Yale Psychiatry Grand Rounds: January 28, 2022

Transcript

• 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.