20:3313 hour,
20:33half life and being able to again
20:35demonstrate a dose response where
20:37you get a bigger reduction with
20:39that higher dose and these kind of
20:41Seminole studies back in the 90s,
20:43open the eyes in the pharmaceutical
20:45industries to be able to say that
20:48wow doing molecular imaging is a
20:50great tool not only to understand how
20:52patients were but also to understand
20:54how the drugs were to understand
20:56how much occupancy you would get
20:58in different targets at different
21:00doses and learning to extend.
21:02Will the drug dose we need to give.
21:04Be such that we'll be able to
21:06get our clinical effect before
21:08we get adverse effects.
21:10One more is that with the nature of
21:12this very unique molecule beta CIT,
21:15it actually is one that binds
21:17to two different sites,
21:18dopamine transporters, as you've seen,
21:20also serotonin transporters.
21:21And here we take advantage of
21:23the imaging characteristics of
21:24different regions of the brain have
21:26clearly different distributions.
21:28So here we could look at this
21:29now and depressed subjects.
21:31Now we're looking at both the brain
21:33stem looking at that measurement of the
21:35serotonin and showing that reduction
21:37in depressed subjects and how the
21:39interesting relationship between.
21:40What's going on in the in the
21:42brainstem compared to the dopaminergic
21:44signal going on the strident,
21:46so those first early steps of
21:48looking at 2 markers, in this case,
21:502 markers at once with the same
21:53tracer and the same human subjects.
21:55Now I went back and asked, actually,
21:59I'm sorry, one more looking.
22:00Also, going back to cocaine abstinence.
22:02Looking now, evaluating,
22:04understanding the progression of absence.
22:06How can we use our molecular imaging
22:08tools following patients in this case
22:11over absence again with beta CIT.
22:12And again,
22:13now we see this interesting
22:14during the abstinent phase,
22:15we actually see increases in
22:17the availability of our tracer.
22:20Now remember that introduction.
22:21This gets interesting because
22:23if I have a higher signal,
22:25is that because I've upregulated
22:27the receptors?
22:28Or is that because I have
22:30lower levels of computers?
22:31Dopamine?
22:31In this case competing at the receptor site?
22:34Little challenge to be able to
22:36take apart that, but one of those,
22:37I know that Bob would wax poetic on
22:39thinking about the right experimental
22:41designs to try to take those mechanistic.
22:43Issues apart in real human patients.
22:47Now, as I was mentioning,
22:48I went back and asked for some
22:49remembrances from Bob and his.
22:51Bob of course, was at Yale here
22:53in psychiatry for many many years
22:54and he he worked closely with Bob
22:57in those original kind of studies.
22:59He described Bob kind hearted, warm,
23:01intelligent, hardworking and modest.
23:03You're going to hear these over
23:04and over again,
23:05but Bob sends a wonderful anecdote that I
23:06was really excited to share with you today.
23:08He remembers those long nights
23:10they spent working in with the
23:12monkeys two or three morning.
23:14Apparently so back then, to do spec that.
23:17Yeah, what you had to do in an animal?
23:19Well, you could use the
23:20cameras over at the hospital,
23:21but only after the clinic was closed
23:23so they locked down a baboon.
23:25Get the ready apparently have
23:26to install a diaper,
23:27take the tunnel over to your New Haven,
23:29and then you start scanning a little
23:31evening or midnight scanning there.
23:33And of course, we had that 13 hour half life,
23:35so these could go for quite some time.
23:38And and Bob Dennis describes,
23:39our dear Bob is just a real trooper.
23:41Great companion in those long ones,
23:43but he replies with one really good anecdote
23:45and we'll see Jean if you remember this.
23:47That that was one night where neither
23:49of our two psychiatrists apparently had
23:51trouble putting in an intravenous line.
23:53A venous line.
23:54We inject that in all of our tracers.
23:56So Bob called Gene.
23:58At that point she was doing her residency
24:00in ENT and Jean came over for the console.
24:03We don't think she dealt with
24:05such hairy patients routinely,
24:06but nevertheless with moved,
24:07you know, follow very positively to
24:10a successful outcome for this study.
24:12So I've been a share is that,
24:13you know,
24:14losing Bob so early was just terribly unfair,
24:16not only a wonderful human being,
24:17but a tremendous.
24:19Professional accomplished so much
24:20and certainly had much much more
24:22to be able to contribute.
24:24Well,
24:25I mentioned that Yale moved from
24:28SPECT to PET and and I know,
24:31we know there's a lot of technical reasons.
24:33I outlined.
24:33My pet might be better,
24:34but I think one of the biggest reasons
24:36was those short half lives in pet.
24:37You cannot scan into midnight,
24:39so I think operationally,
24:40it's just a better place to do so.
24:42Let me try to share some of Bob
24:44selected accomplishments in our last
24:46now decade and a half that I had
24:48the luxury of being able to work.
24:50With people like Bob here at
24:51Yale with our pet center,
24:53so I'll start with one of his initial
24:55studies here in cocaine subjects,
24:57working with a particular Tracy.
24:59Now a new target,
24:59and we'll have the numbers of
25:01new targets and pet.
25:01This is binding to the norepinephrine
25:03transporter again going to be
25:05sensitive to that in cocaine.
25:07And here's what some of the images look like.
25:08You may zoom in with pet.
25:09We can see some high resolution targets.
25:11We could see the midbrain structures,
25:13even the locusts arulius.
25:15And in fact when you look very
25:16carefully at the shape of the uptake,
25:18you actually see the ring
25:19shape of the of the locus.
25:21And now again,
25:22taking advantage of that quantitative issues,
25:24doing things like recognizing
25:25age effects in norepinephrine,
25:27transporter availability and then
25:29looking again between a healthy
25:31controls and a cocaine subjects
25:32and seeing even in the locusts,
25:34even in that small region
25:36and apparent up regulation,
25:38I'll use that word carefully.
25:39Bob would correct me because we
25:41don't know the combination of as
25:43an increase in urban efferent
25:45transporters or decreased occupancy
25:46by endogenous norepinephrine,
25:48interesting stories and those answers
25:50are still still still to be obtained.
25:52We moved on with many other targets here.
25:54Here's the collaborative study where
25:55Bob working with one of his men tease.
25:57They've met a ski,
25:58who I know will talk later and is now
26:01the medical director over in the pet
26:03center about serotonin 1B and again
26:05looking in cocaine dependent subjects.
26:07Here's what those images look like.
26:09A very unique distribution looking
26:11high uptake in striatum and
26:13simple cortex there and again.
26:15Here we see the opposite effect that
26:17we're seeing in the serotonin 1B targets.
26:20We're seeing reductions in frontal cortex.
26:23In hypothalamus etc.
26:24Compared to the healthy controls
26:26and again we have that confound
26:29this receptor downregulation,
26:30is this alterations in serotonin because
26:32we do know this market from other
26:34studies is sensitive to serotonin levels,
26:37so good challenges there in terms of
26:38the tools that we can investigate.
26:40So we follow patients along and look
26:43at their neuropharmacology in vivo.
26:45But a real important target we went
26:48through was looking at dopamine
26:49targets again in cocaine.
26:51Obviously the relevance of dopamine
26:53given cocaine's direct effects
26:55at these targets there.
26:56And so here's where we see
26:58that now using a new tracer,
26:59something called pH.
27:00You know this is an interesting target.
27:02This is a an agonist.
27:03It was originally developed by
27:05Merck in the 80s as a possible
27:07drug for a number of different.
27:08I believe in Parkinson's disease at the time,
27:11but it also has an interesting
27:13characteristic 'cause this
27:14tracer binds to both dopamine D2.
27:16And D3 receptors,
27:17and the differential distribution
27:18of those in the brain lets us
27:20look at both at the same time.
27:22Now people have been using other
27:24molecules than pH, you know,
27:26and found D2 changes,
27:27but here it could look at the D3
27:29changes and looking down at a very
27:31focal region in the Niagara and then
27:33you can see that our cocaine subjects
27:34have a higher availability in the night.
27:37Are the source of the dopamine neurons
27:39compared to the healthy controls?
27:41And interestingly within those
27:42values you can see that lovely
27:45correlation. Between in this case,
27:46their years of cocaine use both in
27:48the Niagara and also in the Palatine,
27:50an area rich in D3 receptors.
27:53This was a good challenge.
27:55This was an area we needed to
27:57know what's going on there.
27:59Is that because there's increased receptors
28:01is there less dopamine that's going on?
28:04And it had great relevance in terms
28:06of how you might treat these patients,
28:08and one of the great joys of my life was
28:10writing a beautiful grant with Bob to
28:12be able to directly address this comment.
28:14And I would love to show you
28:16the results of that. Grant,
28:17but unfortunately we didn't get it funded,
28:19so but it was a great joy.
28:20I'll come back to the story
28:22of writing with Bob.
28:24Some more recent studies,
28:25again with pH.
28:26Now again,
28:26Dave Matuseski leading those but
28:28led by Bob or in terms of looking at
28:31social status studies or being able to
28:33look at the interactions of other markers.
28:35Obesity as well as that again
28:37in cocaine use individuals.
28:39And again,
28:39here's some of those if we look now
28:41looking at measures of social status,
28:43the BS MSS.
28:44Across both cocaine use and healthy controls,
28:47we get much more of a dynamic range
28:48and it gets to be interesting.
28:50Is this one common pathway across both pitch?
28:53Whereas there are different?
28:54Relationship that we see here or if
28:57we bring in obesity this relations
28:58again in the substantia nigra or
29:00overlapping with the ventral tegmental
29:02area and looking at our pH now.
29:04Our dopamine measures that we go there
29:05and being able to see that relationship.
29:08The interaction of drug abuse disorders,
29:11cocaine use disorders and in this
29:14case obesity as measured by BMI.
29:17The last paper I wanna do and this one
29:19is even sadder because it didn't come
29:21out till after Bob passed the most
29:23recent work using our synaptic density agent.
29:25You see BJ led by Gustavo and and
29:28of course pioneered and mentored.
29:30Of course by Bob.
29:31What kind of changes do we also
29:33see in the synapses?
29:34Again,
29:35the marker we have is sensitive to a
29:37presynaptic terminal there and what
29:39basically able to see in multiple
29:41parts of the brain reductions and singulate,
29:43prefrontal cortex etc.
29:44No differences in the white matter.
29:47Kind of our control region.
29:48And when you do the parametric
29:50imaging it focus in particular on
29:51the prefrontal cortex and then not
29:53just the group differences there.
29:55But to me often these are the most
29:58interesting ones about looking at
29:59their relationships within the
30:01patient populations.
30:02Kind of in an R Doc way of measures
30:05here of usage of cocaine over days
30:08or chronicity there.
30:09And looking at that in terms of the
30:12different directions that we get and
30:13when you got a graph like this where
30:16you have interesting differential changes.
30:18Of either frequency of use
30:20or length of absence.
30:21From there you could just see
30:23and hear the wheels spinning and
30:25Bob working with cassava to build
30:28the possible hypothesis.
30:29The story of what might be going on.
30:32How do we interpret our imaging data both
30:34to look at what it's telling us about the
30:37disease and progression of the disease
30:39and absence of disease at the same time?
30:41Really thinking hard about what might be
30:43the the artifacts that might be getting.
30:46If you don't think about
30:48interpreting your data correctly.
30:49Well, I reached out to some of Bob Morrow.
30:52One more thing that could keep
30:53forget that thanks to Bob.
30:55Remember that little residency Bob
30:56did down in pen for a year while he
30:59built relationships there as well.
31:00And thanks to that we have a
31:02collaborative grant with the folks
31:03at Penn and their addiction center.
31:05Do you able to look at addiction and
31:07looking at things like MU and Kappa
31:09opioid receptors which we can do with pet.
31:11Looking at neuroinflammation markers
31:12and unfortunately as the grant was
31:15getting kicked off we lost Bob and so
31:17now every year at our annual meeting.
31:19We have the official Bob Robert team
31:22Allison Lecture and Marco Leyton gave
31:25that about addictions and imaging of
31:27addictions at at our at our last so
31:30called Pace day that we like to call.
31:32Well let me share some other thoughts
31:34about Bob from other imaging colleagues
31:36that we've had to work with and
31:38I I asked that I got some really
31:40nice stories from people.
31:41So Arena asked you was shared with me about
31:44Bob was always generous with his time,
31:46whether it's for career
31:48advice or granted vice.
31:50Then just came to the point and even
31:53helped mentor your marinas bentes
31:55something that's really really
31:56valuable and she mentioned you know
31:58when they made a conference is
32:00he was just a normal human being.
32:02You know,
32:02you talk about the weather and eating a nap,
32:04but he was always there.
32:05Whatever you needed, he was always there.
32:09What a joy to have someone like that,
32:11and Mark pretends to share just
32:13remembering of that laugh.
32:14I can't help but smile when I
32:16remember and read, read my brain,
32:18you know, replace his laugh.
32:19His sense of humor, his nature,
32:21it just glued people together.
32:24And when you had those meetings and
32:25how things worked well and I remember,
32:27you know,
32:28Mark was leading a multi multi ply grant.
32:31Different folks for awhile.
32:33Jane Taylor.
32:33I was lucky to be part of that and
32:35sometimes they're pretty complicated.
32:37You know you were you were mixing preclinical
32:39and clinical and different aspects of that.
32:41And Bob was just a glue that kept these
32:43kept these groups working together.
32:45Keen understanding of what's going
32:47on in science.
32:48Deep love for his family and just
32:51a wonderful wonderful human being.
32:53Got a lovely story from Evan Morris.
32:56He says, you know,
32:57as we as as John mentioned.
32:59Obviously Bob was playing his
33:00cello in the Yale Medical School,
33:02and Evan shares that, you know,
33:04he and his family.
33:05His lab would go there and
33:07watch Bob Play and Evan shares how
33:09Bob played with his eyes closed.
33:10And of course we images are imagining.
33:12That he's got some nice hi-tech projection
33:14of the music on the inside of his eyelids.
33:17Probably not the case,
33:18but only playing with his eyes closed.
33:20But what that lovely grin
33:22that supply management?
33:23You know when we think about science,
33:25it's hard to know.
33:26How do we map those into our brains?
33:28And for people who are good at music,
33:30not me. You know,
33:31you can imagine it's the same kind of.
33:33It's a hard thing to quantify.
33:35He reveled in that music.
33:36It gave him great pleasure and it was
33:38related to how you think about science.
33:41How you can work together as a group.
33:43As an orchestra must do to build some beauty,
33:46to do something that you
33:48just couldn't do alone,
33:49and being able to translate
33:51that from something like music
33:53into something like science.
33:55It is really a joy and really,
33:57reflection of Bob.
33:57Now one of my favorites came from
34:00Sophie Holmes and it ties into the
34:02music that that Evan brought up,
34:04and Sophie relates that.
34:05Few years ago she was he was Bob was
34:09talking or talking about his latest project,
34:11the impact.
34:12The vitamin D most recent grant,
34:14how it affects brain and dopamine
34:16and so Sophie Shiver. Then.
34:17Now she's studying Parkinson's disease.
34:19OK, there was some synergies,
34:21and so they began to meet and they
34:23would talk about everything you know,
34:25that's the what happened when
34:26you talked to Bob.
34:26You didn't just stay on the science,
34:28talk about life and.
34:29And apparently music,
34:30so Sophie tell Bob about a BBC
34:32Radio show that she was aware
34:33of called Desert Island Discs.
34:35And apparently what happens on this show?
34:37Famous people come and talk about if
34:39they were stranded on a desert island,
34:40what would be the 10 discs that they do so?
34:44Both sadly and not surprisingly,
34:45Bob sent her.
34:46This was this is the cut from
34:49the list of Bobs Desert Island
34:51Discs that he would like to do
34:53in a cut and paste those off.
34:54Thanks to Sophie for sending
34:56a good chunk of classical.
34:57Some of the favorites, some Beethoven,
35:00some Brahms, some Elgars Enigma variations,
35:03the dodgy over springs seaberry
35:05Bob and then some popular things.
35:07Pretty Woman.
35:08I can see clearly now.
35:10Build me up,
35:12Buttercup theme from Forrest
35:13Gump and over the rainbow.
35:16How Bob to be able to put those
35:18things together so Sophie joins us
35:20to say how well you know she really
35:22tries to channel Bob about being not
35:24just a good scientist doing it with
35:26humor about being a good human being.
35:28We know with science will live
35:29on and so we had said she takes
35:31vitamin D every day so perhaps
35:33another good legacy of Bob.
35:34Alright I need to sum it up.
35:38I miss him. I think we all do.
35:41It's a great friend colleague.
35:44Now I'm, you know, I'm a math
35:46engineering by so you know you gotta,
35:47you gotta organize your points added up,
35:49try to be quantitative alright?
35:50So what are the points I want to make of
35:52that pop respectful goes back I remember one
35:55of the very first group meetings I had with
35:57Bob on a protocol was that cocaine study.
36:00This was really early in
36:01the pet Center small group.
36:02There we got everybody together
36:04to set up the protocol.
36:06Now we have a young team,
36:07pretty small and and some of the medical
36:10staff that we had some our ends at the time.
36:13You know they were not experience
36:14working with. Addiction.
36:15And they were expressing a little bit
36:18of angst, a little bit of confidence.
36:20There's Bob and what he did.
36:22Oh, I remember that to this day.
36:24Just how you express how you
36:26treat people respect you,
36:27tune into their anxiety,
36:29their concerns express the
36:31thing being ready to helping,
36:33ready to talk about how to explain
36:35the importance of what you're doing,
36:37how to do it carefully, it was unbelievable.
36:40I was the mentee that day for sure.
36:44Obviously,
36:44we've already heard about his creativity,
36:46the ability to bring in ideas
36:48from the basic sciences from the
36:50technical from the imaging side,
36:51into the clinical realm,
36:53how to synergize those things
36:55together that was fun.
36:57Obviously a fabulous collaborator.
36:58How to bring people together and
37:01whether it be because of that laugh or
37:03just because of his nature personality
37:05more come out this some much greater
37:07than that of the individual parts.
37:10Talked about his generosity with
37:11his time with his interest funding.
37:14All of those things are great collaborator.
37:16What you'd like to be?
37:18I'd love to watch his brain work.
37:21That last study we mentioned imagining when
37:23one factor was positively one was negatively.
37:26What's the mechanism?
37:27What's going on?
37:29How could we do that?
37:30How would that tie in with the
37:32animal work that we might do as we
37:34translate that into human subjects?
37:35We already heard about his modesty?
37:37You know,
37:38he just talk about a poor
37:39physician from Idaho, but boy,
37:41underneath so much more there.
37:44And just a key to helping
37:46them build that team.
37:48When he put things together,
37:50he craft them building that story and
37:52it could be done at whatever was the
37:55appropriate level for the audience involved,
37:57and that was great just to be able to say.
37:59How do you start that in the beginning?
38:01How do you put things together?
38:02How do you add those things together
38:04and not to make not only to be able
38:06to make it scientifically relevant,
38:07but also incredibly entertaining?
38:11You'll hear later this afternoon
38:13about he's a mentor extraordinaire
38:15to all of us at that point,
38:16and just so giving about that and getting
38:19great joy and seeing his mentees grow.
38:24And Oh my God,
38:26I wish I could write like
38:28I mentioned that grant.
38:29And what a joy and boy,
38:31if you read this grant,
38:32you know you could tell which paragraphs
38:34Bob wrote and which ones I wrote.
38:36Mine was pretty, you know,
38:38tedious and technical and boring and Bob
38:41Hope it just jumped off the page. What a joy.
38:45All part of his ability to synthesize the
38:48tell the stories to bring people together.
38:51What a joy. Alright?
38:52Well, how do we sum it up?
38:53You know, I I'm you know I'm bad tend to,
38:57you know give numbers and sum up the scores.
38:59What is the bottom line?
39:00When you add up all of these
39:02characteristics of a fabulous scientist,
39:04what do we look for?
39:05We look for quantitative metrics.
39:07We look for a comparative marker.
39:09While Bob was it,
39:10he was the gold standard of human beings.
39:14We'll miss him tremendously.
39:16Thank you.
39:19Thank you.
39:26Thank you so much, rich for
39:28sharing that both the science
39:30and the memories of Bob Person.
39:32We're going to pivot now after hearing
39:34about all of those extraordinary
39:36accomplishments and functional
39:37brain imaging it will astonish
39:39those of you who didn't know Bob,
39:41but not those of you who did that.
39:42He had an entire other scientific
39:44career looking at genetics.
39:46Bob already well established
39:48in brain brain imaging,
39:49pivoted in mid career to to learn about
39:52genetics and and explore their and
39:54his companion and collaborator and I.
39:57Believe teacher, there was Joel Gertner,
39:58who's with us today.
40:00Joel is foundation fund professor
40:02of psychiatry and a really a
40:04giant in psychiatric genetics.
40:06And a longtime collaborator across
40:08time and across continents.
40:09With Bob and Joel,
40:10thank you for being here to share some
40:12of your thoughts and memories today.
40:17Thank you Chris and. Thanks Richard,
40:21that was really the Bob I knew too.
40:30So I'm going to talk about our work together
40:33in Thailand over a period of two decades,
40:37and I'm going to break it into three parts.
40:39I'm starting with our work on
40:42opioid use disorder and in northern
40:44Thai Hill tribe population.
40:46Then I'm going to talk briefly
40:48about our training grants.
40:49We had two D 43 five year training
40:52grants which were quite successful.
40:54And then our current and continuing
40:56studies of substance use disorders
40:58in Bangkok and Shanghai, Thailand.
41:04So starting with opioid use disorder
41:07and northern Thai hilltribe population.
41:10And it was really interesting
41:12how this work came about.
41:14The starting point was Bob's
41:16recruitment of a postdoc,
41:18Doctorado, Polsak and Aaron.
41:20And he came to work on Bob's cocaine
41:25Health Administration paradigms and.
41:28His other imaging work,
41:29but he also had an interest in
41:32genetics and he was a Thai national.
41:35And his mom was the founding chairman
41:38of Psychiatry at the CU Longhorn
41:41Faculty of Medicine in Bangkok,
41:43which is one of the leading
41:46academic institutions in Thailand.
41:48Around the time that Adipol
41:49came to work with Bob,
41:51Bob and I had been talking for a
41:53few years about wanting to start
41:55work researching substance use
41:57disorders and a genetic isolate.
41:59So at the time, this was a very.
42:03Popular and prevalent way to do
42:06gene mapping population isolates
42:07have lower heterogeneity.
42:09On the genes that are important and
42:12isolates might have lower effect sizes.
42:16And so we decided to seek
42:19such an isolate in Thailand.
42:22And the started where we all angled
42:26invitations Bob at Apple and me to
42:29a night of Sponsored Conference,
42:3210 Pacific Conference on stimulant use
42:34in Bangkok that was in October 2000.
42:38So at this meeting we met various Sud
42:42researchers who are active in Thailand.
42:45Alan Leshner,
42:46the director of Hnyda,
42:47also attended and we talked to him
42:49about our plans for work.
42:51He was very enthusiastic about our
42:53plans and about Human Genetics and
42:56substance use disorders in general.
42:58And we also met several people
43:00at that meeting who continued to
43:03be collaborators on our project,
43:05including Kepong Center Twinkle.
43:07And by the way,
43:09the custom in Thailand is to use
43:12first names preceded by the honorific,
43:14so I'll call him Doctor Ketapang,
43:17because the last names are complicated
43:19even for people in Thailand.
43:21Doctor KPT was then as now a director
43:24of Swan Prong Hospital in Shanghai,
43:26which is the largest hospital
43:29in the north of Thailand.
43:31So this is a picture of Bob and add
43:34a poll that's adipol on the right
43:37at the Grand Palace in Bangkok.
43:39This was taken, I believe,
43:40on our second trip to Thailand,
43:42which would have been in 2001.
43:46So we researched possibilities for
43:49finding an isolate in Thailand and
43:52our inquiries let us to the north
43:55part of the country where there
43:59were numerous villages that had
44:03homogeneous minority Hill tried,
44:05tried populations.
44:06So a specific hilltribe that was
44:09important and opioid trafficking
44:11was identified and then a specific
44:14town about 40 minutes from Shang.
44:16My past mayor rim.
44:17And in this town there was a very
44:19high rate of opioid use disorder,
44:21which is what we were looking for and
44:23also all of the inhabitants mapped
44:25to one of five clans or extended pedigrees,
44:29which is ideal for linkage mapping
44:31which was the main technique that
44:33was used before the GWAS era.
44:35And we pretty promptly received
44:38a supplement on my ongoing hnyda
44:40opioid use disorder grant to start
44:43work training interviewers and
44:46recruiting in the town that we identified.
44:49So popular belief was that opioid
44:53use was prevalent all over
44:55Thailand and at one point it was,
44:57but by the time we started our
44:59work this was no longer the case,
45:01largely due to what was
45:02called the Royal Project,
45:03where the Thai Royal family invested
45:05a lot of effort and political capital
45:09and a crop displacement program that
45:12was and remains to this day highly
45:14successful at diverting opioid production
45:16to production of various vegetables.
45:19This is a photograph of a historic
45:22I've taken about 10 years ago at
45:23the airport in Shanghai, Shanghai,
45:25showing some of the products that were
45:29grown as an alternative to opioids,
45:32but there were still isolated areas
45:35where there was a lot of opioid use.
45:38So this is a picture taken in Mayor M.
45:41It's out of pole on the far right to
45:44out of polls left is Kim Chancery
45:46who is a social worker who worked in
45:49many of the hilltribe populations.
45:51And then Bob and then the guy on
45:53the far left is our collaborator
45:56from Shimla University.
45:58This picture I took a few years later,
46:00but it showed an annual Hmong Hill
46:03tribe gathering and the theme of
46:05their annual gathering and parade that
46:07year with substance use disorders,
46:09which shows how recognized the problem is.
46:11Even in that community with a kid
46:14dressed up as a pack of cigarettes and
46:16someone else dressed up as a strange.
46:19And the location of the village was
46:22also very close to the Golden Triangle,
46:25which at one point was a very important
46:29Nexus through drug trafficking
46:31in Southeast Asia.
46:37So I will digress briefly.
46:41And discuss some of the travel
46:43that we did over the years.
46:45This is a one way trip from JFK to Bangkok.
46:49It covers nearly 10,000 miles each way,
46:52so 20,000 miles in throughout trip.
46:5531 hours door to door,
46:58but we didn't always go through Tokyo.
47:02And in covering I would estimate
47:061.2 million miles over 19 years.
47:09These are some of the airports
47:10that we visited in some of the
47:12layer overs that we had and I don't
47:15know if you can see my pointer,
47:17but that's Narita and Tokyo,
47:20Shanghai, Hong Kong, CSX is Changsha,
47:23China, Saigon or Ho Chi Minh City,
47:26Bangkok, Shinmai and Pucket.
47:29We visited Pucket IN20O4 on a PTSD
47:32project after the big tsunami.
47:33There.
47:35And in seeking the most economical
47:39fares so that we could stretch our
47:41grant money as far as we could,
47:43we often had to accept overnight layovers.
47:46This is Bob making the best
47:49of a forced layover in Paris.
47:52This is walking along the water in Helsinki.
47:56There was a period of time when
47:58the best fares were on thin air,
48:00but at the cost of really long layovers.
48:02So we did that a few times and
48:05really kind of enjoyed them.
48:08Getting back to the work in
48:09northern Thailand in order to
48:11proceed with this project,
48:12we had to meet with the town elders
48:15to establish a research collaboration
48:18and get on the agreement of the
48:20heads of the town and the leaders.
48:22So this was taken at one of the
48:25meetings that we had the guy in
48:26the lower right is named when and
48:28he became one of our collaborators
48:30and our local team leader.
48:32He was also the town headman.
48:34This picture actually reminds
48:35me of Rembrandt's night watch.
48:37If you can call that to mind briefly.
48:40And that was in July 20.
48:43Oh one.
48:43And this is after that meeting you
48:46can see Chancery again and Bob and our
48:49dear friend and collaborator Henry Krantzler.
48:51You did a lot of work with us in
48:53setting up the assessments and the
48:55translation of the instrument into
48:57Thai and the testing of that instrument.
49:00So we translated our instruments into Thai.
49:04This is a screenshot of the sada,
49:05the semi structured assessment for
49:08drug dependence and alcoholism,
49:10which is the same instrument
49:12that we use here.
49:13So we have directly comparable
49:15measures in Thailand in the US.
49:18And indeed,
49:19one of our publications that Bob led out
49:22of this work was a study in interrater
49:25liability of the TICADA instrument,
49:28which was done with.
49:31Several of our most important
49:33tie collaborators, Dr.
49:34Rossman,
49:34who we do a lot of work with.
49:36Doctor Kepong,
49:37who I already mentioned out of
49:40Whole Bob's former postdoc and OP,
49:42what who is a cancer genomics
49:45researcher at Chulalongkorn,
49:46who we still do a lot of work with?
49:50In order to get this work done,
49:52we went with the team to descend
49:55on the village a few times to
49:57help with the interviewing.
49:59Which basically meant that we move
50:01papers around because neither of us
50:04speak Thai except for really important
50:06words like thank you and mango.
50:09And that's at a pole.
50:11And this is Bob doing the
50:13blood draw in the village.
50:16The nurse is a nurse from
50:19Swan Prong Hospital,
50:20Ketapang Hospital.
50:23So we canvassed the village and we
50:26found that as we thought there were
50:29high rates of opioid use disorder in.
50:31This village close to Shanghai.
50:36And we did get some very
50:39interesting population genetics
50:41publications out of this work.
50:43Two of them, the one on top.
50:44We showed using genetic markers that the
50:47Hmong are genetically quite different
50:49from the Thai and Chinese who make
50:52up the bulk of the Thai population.
50:54And then if you look at the lower
50:56figure from another publication
50:58with a more extensive marker
51:00set on in the lower right,
51:01you see data that one of our postdocs
51:04collected with a set of different
51:07hilltribe populations in northern Thailand,
51:10showing that they are also genetically
51:12distinct from each other,
51:14which has implications
51:15for our continuing work.
51:19So for the hilltribe work we
51:21ended up with participation
51:22from four of the five families,
51:24about 200 subjects and all which it
51:27may be hard to imagine in today's era
51:29of sample sizes of over a million
51:32actually can be sufficient for linkage
51:35mapping in a population isolate,
51:37but the problem we had was that the
51:39fifth family was the one with the
51:42greatest concentration of opioid use
51:43disorder and the greatest involvement in
51:46trafficking and that family despite our.
51:49Assurances at the beginning of the project
51:52declined to participate in the study,
51:54so we were left with insufficient power.
51:58However, we had collaborations
51:59in the north of Thailand.
52:01We had our instruments translated into
52:03Thai and we had a basic understanding the
52:06population genetics in the majority and
52:09the minority populations in Thailand,
52:11and with that we decided to continue
52:13our work in outbred populations as
52:16opposed to population isolates in
52:18Bangkok with a focus on methamphetamine
52:21dependence rather than opioid dependence,
52:23and that shift in substance focus
52:25was a matter of necessity because.
52:28Methamphetamine,
52:28as a result of the royal project,
52:31was by now the nature substance of abuse.
52:33In most of Thailand.
52:37Before I go on and talk
52:39specifically about that work,
52:41I I would like to talk briefly about
52:43our D 43 international training grants.
52:47We've had numerous trainings over
52:49the year and we were very proud that
52:52most of our key collaborators in
52:55Thailand now are graduates of the
52:57Yale Chu Longhorn Training program.
52:59And they were quite productive,
53:02especially Bob's trainees,
53:03and work with him where you see
53:06work done in the US and our samples
53:09here when Doctor Rossman was
53:12here in Bobs Lab working on his.
53:17Very important cocaine self
53:19administration paradigm.
53:23But that work also continued in a
53:27tide treatment cohort that rossmont
53:29collected mostly by herself.
53:31She also did work in Rus Sodis
53:35sample when she was here and
53:37again continued the work with.
53:41Studies of the that rate of
53:44methamphetamine use and sex differences,
53:46and that I'd treatment center and
53:49I'm going to tell you about that Thai
53:51treatment center tenure at hospital a
53:53little bit more in the slides ahead.
53:57As part of the D 43 grants,
53:59we also had over the years,
54:01about half dozen training courses
54:05for trainees at true Longhorn and
54:08other institutions in Thailand
54:11where we brought faculty from
54:14multiple institutions in the US.
54:16But we were also very glad to bring people
54:19from Yale UC Godfrey Pearlson here,
54:21along with Bob myself and Doctor Ming Lee,
54:25who at the time was at University
54:27of Virginia.
54:28So those training courses went
54:29very well and I think we're much
54:32appreciated by the people at Chula,
54:34and this is from another chorus.
54:36This is the chorus.
54:38In the SADA instrument where the
54:41main instructor was Jordi Nunez,
54:43who continues to work with us.
54:46On our type projects,
54:47and she's the person in the
54:49photograph who is neither Bob nor me.
54:54So I'm going to spend the rest of the time
54:57talking about our studies of substance
55:01use disorders in Bangkok and Shanghai.
55:06So our acquaintance with substance use
55:10disorders and the research situation
55:14in Bangkok and Chiang Mai dated
55:16back to some of our very earliest
55:18trips where our Chula colleagues
55:23took us to tour Tanya Rock Hospital,
55:27which is the largest substance use
55:30disorder hospital in Thailand.
55:35This is a photograph that I took
55:37many years later of one of the open
55:39wards and Tonya Rock Hospital,
55:41but I also still recall on the
55:44first trip I made there with Bob.
55:47We walked around the grounds which are.
55:51Quite beautiful with beautiful tropical
55:53vegetation like most places in Thailand.
55:56But one of the awards it was award
55:58where they were treating adolescents
56:00with methamphetamine use disorders.
56:03And they were, you know, kids.
56:04They looked to be ages something
56:07like 14 to 16 and they were sitting
56:11around a table in the center of the
56:14room coloring and coloring books.
56:18Also, these are a couple of.
56:23Menus of places that we went
56:25to and non tourist areas.
56:27I found this one particularly chilling.
56:33And.
56:36After we finished our work
56:40in Northern Thailand,
56:41we got our 01 funding.
56:44So far two RO ones to study the
56:48genetics of methamphetamine
56:50dependence and type populations.
56:52So the most recent one which
56:54was funded in the mid 2000s,
56:57had aims of collecting
56:592000 subjects in Bangkok,
57:021000 severely affected with
57:04methamphetamine dependence and 1000
57:06exposed controls and assess them all
57:09with the full version of the TICADA.
57:12So I want to stress that this
57:13is a very extensive instrument.
57:15It has over 3500 items.
57:18It covers all major SUD's major
57:21psychiatric traits and medical history.
57:23So to collect 2000 data points with
57:26this instrument that often would
57:28take two to six hours to go through
57:31was a really major undertaking,
57:34but it also resulted in a trove of
57:37information because the interview
57:39was so detailed it required.
57:43Putting together a large and very
57:46carefully trained cadre of interviewers,
57:49and this required a lot of involvement
57:53from Bob and myself and up to his death.
57:56Bob participated weekly in ASADA
57:59meeting to review cases with our two
58:02Longhorn and Swan Prong collaborators
58:04to maintain quality control.
58:07And we also traveled to Thailand
58:09quite frequently.
58:10And Jordi Nunez often traveled
58:12with us to hold.
58:13Training refresher courses in
58:15the SADDAH to make sure that our
58:17diagnosis continue to be valid and
58:19reliable and then the eventual
58:21goal is to collect enough subjects
58:23for a reasonably powered set of
58:26genome wide association studies.
58:29This is a picture taken at one
58:32of the kickoff meetings we had
58:34for this grant project at Chula,
58:37where we held a big soccer training
58:41with many interviewers who came to
58:44work with us in this iPhone Panorama photo.
58:48You can barely see Jordi at the
58:51front showing slides and leading
58:53the training course.
58:57Just I'll come back to this number again,
59:00but jumping forward to the present day.
59:02We've succeeded in recruiting
59:04already almost 5000 subjects,
59:06which is much more than twice
59:08our goal of 2000 subjects.
59:10So I view our effort in Thailand today
59:16as highly successful in this way.
59:18And also, although.
59:25Please mute whoever that was,
59:27although we don't have enough power to
59:30study methamphetamine use disorder,
59:31yet there are some genes of large effect
59:35for alcohol use disorder and therefore
59:38using our Thai sample we were able to
59:41publish the first substance, use disorder,
59:44GWAS and type population in 2018.
59:48The lead analyst on this was Hung Zhao,
59:51who's now assistant professor.
59:53Here at Yale.
59:55And this shows a Manhattan plot in a
59:59regional Manhattan plot indicating
01:00:00the genome wide significant
01:00:02finding that we had in this Thai
01:00:05population for alcohol use disorder,
01:00:07which is that LD H2,
01:00:10which is a known genetic variant in
01:00:13some Asian populations where there is a
01:00:16functional null variant at LDH 2 that
01:00:19interferes with alcohol metabolism.
01:00:23We have since gone on and added
01:00:26more Thai subjects to our goose and
01:00:29also none of meta analysis with a
01:00:32relatively small number of additional
01:00:34Asian subjects we could put together
01:00:37and we have a paper in press led by
01:00:39Hong Zhao and Neuropsychopharmacology
01:00:41with the largest yet eud GWAS,
01:00:44where we now have two very strong hits.
01:00:47For those of you who aren't
01:00:49familiar with Manhattan plots,
01:00:50this is a log rhythmic scale.
01:00:52One at 80H1B and the other close to 80 H 2.
01:00:55So the alcohol work moves forward. Uhm?
01:00:59Our analysis for methamphetamine dependence
01:01:02have not yet yielded significant results.
01:01:06This is a preliminary analysis we did a
01:01:09year ago to go with the grant submission.
01:01:12Where I would say this Manhattan
01:01:15plot looks promising,
01:01:16although we don't have
01:01:18significant findings yet.
01:01:19But again, we're presently updating
01:01:21it with nearly twice the sample size,
01:01:23so we have high hopes for
01:01:26methamphetamine dependence.
01:01:27Also, if we're able to renew the grant.
01:01:31This is a picture of Bob and
01:01:34Rossman in front of OP.
01:01:36What slab building this was
01:01:38taken about five years ago.
01:01:42On one of the last trips
01:01:44we all made together.
01:01:46And this is a trip I made to meet with
01:01:49collaborators in Thailand last December.
01:01:52And dumb. OP E Watt and Rossman now
01:01:56masked up the hotel lobby with COVID Santa,
01:02:00but the work is moving forward.
01:02:05So if we think about.
01:02:09This part of Bob Bob's legacy,
01:02:11and as we've already discussed,
01:02:12Bob has many, many legacies.
01:02:15But if we consider the legacies
01:02:17of the work in Thailand.
01:02:18Uhm? Together,
01:02:21we've completed the most detailed
01:02:23work today on population genetics
01:02:26of minority type populations.
01:02:28We worked on the translation of
01:02:30two modern psychiatric assessments
01:02:32and to tie the Sada and a new
01:02:34bio bank instrument which
01:02:35will be using moving forward.
01:02:37We have collected the largest
01:02:40Asian Asian sample to date.
01:02:42Ascertain very carefully and
01:02:44informative for substance use, disorder,
01:02:47genetics and we published the first
01:02:49suw glosses and that population.
01:02:52We have now a very richly phenotyped sample,
01:02:57because remember how detailed
01:02:58the sada is a method?
01:03:01Methamphetamine dependence and psychosis
01:03:03but also of alcohol use disorder,
01:03:06nicotine dependence,
01:03:07kratom ketamin,
01:03:09PTSD,
01:03:10depression and a range of psychiatric
01:03:13traits and deeply phenotype
01:03:15sample of over 5000 subjects.
01:03:17That's including the ones on this
01:03:19R 01 that I showed you and also 800
01:03:22collected previously by Rossman.
01:03:24On another on study that our
01:03:27friends and colleagues in Bangkok
01:03:29are mining at this very moment.
01:03:32And most important,
01:03:33and I think this would have been
01:03:35the most important thing to Bob.
01:03:37The training of a cadre of outstanding
01:03:40independent researchers in Bangkok
01:03:41at Chula and in Chiang Mai,
01:03:43and psychiatric genetics and neuroimaging.
01:03:48Who currently are the basis of our
01:03:51collaborative team and who also
01:03:53continue to press forward with
01:03:56their own independent research
01:03:58and their other collaborations.
01:04:01And we have many plans to cement
01:04:03that legacy and continue the work.
01:04:06We want to continue the time
01:04:08meth project on the A1 for the
01:04:11competitive renewal is about to be
01:04:13submitted now in a biobank format
01:04:16with the aim now to collect.
01:04:2010,000 additional subjects,
01:04:22the D 43 renewal is pending.
01:04:25We've gotten on good signals that it could
01:04:28be funded in the next couple of weeks.
01:04:31The name of the project is now
01:04:33the Robert team, Allison, Yale,
01:04:35Chulalongkorn, stress alcohol use and
01:04:39psychopathology training program.
01:04:41It's directed now at NI AAA and NIMH.
01:04:44As Nidahas continued today,
01:04:46emphasize Human Genetics work.
01:04:48We have a new R 01 with the Thai
01:04:51collaborators about to be reviewed,
01:04:53extending the work to PTSD and depression.
01:04:56And with thanks to all
01:04:58my other collaborators,
01:04:59very deep thanks to Mark.
01:05:01But Enza, who has stepped in and
01:05:03helped to continue this work,
01:05:05and our many collaborators at.
01:05:07Yell Chula and swadhin problem.
01:05:13And so. This is Bob.
01:05:19At a restaurant in Bangkok?
01:05:21I'm in a great mood with a
01:05:24colorful beverage with a
01:05:25flower in it in front of him.
01:05:27He liked those kinds of drinks.
01:05:30Looking forward to.
01:05:33The meal, but mostly to the meeting
01:05:36with Ross Manapua and our other
01:05:39collaborators that we're about
01:05:41to go onto that afternoon. And.
01:05:47We owe Bob a big. Thank you for
01:05:52all of that and it was a real
01:05:54privilege to work with them.
01:05:56Thank you for your attention.
01:06:04Joel, thank you.
01:06:06It's really extraordinary
01:06:07to see the breadth of Bob's
01:06:10work across these two talks.
01:06:12And the breadth of the the universe
01:06:15of people he touched across
01:06:17generations across the globe across
01:06:19areas of science and medicine.
01:06:26Thank you all for being
01:06:27here today. I'm sure we could stay for hours,
01:06:29sharing memories and talking about Bob.
01:06:32There will be a chance to do that
01:06:33with some of his men tease at the
01:06:35NRTP seminar at 11:45 and I've again
01:06:37pasted that link into the chat.
01:06:38Please feel free to join us if you have.
01:06:41If you have the time. Mitchell,
01:06:43John, thank you for your comments.
01:06:44Your memories and thank you everyone for
01:06:47being with us today as we as we remember
01:06:50a friend and a giant in our department.