Sep 27, 2017
Speaker1:Hi everyone. As a quick introduction, this is the full lengthrecording of Anwar Chahal's interview with Calum MacRae from August2017. A portion of this interview was included in episode seven ofthe Circulation Cardiovascular Genetics podcast "Getting Personal:Omics of the Heart". As we couldn't fit everything into thatregular podcast episode, we've released the unedited version as aspecial, feature-length podcast. Enjoy.
Dr AnwarChahal:My name is Dr. Anwar Chahal. I'm a Cardiology Fellow in Trainingfrom London, U.K., and I'm doing my research fellowship here at theMayo Clinic, and I'm very honored and delighted to have our guest,Dr. Calum MacRae. I searched for Dr. Calum MacRae's biographyonline and it came up with a Wikipedia page talking about somebodywho's a rugby coach. So, Dr. MacRae, I hope that's not another oneof strings to your bow, that's something else that you manage tosqueeze in amongst everything else that you do in your busy andpunishing schedule.
Dr CalumMacRae: I didplay a little rugby in my day, but I haven't coached any, I canassure you.
Dr AnwarChahal:So, you are the Chief of Cardiovascular Medicine, you are an MD,PhD by training, and you are Associate Professor at Harvard MedicalSchool, and your expertise, amongst many other things, internalmedicine, cardiovascular diseases, but in particular, inheritedcardiovascular conditions. Is there anything else that you wouldadd to that?
Dr CalumMacRae: No,I'm a big fan of generalism, and I am quite interested incardiovascular involvement in systemic disease as well, but largelyas a means of keeping myself abreast with the biological mechanismsin every system that seems to be relevant to cardiovasculardisease.
Dr AnwarChahal:So, that reminds me. Once I heard you talk, and you mentioned toall those people that were considering cardiovascular genetics theimportance of phenotype and actually how people have becomeincreasingly super-super-specialized, becoming the bundle branchblock experts or the world's authority on the right coronary cuspof the aortic valve, and how things were now going full-circle aspeople actually need better and better, more general understandingso that we can accurately phenotype. And you once joked that you'dactually done residency three times, so you know the importance ofhaving a good generalist base, so could you expand a little bit onthat?
Dr CalumMacRae: Well,I have to tell you, it wasn't a joke. I did actually do residencythree times. But, I think the most important element of that themeis that biological processes do not, unfortunately, obey the silosin which medical subspecialists operate. So it is increasinglyimportant to have a broad-based vision of how phenotypes mightactually impact the whole organism. That's particularly truebecause it helps us ratify disease, so that there are mechanisticinsights that come from the different cell types and tissues andbiological processes that are affected.
I think, in general, that is something that we've all appreciated,but as time goes by and people become more and more specialized,it's less regularly implemented in day to day clinical practice.And so, particularly as molecular medicine becomes more and morepenetrant in clinical disease management, I think you're going tosee a return toward some generalism. Obviously, proceduralspecialties are the exception in many ways in this setting, becauseyou need concentrated procedural skill. But in general,particularly for translational scientists or scientists who areinterested in the underlying mechanisms of disease I think, I see ageneral movement towards a degree of generalism.
Dr AnwarChahal:Indeed, and in terms of, as you say, trying to understand thosedisease processes and trying to, let's say for example, make senseof the incredible amounts of information that can now be gatheredwith genomics and high throughput omics, you believe that it isactually more of a requirement to be able to understand that nowthat we can gather this high resolution and broad depth ofdata?
Dr CalumMacRae: Yes,I agree. I think one of the core elements of modern clinicalmedicine is that the phenotypes have, in the last 50 to 100 years,we've really focused more on improving the resolution of existingphenotypes than expanding the phenotypic space. To be completelyfrank, I think we've extracted a lot of the information contentthat we can from the phenotypic space that we've explored, and whatwe need to begin to do is to find ways to systematically expandthat phenotypic space.
I think there are a lot of reasonable ways of doing it just bythinking about other subspecialties. So, for example, incardiovascular disease, we've focused very heavily on anatomy andphysiology, but we haven't really done much in the way of cellbiology. Whereas, in immunology, partly because there's access tothose cell types, it's possible to do much more detailed cellularphenotyping. In neuroscience, we're now doing functional MRI, andlooking at individual subsets of cells in the brain, and theirfunction in the context of particular challenges.
My general thesis would be that the type of strategy would serve uswell and that there's also, I think, an important mismatch betweenthe dimensionality of phenotyping that we currently undertake andthe scale of the genome and epigenome, transcriptome, et cetera.So, it's not surprising that we can't be convoluted genome of 10 tothe nine variants with a phenome that are present only really hasabout a 10 to the four phenotypes. And so, I think some systematicright-sizing of that balance will be necessary.
There are lots of things that we record that we don't even think ofas phenotypes, and there are phenotypes that we record that wedon't really think about how to optimize the information ofcontent. And so that's one of the things that we have begun toinvest time and energy in. And thanks to the support of theAmerican Heart Association, Verily, and AstraZeneca, as part of theOne Brave Idea, we have elected to fully focus on that area inparticular in coronary disease. But I think it's a generalizableproblem with much of modern medicine that we tend to have focus onphenotypes that, in many instances, date back to the turn of thelast century rather than to modern molecular and cellularbiology.
Dr AnwarChahal:So, you beautifully brought us to the first question, which was toask you about One Brave Idea. Could you just, for our listeners whoaren't familiar with that, just give a little bit of a backgroundon One Brave Idea, and you've already thanked the people who havefunded that, but how did you actually reach the point where youthought that this is something that really, really needs to bedone? What's the process of reaching that point of bringing thisidea to fruition?
Dr CalumMacRae: Ithink we had recognized in many instances that the families that wewere seeing in cardiovascular genetics clinics were much smaller,the diseases appeared to be less penetrant than the originalfamilies that we studied when we cloned many of the disease genes.This was work that I did as a post-doctoral fellow in John andChristine Simons lab many years ago.
One of the things that was pretty obvious was that there weresubtle pre-clinically or sub-clinically affected individuals inalmost every family. And that made me ... That implies that theaverage family is so different from the extreme family. Is itsomething to do with either the resolution with which we wereassessing disease or are we actually just measuring the wrongelements of the underlying genetic trait? So that, for example, isa dilated cardiomyopathy family actually a family that issusceptible to dilated cardiomyopathy in the context of someunmeasured conditioning variable, maybe a viral infection or anexposure. And because we're not measuring the exposure, or we'renot measuring the underlying diaphysis, we're only measuring thefinal state, so we only classify people as being affected if theyactually have an extreme phenotype. Are we, therefore, missing thecore elements of the biology?
As part of doing that, we began to look outside the heart for otherphenotypes, and one of the things we recognized ... This was incardiomyopathy ... Was that different cardiac phenotypes werereally aggregates of much more granular, multi-system phenotypes.So there would be families who would have dilated cardiomyopathy,but they would also actually have abnormalities, for example, ofthe distal interruptus muscles, and no other muscle group in theirentire body. And in fact, the distal interruptus muscle phenotypewas much more obvious than any cardiomyopathic phenotype.
So you start to understand that either other extra cardiac orelectrical phenotypes, or maybe even sometimes neurofunctionphenotypes are more penitent features of some of these disorders,albeit rare disorders. And so that immediately leads you to thinkare most of the common traits that we look after really aggregatesof things that really only share the relative frequency of the corephenotype, which often dates back to decades earlier whenphenotyping was at a much more superficial level.
So that vicious cycle perpetuates itself if we never look moredeeply or look outside the constraints of a particularsubspecialty. And so we have begun many, probably almost four yearsago, to build a sort of next generation phenotyping clinic where wetried to bring either cell biology or molecular biology fromoutside the heart into phenotyping patients in a cardiovascularclinic. That idea was in our DNA, that's probably not the right wayto say it, but it's something that we had worked on in acardiomyopathy setting.
Dr AnwarChahal:Right.
Dr CalumMacRae: Andso then when the RFP for One Brave Idea came out, it seemed like anatural expansion of that to try and think about how you couldapply new phenotyping in current disease. One of the inferencesfrom that line of thought is to move, essentially, beyond ideallymuch upstream of the shared final common pathway so that you canbegin to identify discreet underlying mechanisms.
And then, given the success of cardiologists, and cardiology ingeneral, in prevention, it became obvious that really what wewanted to do was to try and understand not just disease, but alsowellness. And to do that in a way where we could potentially detectthe transition from wellness to the very first stages of thedisease or the diseases that we have labeled as atherosclerosis orcoronary artery disease.
That was the genesis of the central idea of the application andsomething that, obviously, we were excited to get the chance topursue as a result of the generosity of the funders, and the visionof Nancy Brown at AHA and Andy Conrad at Verily, to not only awardfunding in a different way, but to also really try and drive us tothink differently about how we executed on a research product. Howwe move forward, not with a five-year plan, but with a rapid cycleearly hypothesis testing, fail fast and fail early, if you aregoing to fail, strategy. Rethink not just the focus of the researchproject, but the mechanisms by which you execute on it.
I think one of the core elements of this is, obviously, we want tomake sure in doing this that we build on all of the incredible workthat's been done in the last 25 or 30 years in coronary disease,whether it's the pharmacologic work, or the genetics work that hasemerged in the last few years. Those are all important buildingblocks, and what can you do that leverages all of that existingdata and adds to it? Phenotype is obviously one of the mostimportant areas where you can bring something to the table that addto existing genotypes and also layers in on top of existingpathophysiologic models.
From my standpoint, it was an efficient strategy, and one that wehoped would also help us engage the people throughout the communityin different ways of using data that might already have beencollected or we were going to be able to collect for the firsttime.
Dr AnwarChahal:In terms of One Brave Idea, where is that right now in terms ofexecution, as you mentioned? What's the progress so far, and isanything that's come out already that you can share with us?
Dr CalumMacRae: Yeah,of course. So we have begun a variety of different approaches tothinking through the best way of exploring this phenotypic space.One of the obvious things is you can take a couple of strategies tomove into this unknown unknown. One of them is to take anincremental approach to move slowly from the areas where we havealready established knowledge, and to move into new areas from thathome base. And the other is to take a more agnostic strategy, whichis to say are there orthogonal ways of thinking where you couldlook at a particular type of biology in a very focused way incoronary disease. You can define that in lots of different ways.You can say maybe we do it at an organelle level, or maybe we do itat some orthogonal component. The microbiome might be an obviousone. Another one that has been considered would be nutritional orother common environmental exposures.
The nice thing about the flexibility of the funding is that we canafford to test multiple different hypotheses early on, see which ofthem has the best signal, and then invest more deeply in those thathave shown early signal. At the moment, we have multiple activeprojects that are really testing those initial hypotheses. Is therea way of moving from the known genes that cause coronary arterydisease and trying to understand are there novel phenotypes thatare associated with those. And then another approach would be totake people with very early or pre-clinical disease and test areasof biology that have never been tested in atherosclerosis or incoronary disease in a systematic way.
We could imagine lots of ways of doing it, but you might thinkabout, lets say, looking at endocytosis, a process that we knowalready is affected by the core genes in familial hypoglycemia, butwe've never really found ways to measure that in a rigorousfashion. In large populations of individuals, are there different... Well, we know already there are different forms endocytosis,but are there discreet port ablations that might affect those.
Another way of looking this might be to pick an organelle. Pick theperoxisome, or pick the nucleolus, pick some other element and askhow does the function of this organelle change in individuals whohave early coronary disease. Where its boring each of these typesof things systematically, and trying to learn not just which arethe most important areas to focus on, but also trying to learn arethere strategies that are useful that you could use in anotherdisease. In other words, are there generalizable approaches toexpanding phenotypic space that makes sense.
I think one of the things that perhaps we underestimate about agenome is that it is the only bounded dataset in all of biology atthe moment. There are no other bounded datasets. There is aninfinite number of potential exposures. There's an infinite numberof potential phenotypes that we could record, or at least as far aswe know, are there ways of beginning to establish the boundaries ofthe phenome, the boundaries of the exposure or the exposal and howdo we begin to do that in a way that efficiently yields newinformation. That's where we, as a consortium, have focused in thelast few months.
We're also, obviously, investing time and energy in thinking how dowe begin to remodel the way in which research is evaluated andfunded. The strategy that we've taken there is almost like anot-for-profit venture fund where we try and bring in ideas that wethink might be able to leverage what's known already and move thefield faster towards new pathways or new approaches to prevention,which are the core deliverables of the One Brave Idea award. Aspart of doing that, we obviously get the chance to interact withlots of exciting and creative scientists and that's something we'relooking forward to doing in lots of different venues. We'rereaching out to lots of people and lots of people are reaching outto us. We're trying to find ways to evaluate and prioritize scienceand then bring that science to fruition through novel approaches tofunding it, either directly or as a joint venture with a foundationor some other funding source, or even as a joint venture with acommercial partner to try and move the field forward as efficientlyas possible.
Dr AnwarChahal:Thank you very much for that, and I'm sure we all eagerly lookforward to the results that are going to be coming out from OneBrave Idea over the next few years. I'd like to now move on togenomic medicine training and you were involved in a statement thatwas put out regarding this. I think training across the world hasincreasingly recognized the importance of genetics and genomics,but I just want to share one little anecdote.
My wife is a primary care physician, and I was visiting the GPpractice where she works, and she'd mentioned that I had aninterest in genetics and genomics. One of the partners came outwith one of these reports that a patient had sent their sample to aprivate company, got this analyzed, brought it in to the clinicappointment and asked for an interpretation. The GP partner said tome, "I've absolutely no idea what any of these numbers, values, etcetera, mean, and I actually am looking forward to my retirement,because I really don't want to have to cover all this. Can you helpme with it?"
I sort of remember hearing Dr. Weinshilboum talk here at MayoClinic, who's really pushed forward pharmacogenomics, and he's beenarguing for quite some time, as I've heard you say as well, thatgenomics and genetics is just going to be a part of the medicalrecord in the same way that hemoglobin or a chest x-ray is. Peoplebetter catch on because it's here, it's available commercially.People can send their samples directly, without the doctor'sinvolvement, and then it's trying to make sense of all of that.
I think, as a community, research and clinical, we have to takethis very seriously. I'd be grateful for your insights on that, andthen if you could then tell us what would be the best way for theup and coming generation and for programs to incorporate that intotheir training?
Dr CalumMacRae: So, Ithink you're right. There is a general tendency in the publicdomain to test a variety of different genotypes. And in manyinstances, I think, the key elements are how do we as a profession,conceive of these tests? I think one of the things that we forget,perhaps at our peril, is that many of these things are problemsthat we've encountered before. There's a natural cycle of differenttests in medicine where they start off in the academic medicalcenters, they propagate into the periphery, and then eventuallythey're assimilated as part of internal medicine.
I think the scale of genomics is obviously somewhat broader thanmany individuals have seen in the types of data that they deal withon a day to day basis. But I think that's something that'shappening in everybody's life. In every aspect of your life, youhave many more channels to deal with. You have many more choices inthe supermarket to deal with.
So, I don't see this as a sort of existential challenge tomedicine. Quite the opposite. In my experience, the core thingsthat we need to remember is that DNA is no different from any otherassay except for the fact that it's relatively straightforward todo DNA diagnostics. It's technically not as sensitive a set ofbiochemical issues, as are many other assays that we use in day today clinical practice.
The other thing that I think is perhaps a key element is it, as Isaid a few minutes ago, it's a bounded dataset, and it's stable foryour whole life. You only need to have it tested once. So, to sortof invert the typical diagnostic paradigms, instead of a primarytest being interpreted in the context of an ongoing clinical event,the test may have been present for decades, and the result willevolve over time, in light of the changing phenotype or some newinformation with respect to that genotype.
What I've actually looked on genomics as is almost an organizingprinciple for the way that you build care. In fact, I see quitefrequently, we now probably have an average one or two new patientsa month in my clinic who bring their entire whole genome with them,either an axiom or a whole genome. And so, we've begun to reallyget to know quite well how to manage patients. Obviously, there area selective of patients. But one of the things that I have found isthat patients are really quite astute in understanding thatgenotype and phenotype are not deterministic relationships. Whatyou have to do is always interpret these things in context of aprobabilistic understanding.
Most patients, I think, when they're told this, understand thatwe're going to learn much more about genomics going forward than wewill ever imagine we could know at the present. That will involvelots of different things. It will involve new ways of displayingdata, new ways of thinking about the data in the clinical context.I actually think one of the most interesting things about genomics,and to be honest, any assay is that they rarely reach any form ofmaturity until they are used in the clinic, until they are actuallyused in implementation. For example, many genetic tests at themoment, don't change therapy and they don't change outcomes. Butpartly, that's because they've never been studied in thatcontext.
One of the things that I think Glen [inaudible 00:26:58] has to bereally congratulated for is his focus on pharmacogenomics as beingone of the early areas in which this will really move forward. Ibelieve that by immersing ourselves in it, by actually trying it inthe clinic, we're going to learn much more.
Part of that gets back to the original topic that we spoke about,which is phenotype. The only way to really begin to understandcollection of phenotype is if you do it in the context of existinggenotype, I think. And so, as we move into new phenotypic areas,we're not going to be able to test everything and everybody. Ithink there, the genome will end up being an important framework,lifelong framework for the management of a patient's diagnosis,prognostication, and then therapy, potentially in that order.
I think you need a whole different set of skills. You need a wholedifferent set of technologies. But most importantly, you needinformation that you can interpret in the context of the person infront of you. Until you can make mechanistically important insightswith one person, it's going to be very difficult for genomics toreally change medical care. That's something that I think we shouldbe focusing on.
I think we've tended to have an associate of strategy for genetics.We haven't driven it into the clinic. As we drive tests into theclinic, whether it's troponin T or whatever, you begin tounderstand much better how to use them. Although, sometimes, thatcan also go in quite extreme directions that you may notnecessarily anticipate. Troponin originally was a stratificationtool for acute coronary syndromes, and now it's virtually adiagnosis in its own right. And I think you'll see that tendencyrevert over time as people begin to understand the biology oftroponin, of isoform switching, and peripheral tissues of the wayin which troponin may represent very different diseasebiologies.
At the moment, it seems like it's a very simple and straightforwardyes/no type of test. There's no such thing in medicine, and I thinkthat's what we're learning about genomics. Instead of conceiving itas a series of ten to the nine yes/no tests, we're going to end upwith a very different vision and view of how it can be implementedin clinical practice. And that can only come from having cliniciansand geneticists work together on this. In fact, one of the thingsthat we've been doing in the partners environment with some of ourcolleagues, and I have NIH funding to do this with Heidi Rehm, withSandy Aronson, and with Sean Murphy, is to think about how wedisplay data, but also how we collect information in light of thatgenomic data that helps in an iterative way and a learning fashion,informed genotype/phenotype relationships in a much moreprobabilistic manner than we have done to date. There are lots ofefforts in that space, that just happens to be one that I'minvolved in. But I think it's a generalizable approach that you'regoing to see moving into the clinic in the next few years.
From the standpoint of training, I think what you want to do is toget exposure to all types of genetic information so you understandcommon alleles, rare alleles, genomics, and individual panels. Ithink the best way of doing that is to have that be part oftraining programs. In fact, with one of my junior colleagues, Dr.Aaron Aday, we recently wrote a short piece highlighting howimportant it will be for all of us to come together to think abouthow do we start to introduce the concepts of genomics into standardclinical training programs. And that's something we're working onfairly avidly at the Brigham, and I'm sure there are ... I knowthere are efforts at many other institutions to do similarthings.
Dr AnwarChahal:That article was published in Circulation in July of this year, ifanybody wants to download that. I think if we talk to clinicaltrainees and ask them what are their concerns about training, asyou know, training can be very long in cardiology, which is aprocedurally based specialty, whether or not you become an invasiveproceduralist at the end of it, there is that component at thebeginning. Do you think a standard, in the U.S. a standardthree-year program with two years of clinical and one year ofresearch, can incorporate that at a sound enough level to allowsomebody to practice? Do you think we're going to look atincreasingly a one-year, or a six-month, sort of add-on fellowshipfor those interested more on the inherited side or more on thegenomic side?
I, like yourself, trained in London, and the training programs arelonger in the U.K. It was probably six years when you were there,it shortened to five, and now increasingly, it's going to becomesix and maybe even more with a general fellowship for five years,and then a super-advanced fellowship. Inherited cardiovascularconditions, certainly there, has become a module that is encouragedfor people to take and then become somewhat certified in inheritedcardiovascular conditions. What do you think there, in terms ofincorporating all of that as well as learning basics of echo, anddevice therapy, and catheterization, what are your thoughts?
Dr CalumMacRae:Again, I look at this as a spectrum. There's a trajectory for allof these types of innovation and knowledge. It starts off beingsuper-specialized, it goes into a more general location, and theneventually, it's an integral part of everybody's clinical practice.I do think that what you're going to see is rather than, and thisis already, I think, the case in many elements of medicine.Medicine has already exceeded the knowledge base, even when I wastraining, by probably a log order in terms of the complexity andextent of content, not that I trained that long ago.
One of the core elements that I think that we're seeing is that weneed to move medicine from what I believe has become somewhatdeprofessionalized state, to one where you're actually focusing noton the actual core knowledge that you bring with you to the table,but actually the way in which you integrate knowledge. So, I thinkthe focus of training is going to change somewhat. It has had tochange in other fields. Medicine, I think, for a long time favoredthat sort of single, comprehensive approach in one mind. Andmedicine is going to become more of a team sport, and it's alsogoing to become more of a knowledge integrator profession that ithas been for some time.
It's interesting, when medicine started, there was so littleknowledge that you really had to have almost every physician be anexperimentalist using [inaudible 00:34:48] of one experiments infront of them. I think the way that I see medicine evolving is thatas the knowledge base and the rigor of that knowledge baseimproves, many of the things that we think of as professionalactivity today, will actually devolve through primary care and, tobe honest, into the community. There are many things where therigor of the underlying [inaudible 00:35:12] are as such thatthere's no reason for a licensed provider to be involved. We allowour patients to install their own wireless networks without atechnician. I'm sure most of them could look after their own lipidspretty effectively if they were given the right information.
So, a lot of stuff will begin to move in that direction. And asthat happens, I think the way in which information is displayed,the way in which data are collected, and the workflow aroundintegrating information will change. That doesn't get past thepoint that you brought up, which is that that will probably take acouple of decades, and in the interim, I think people are going toend up training in modules of subspecialty, but I think one of thethings that I sometimes like to ask myself is what's the end game?Where is this going to end up? And can we build systems that traindirectly for that end game, rather than going through theseintermediate steps. I think that's something where I think wetried, in the short piece that we wrote in Circulation, to arguethat everybody should have some exposure, and that that exposurecan change over time. We should be equipping people, not to knowgenomics, but to be able to learn how genomics is impacting theirpatients for the next 50 years.
That model of professional training is actually the one that reallywas the dominant model until maybe 100 years ago. And then, forreasons that don't quite seem obvious to me at least at the moment,we sort of tended to slowly move to more of a learned knowledgebase that was then applied. Physicians sort of steadily got to thepoint where we're now data entry clerks. The actual amount ofprofessional and intellectual engagement has, I think, slowlydiminished in many medical subspecialties and medicalspecialties.
The opportunity that genomics and other advancements in technologyin medicine bring is the chance to, I think, reprofessionalizeourselves to move from just simply defining ourselves in terms ofthe knowledge base that we each bring to the table, but definingourselves rather in terms of how we put the knowledge togetheraround individual problems and individual patients. It's a verymuch more patient-centered biological approach than perhaps we'vehad over the last couple of decades.
I think these are ... I'm obviously stating a lot of this somewhatin extremes, but I think that these are general trends that you seein medicine. They've happened in other fields as well, and peoplehave overcome them. It's usually a function of changing theworkflow itself, of changing the way in which the information endsup in the professional's hands and how you collect the data thatyou use, then, to interpret the existing knowledge. That, Ibelieve, we haven't really reworked probably since Ozler'stime.
It is amazing that we still have workflow ... I mean, it's amazingin lots of ways. It's an amazing tradition, but it is quiteinteresting that we still have workflow that is probably largelydependent on what Ozler liked to do when he was growing up in termsof the times of day that he got up and his workflow. That's sort ofinstantiated in many ways in everything that we do. Nothingentirely wrong with it, but there's a lot happened since then thatwe haven't really changed. Medicine is not yet, in many instances,a 24/7 profession, and yet most other things that have much less inthe way of impact on society, are already 24/7 professions in manysettings.
So, I think you're going to see a lot of demographic changes inmedicine that come from the advent of technology and otherindustries. And I think those will all transform the way that weimagine training in medicine, along the same sort of timeline assome of the traditional approaches that you described, building outa training module and then having a subgroup of people do asix-month or a year of extra training. I see that as a short-termsolution. I think, ultimately, longer term solutions are changingthe whole workflow of medicine.
Dr AnwarChahal:What have you done in your own program at the Brigham to introducegenomic medicine training for fellows?
Dr CalumMacRae: Weare building out ... Obviously we have a fairly largecardiovascular genetics clinic. I think probably the largest in theworld. We have now seven, soon to be eight, providers working onlyand wholly in cardiovascular genetics. We therefore have theability to have our fellows rotate through our genetics clinic. Wehave inpatient and outpatient genetics services. And we also,obviously, involve our fellows in a lot of the academic pursuitsgoing on in both our genetics and genomics programs in thecardiovascular clinic.
As we do, our colleagues are no longer in training. We haveregular, in our clinical conference slot, we have, several times ayear, a genetics component. And then, what we have also, is anintegrated training program with clinicians and pathologists thatis really bringing the individuals who are understanding thetechnical aspects of the genetic testing with the individuals whoare learning and understanding the clinical aspects of thattesting. And so, we imagine over time that this will evolve intopotentially the type of specialist module that you described. Butalso, into a fixture that goes all the way through our two-yearclinical training program.
We've sort of taken the point of view that we probably need to do abit of both. We need to, given what I've said in the last fewminutes, that we need to take a thread that recognizes a short termand intermediate term need for specialization, but also recognizesthat we have to equip every one of our trainees, and every one ofour physicians with the ability to begin to learn the underlyingsides of genomics, and the underlying approaches to using genomicsin every aspect of clinical cardiology. And so, we're doing both ofthose things, and have active efforts in both.
Dr AnwarChahal:You mentioned integration with pathologists, but for our colleagueswho are not clinicians, what about the research angle, and thescientists, when they're in training? Is that integrated so that weare getting this meeting of minds that is essential?
Dr CalumMacRae:Absolutely. In fact we, thanks to a variety of efforts at BrighamWomen's, we have now at least three separate venues in which thisoccurs. I mentioned cardiovascular genetics clinic. We also have agenomic medicine clinic, which I'm one of the clinical co-directorsfor, where we actually have cases that come through routineclinical care that seem as if they would benefit from whole genomeor whole axiom sequencing. And then we have a weekly conferencethat's actually led by Dick Maas and Shamil Sunyaev, two of ourgenetics colleagues, and taped in specialists from Althrop Medicineas well as scientists from the entire Harvard Medical Schoolenvironment. So we bring everybody together around mechanisticallysolving individual clinical cases.
And then the third venue is one that's part of a national network,the Undiagnosed Diseases Network. We are one of the sites on thenational NIH-funded UDN network. And there again, one of the themesis identifying individuals or families who would benefit from bothrigorous genomic analyses as well as much deeper phenotyping.That's been a program that I think has been very exciting, and onethat we, again, have learned a huge amount from in terms of how doyou begin to build the infrastructure that brings, not just thefresh clinician to see the patient, but somebody who ... A wholeteam of people, who understand and can evaluate all the biologicalaspects that are relevant in that patient.
It also brings to bear the scientific expertise that you might needin order to make a mechanistic connection between genotype andphenotype in that one individual. And some of that involves animalremodeling. In cancer, for example, there's a concept that hasemerged over the last two to three years of what's calledco-clinical modeling. Once you've identified some of the genomicfeatures, it allows you to begin to model in an animal, in parallelwith the trajectory of the patient, and individual [crosstalk00:44:54]-
Dr AnwarChahal:As some people call them.
Dr CalumMacRae:Exactly. Creating an avatar. And in many instances, that's anavatar that includes multiple different disease models. We havebegun to do that in the cardiovascular space. I think, obviouslyit's early days yet, but I think there are lessons to be learnedabout how you build the types of infrastructure that allow peopleto move beyond this state where a patient's outcome is dependent onhim seeing the right doctor, on the right day, at the righttime.
There are actually systems that funnel the patients into the rightvenue based on objective criteria at every stage. I think that'sthe type of reorganization, re imagination of the medical systemthat we need. We sort of duplicate things in lots of differentareas, and you're still dependent on hitting the right specialist,on the right day, at the right time. Or not seeing a specialist.Seeing a generalist on the right day, at the right time, who isable to put everything together. Or even hitting somebody who hasthe time to listen to your story in a way that helps you identifythe exposure or the genetic basis of your condition.
If we recreate the professional environment that I talked aboutearlier, I think in ways that are both traditional and novel at thesame time, I think we will do ourselves a great service and build aplatform that lets all of the technologies, including genomics thatwe've talked about today, begin to impact patients in a real way ona regular basis.
Dr AnwarChahal:Thank you for that. One question I think is important to look atfrom the other side, you've gone from One Brave Idea to onerevolution in medicine if I can be so bold. You mentioned so manyother services are 24/7. You give an example, you can book yourhotel in Shanghai sat in the Midwest, and you can change yourbooking on an app on a phone, and yet in medicine, it's sodifficult to arrange an appointment. We have resisted that 24/7service, aside from the acutes. But for the sort of chronicworkload that we have, the 24/7 model has been resisted. What doyou think are some of the challenges? Because I can almost hearmembers of our profession saying, "Well, who wants a 24/7 serviceand who wants to provide that 24/7 service?", and is it alwaysnecessary to have that 24/7 service?
As you say, so many things, such as hypertension treatment, youmentioned lipid management, could actually be done reasonably wellby patients who are well trained. And certainly in heart failure,you can teach patients to take their Furosemide or their Lasix byweighing themselves and adjusting it, and can do it relativelywell, and relatively safely. What do you think are the challengesto get the profession to realize that this is what's going tohappen, and they've got to get on board?
Dr CalumMacRae: Well,I don't think you want to make it somehow mandatory. I think thereare elements. Every patient is different. I think that's somethingwe've used as a chivalrous for many decades as a profession. Thereality is that we don't do very well. It takes, from the time amedication hits the guidelines, not the trials are finished, butthe time that it gets accepted into the guidelines, let's say as aClass I recommendation. The average time to reaching equilibrium inthe population is 12 to 15 years in cardiovascular disease. Soyou'd hate to be the person who got that drug in the 11th year, ifyou actually end up having your event in year three or four. Andyet you can upgrade software for your phone, and hundreds ofmillions people upgrade it in the first couple of days after arelease.
So, we have to build systems that allow us to be as efficient asevery other element of our lives, and yet don't, in any way,diminish the importance of the personal interaction, the healinginteraction that comes from a patient provider encounter. I thinkwe do ourselves a disservice if we just imagine everything inexactly the same way as it's always been. A lot of it just requiresus to make relatively modest changes to the types of things that wedo, and to cede some control over some elements of it.
People are not dependent on making cyclical appointments to havedoses of drugs tritrated. But once we've identified that a drugneeds to be on board as a result of a primary indication, that weallow the titration to take place in an efficient andcost-effective manner. I think a lot of what we do is driven by howwe get paid. A lot of ... And that's not criticism, it's natural inevery single profession on the planet. You do things the way thatthe system is set up to have them be done.
And so, I think with relatively little in the way of systemsengineering, you can have a 24/7 system without having 24/7physicians. There are some areas, obviously intensive care units,where you do have 24/7 coverage already, but people are so used tohaving asynchronous care that being able to literally come homeafter a night shift and make their reservation for a restaurant thefollowing evening, on their phone, often on another continent, itis a little bit strange that we literally can't book patients intoyour own clinic without calling up a couple of people.
I just think that some of this is resistance for resistance's sake.Some of it is people actually simply restating the things that weall believe are important parts of medical encounters. I think wejust have to be creative about how we move from here to there. Ithink the thing that I find perhaps most interesting is thatsomehow the creativity of physicians is not fully exploited. Wehaven't really asked doctors and patients to come up with newapproaches to how care is delivered, to how patients are seen. ButI think if we allowed venues where that could happen, that would beactually the way in which we would evolve a very differentsystem.
I think some of that, as I said, just goes back to the way in whicheverything is structured. All of the payment models, all of the ...Even the types of places that we see patients, are very muchanchored in history. They're legacy items and there are lots ofreasons why that's the case. Medicine, you can't show up with aminimally viable product. You need something that works perfectlyday one, because of the liability. And so, what we need are just torethink the way in which we even move medicine forward. What weknow we can't do is just keep doing what we're doing, and changingmodestly, rearrange the deck chairs.
What we need to actually be able to do is find places where we canactually, or venues where we can change things and test new modelsof care in a relatively low risk situation. I think you already seelots of payers, the federal government, and the NIH all thinkingabout how you can do that. Some of the [inaudible 00:52:55]efforts, some of the ... Even the NHGRI efforts in genomics. One ofthe nice things about genomics is because it's a new tool, itallows you to reinvent the way in which medicine is delivered. Andso, I believe things as diverse as the precision medicineinitiative, and as some of the most fundamental ways in which NIHfunding is being restructured, will all potentially impact the wayin which creativity and innovation start to evolve within thehealthcare system.
I don't want to sound revolutionary. We're all doing all of this,all of the time. It's just not structured in a way that seems tovery efficiently reach reduction to practice across the entiremedical ecosystem. Part of what I think we need to do is, as aprofession, build better ways of identifying where the innovationis occurring, and I will tell you I think it's occurring almostevenly across the entire medical universe, it's just that itdoesn't propagate. All medicine, at the moment, is quite local. Ithink the things that you start to see happening in the industrythat will change it are the fact that medicine is becoming muchmore like every other area of endeavor. It's becoming linked bytechnology. And once information flows more efficiently, I think alot of the things that sound as if they're revolutionary, will endup actually just seeming like a series of obvious conclusions,based on the information that we've gleaned from early outlets orsuccess stories.
Many of the things that I've mentioned today, they're notrevolutionary at all. There are entire healthcare systems that usethese approaches. But they just haven't become generalized becauseof the way that medicine works. And so, I think that's one of thereasons that I'm a believer that technology in particular will havea transformative effect, just on the way that doctors talk to otherdoctors or relate to their patients, and the way in whichcreativity and innovation propagate through the medical system willchange very rapidly as a result of that.
And that's one of the great benefits of the electronic healthrecord. I don't think EHR's now are perfect. In fact, in many ways,they're where other industries were 15 or 20 years ago. The supplychain in many large retail organizations was much moresophisticated in the mid-80s than the average EHR is. But whatthey've done is begin to collect the data in the right place, andin the right way, in a structured format. But as technology beginsto cut across different EHR's and across different healthcarenetwork, you'll see things, synergies begin to emerge that willaccelerate the pace of change.
It's not by chance alone that medicine has attracted differenttypes of people over the last 50 or 100 years. I think they'll justsee the types of individuals that come to medicine be more diverseand more distinctive, and that also I think will help. Moredistinctive in their skillset, and that will help accelerate changein ways that again, will seem far from revolutionary fairlyquickly.
Dr AnwarChahal:Thank you for that. I wanted to come to the last section of thepodcast, and sort of back to where I said it was joking, and yousaid I wasn't joking about doing three residencies. So, could youtell us a little bit about your own training and your own path?Originally from Scotland, through to London, and then over to theU.S.
And also, if you could share some of those pearls that you'vepicked up that aren't obvious to us in books, or sometimes are soobvious that they're elusive and not always apparent to young, upand coming trainees, both on the research side as well as theclinical.
Dr CalumMacRae: Yeah,sure. I trained in [inaudible 00:57:15] which had I think a veryhealthy attitude to specialism and generalism, and the relationshipbetween them, and instilled in all of the specialists the need toalways maintain some general medical capability. To this day, Istill intend on general medicine for that reason.
I then moved, I did cardiology training in London, and wasfortunate to work in a couple of hospitals, one of which had a veryinteresting, I supposed, quaternary care clinic which had extremelycomplicated patients. That's where I did my second internship, atthe Ross Graduate Medical School in Hammersmith. And everybody whowas an intern in that setting had already basically been boardcertified in internal medicine, so they'd all finished theirmedical training, come back to do an internship in thatsetting.
And there, I saw some amazing cases. There was an entire servicefor carcinoids, there was an entire service for many rare andwonderful diseases. At that point, you began to see howsuper-specialist knowledge can be incredibly helpful. But it canalso be restrictive if it's not applied in the right way.
And then I did cardiology training at St. George's Hospital inLondon with some amazing mentors. John Camm, who many people willknow from his work in atrial fibrillation and sudden death. DavidWarr, another very well known electrophysiologist, one of the earlypioneers. Bill McKenna was my primary mentor, and he was somebodywho had worked on the very earliest descriptions of hypertrophiccardiomyopathy when he had originally been at the Hammersmith, andthen moved to St. George's.
He taught me a lot about, well many things. First of all, focus inyour career, understanding the skillsets that you needed toaccumulate in order to a) build a distinctive portfolio and b) tomaintain your relevance by accumulating new skillsets as you moveforward. And he had actually established a collaboration withSimon's. That was one of the reasons that I ended up moving to theU.S., and had a fantastic time with John and Cricket, at one of theearliest times in genetics moving into cardiovascular disease.
I learned a huge amount from colleagues, at that stage, both at thebench. Hugh Watkins is now chair of cardiology and lecturer ofmedicine now in Oxford, was a bay mate who was there a couple ofyears ahead of me and I learned a huge amount from him. I realized... My wife is from New York City, from Long Island rather, and Irealized I had to probably stay in the U.S. for those reasons, andI retrained at that stage in internal medicine again at the Brighamwhere mentors such as Marshall Wolf and, actually cardiologymentors at that stage were people like Punky Mudge and Pat O'Gara,who then helped me to adapt to the U.S. system.
The only thing I will tell you is that I don't think I ever learnedas much as I did in each of my internships. I think the learningcurve is incredibly steep. I'd been out of clinical medicine forfour or five years, focusing on the lab, before I went back to mythird internship. But I still think it was one of the most amazingexperiences, largely because of the fact that you learn from everycolleague, and you learn from every patient. I think if you gothrough most of your life thinking like that, I think you can endup doing very well.
Actually, one of the other things that's really important isactually emphasizing those personal connections. The first fellow Ihad at Brigham and Women's when I was an intern was Joe Hill, who'snow the editor of Circulation, the chair of cardiology at UTSouthwestern. Almost everybody that I know in cardiovascularmedicine, I've encountered in those types of settings. Either intraining settings, or in research collaborations, or at researchmeetings. You just begin to see a whole list of people that haveworked together in different ways, and have learned from eachother. I think that's one of the most powerful things to take awayfrom research or clinical training.
I then was fortunate enough to get the chance to do a secondcardiology fellowship at Mass General. There, I went to MassGeneral actually because of the focus on zebra fish genetics. Irealized at that stage to really be able to study things at thescale that I thought was going to be necessary, I needed a high[inaudible 01:02:40] system, and Mark Schwartz, before he went toNovardis, on the zebra fish and the cardiovascular system, was veryinspiring and I had a great time there. And then, ended up spendingsome fantastic years at Mass General where I eventually became theprogram director. But again, there I learned an incredible amountfrom people like Bill Dec, from Roman Desanctis, from Dolph Hutter.All of whom had very strong clinical presence, as well as from theresearchers. Mark Fishman, the late Ken Bloch, and many others.
And then also, perhaps one of the most important people in my longterm training was Peter Yurchak, who had been ... He had actuallydefined, I think, the training programs in U.S. cardiology about 35years earlier. He had been the program director since its inceptionin the 50s until he retired in 2005 I think it was. And then Ibecame the program director and was there until I moved back to theBrigham in 2009, and became chief in 2014.
I think the trajectory is really, I outline it only to highlightthe fact that it took me a long time to get where I was going, butthat I spent most of my life enjoying the journey. And I thinkthat's actually one of the most important lessons I took away fromit. You can end up finding situations where you feel like you mightbecome frustrated, but in fact, if you go into them with the rightattitude, and not only that, if you do it with the right people,you can take a huge amount out of it.
I was incredibly fortunate in the fellowship class that I had atMass General. Mark Sabatine is now the chair of TIMI, PatrickEllinor, who is the head of EP and a pioneer in atrial fibrillationgenetics. Stan Shaw, who is now the chief scientific officer withme in One Brave Idea. Danita Yoerger, who's the head of ECHO, andan outstanding ECHO researcher at Mass General. Mark Rubenstein,who's a very successful cardiologist, and a fabulous clinician.That group of people actually, I think, together helped me realizehow much you could take from training no matter how old you are,and no matter how grumpy you seem when you don't get the fullnights sleep.
In the research side, I think the other thing that was obvious wasthat so many people bring so many different things to the table inresearch that you should never over or underestimate any aspect ofthe entire profession. I think I still get remarkable insights intoresearch questions from colleagues who are clinicians, who've neverdone any research, just from astute observation and declaring aproblem in a way that encourages investigation. I think that's oneof the most important elements of training is how do you work outwhat you need to do, and how do you make sure that everything thatyou do between the start and the finish of that journey is used tohelp and to improve the way in which you end up doing what youultimately find as your sort of settling point in your career.
I think the other thing that I will say from the standpoint ofresearch is it's always best to try and think about blendingdifferent fields together. What you don't want to do is end upbeing a clone of one of your supervisors or your mentors. It'sreally an important thing, and I encourage this in all of ourtrainees the importance of being a bridge between differentdisciplines. I think that's something that requires realemphasis.
And then, finally, never ever forget that the single most importantthing in all of this, whether it's the reorganization of clinicalcare or the core research environments, is the biology in thepatients in front of you. And so, one of the things that I'mparticularly and acutely aware of almost every time I see patientsis that the patients often know much more about the condition thatthey have than you ever will. Listening to them is actually veryimportant piece of everything that you do.
In fact, one of the reasons that we began to move outside the heartin our heart failure research was talking to patients about theirpre-clinical elements that they found in their families. So, often,when you see a family with inherited heart disease, before the geneis identified, before anybody has a phenotype that you recognize,the patients themselves can assess who's likely to develop thedisease from their intrinsic knowledge of their siblings, and theircousins, and their other family members.
So, for example, one of the families that I've worked on intensely,there's a anxiety disorder that is a much more stable and much morespecific part of the phenotype than any of the cardiac arrhythmias,and it's actually turned out to be quite a difficult anxietydisorder to define using even DFM criteria. But when we asked thefamily, they were very able to tell the people in the family whojust were at the normal edge of neurotic from those who truly hadthe anxiety disorder that co-segregated eventually with thearrhythmia.
The lesson I've learned time and time again is that patients alwaysare a vital and central part of the answer. And it's a pride thingto say, but particularly in genetics and genomics, I think, andparticularly with the reemphasis on phenotype, that I believe isnecessary, I think we do well to try and make sure our research andour clinical care, our discovery, and our disease management arevery tightly aligned. And I think technology is one of the waysthat will help that happen. That actually is part of what being aprofessional really is. If you go back to the early professionalguilds, that's exactly how they were formed. It was groups ofexperimentalists who were interested in particular problems thatformed the original professions in European cities during theRenaissance. I think that's something that we would do well tothink about as we continue to remodel medicine in the 21stcentury.
Dr AnwarChahal:Thank you for that. Lots of important points there, and I guessyour emphasis that enjoying the journey rather than thinking aboutthe destination, but did you always know where your destinationwould be? And, in fact, that brings me to another question. Haveyou actually reached your destination, or is your journey stillongoing?
Dr CalumMacRae: So,exactly. I think that's the key thing. You don't need tonecessarily know where you're going to stop. You just need to knowwhere you're headed. That's something I actually tell people asthey're interviewing for fellowship or residency, that part of whatpeople are looking for when they talk to you is that you havethought through and organized your life around your goals. Andthose goals can change. Nobody's going to hold you ... In face, oneof the most amazing things, particularly about academic medicine,but in medicine in general, is the fact that you can reinventyourself in so many different ways.
I think the most important thing is you have a direction thatyou're headed in at that particular time, and that what you'redoing, and the way that you're doing it, is rationally related tothat direction. So, as I said, thinking where you're headed andwhat skillsets you might need to get there. How are you going toacquire those skillsets. How you are going to blend thoseskillsets. How you're going to establish your own identity. Andalso, how you're going to, in practical terms, make it happen.Where are you going to be living? How is it going to fit with therest of your life?
One of the, perhaps, most healthy things that's happened in thelast couple of decades in medicine, is that people realize that avery good work life balance is critical. And then, also, how areyou going to pay for it? How are you going to fund what you want todo. And I think those are things that medicine has, again, hasperhaps not really encouraged. That sort of entrepreneurial spiritor self motivated, self funded spirit, is something that isn'tuniversally appreciated in medicine. I'm not saying everybodyshould do it, but just as in every other area of endeavor, I thinkhaving the ability to rethink the way in which everything is puttogether is an important piece of what drives change in anyindustry, or in any profession.
Never more so than in something that is so focused on discovery asmedicine and biomedicine still has to be, because there's so muchof a burden. Despite all the advances, we still have major hurdlesto overcome. I think thinking about it in those terms, thinkingabout it not just in I want to have this particular position inthis particular institution, but actually thinking about it as aseries of jobs, each of which you bring different skillsets to, andeach of which gives you different skillsets to take on to the nextposition, is something that would be quite healthy. I sometimeswonder if one of the problems with medicine is that we tend to endup doing the same thing for about 45 or 50 years, and maybe that'sone of the things that would be worth mixing up a little bit, justto allow some of the traditional things to be imparted to theincoming disruptors, but also to have some of the disruptive thingstransmitted and reinterpreted by people who've seen many thingschange over the last couple of decades.
So, I think that type of team-based approach has benefit, not justfor the patient, but also for the career of the investigator. Ihope I haven't rambled too much. These are all things that I thinkare ... I suppose the difficulty with almost everything is it'sconnected to almost everything else.
Dr AnwarChahal:If you can connect the dots, which you so eloquently do.
Dr CalumMacRae:Exactly. That's what it's all about.
Dr AnwarChahal:Absolutely. I remember I met with you a few years back at HRS, Ithink, in San Francisco, and I just want to share this with theaudience that my interaction with you, coming from a system whereoften it was hierarchical in getting access to the movers andshakers in the field, or just your consultant day to day was verydifficult in someone who is junior. And I emailed you to say couldI just meet you for 30 minutes, and you replied straightaway, andwe met up over lunch. I remember you took this yogurt pot, and yousaid if you can't see the connection with this and sudden cardiacdeath, then you haven't understood research. That stuck with me,and I don't know if you remember that, but I share that.
Dr CalumMacRae: I do,unfortunately, but I get into trouble for saying stuff that I saysometimes, but I do mean it. I think that the core element is thatcomplexity is actually ... One of the fundamental things that Iactually find has been deprofessionalizing, although it's verynecessary, is this sense that you can drive everything into analgorithm. My attitude is that what you have to do is take thethings that do work at a certain level of reduction to practice andtake those off the table for a while until you understand thembetter. But to ignore complexity, to have everything be sort ofa*ggregated into a small subset of common diagnoses, that's whatends up being, I think, the thing that holds up progress.
If you recognize an uncertainty and ambiguity andinterconnectedness and complexity, I think, even if you can't getyour arms around it, at least you begin to try and understand it alittle bit better. And I think sometimes, we have had to because ofthe way in which medicine has to be delivered in the currentsystem. We've had to oversimplify it. One of the things that Ibelieve the technological revolution and the connectedness the restof our lives has done, is that it's allowed informatic andanalytics to penetrate every part of an industry. And that stillhasn't happened in medicine. We don't have a system where the worldexpert sitting at the Mayo Clinic, his knowledge can be usedwithout anybody ever seeing him. His knowledge can be used at thebedside in sub-Saharan Africa.
Once we reach that type of system, I think we will at least havemade significant progress. And remember, that's the type of thingthat occurs in almost every other setting in our lives. Theanalytics that people use to drive movie choices on Netflix can beused for many things, and are used for many things in sub-SaharanAfrica. But in medicine, somehow, we've managed to partitioneverything into a series of small boutiques, and we need to startto think about how we allow knowledge to disseminate withouteliminating that personal interaction. So, hopefully, the yogurtand the sudden death are ... That connection will become moremechanistically understood in the next few years.
Dr AnwarChahal:Indeed. Thank you very much for that, Dr. Calum MacRae, for givingup your precious time and sharing your thoughts and insights andexperience, and I hope that our audience really enjoyed as much aswe've enjoyed interviewing you and listening. I hope that we get tospeak again very soon. So, with that, I wish you and your familyand your team at the Brigham well, and thank you once again.
Dr CalumMacRae: Thankyou for your time, and I've enjoyed talking to you. Thanksagain.
Dr AnwarChahal:Thank you, Dr. MacRae.
