So today I'd like to give you an overview, not just of my work, but also of much work by others in, whoops, I just broke the podium, thank you. So this is an exciting time for us in cancer research because as I'll get into, we have tools that are just jaw-dropping in their power to examine the human genome. And I've been using these for quite a few years to study lymphoma, as mentioned. I also now have two jobs, two full-time jobs, the other one being directing all the large genomic efforts that the National Cancer Institute is conducting right now. And these then hope to do what I've been doing for lymphoma for all cancers and do it on a grand scale that will lift the entire field up. So I'll begin today's talk, giving that overview based on what's going on out there, and then I will focus in on my own research and show you some more in-depth studies on how we think about the genetics of cancer. But the broad take-home message is that the current ways that we're diagnosing cancer and treating cancer are changing before our eyes and we're going from a histological diagnosis to a molecular diagnosis of cancer as fast as we can. So when I speak of genomics, what I'm talking about are the somatic changes that occur in the cancer cell, not in the germ line of the individual, although that contributes. But what I'm going to be talking about today are the alterations in the tumor cell that make it different from a normal cell. And of course this begins with mutations that sometimes alter the structure of proteins. There are structural rearrangements of the genome, either DNA copy gains or losses or sometimes translocations of the genome. There's a need to look at the active part of the genome that is expressed as messenger RNA that can be dysregulated in cancer. There are a class of small regulatory RNAs called microRNAs that are important to know about and then there are modifications of DNA such as DNA methylation that lead us into insights into the abnormalities of cancer. And in the latter part of the talk, I'll talk about these I would class as structural genomics and then there's another class of studies called functional genomics where we aim to find out which genes are important by directly manipulating those genes and seeing what happens. The tool that all of us are relying on now are these so-called next generation sequencers. One from Illumina and what we took, we being the broad genomics community took more than a decade to finish one human genome. Now two human genomes can be done in 11 days of sequencing on this one machine. So this is an outpouring of data that obviously requires a lot of computational power to make sense out of and this is courtesy of the Genome Institute is one of their more commonly shown slides. I'm sure I'm showing that here is the drop in cost of computing. I'm sure you all have heard of Moore's law and here's the drop in the cost of sequencing the genome. So it's plummeting faster than Moore's law and we're now somewhere around a $4,000 genome and we hope to be soon at a $1,000 genome, really making it very personal for all of us very soon. So as I mentioned, I'm directing these programs in genomics for the NCI now and they include something called the Cancer Genome Atlas which is looking at adult cancers very deeply. There's a program looking at pediatric cancers and then there's a functional genomics program. And so first I'll tell you a little bit about recent progress in this TCGA program from structural genomics of cancer and the goal here was to study a large number of cancers because we believe that there's this great diversity of human cancer and until we see that in all of its glory we won't know how to understand any individual patient and what's going on. So here are the tumors that we've studied and by the end of the year we will have brought into the program 10,000 tumors that will then be finished in their analysis about two years later. And the first thing we have realized is something we knew before but is something we deal with now that the mutational burden in cancer is very, very high and some of this is of course self-inflicted. We have carcinogens of various varieties, smoking, sunlight, possibly food that we eat leading to very high rates of mutation in, for example, lung cancer, melanoma and stomach cancer way on this side whereas on the other side you have the childhood cancers where very little action is going on. So out of this rather noisy picture we have to discern the biological signals. Some of this is just noise and some of it has led to changes that make the cancer cell malignant. So a recent study that was published out of the TCGA was about kidney cancer, renal cell, clear cell carcinoma and in this cancer, this is a busy slide but it shows you that cancer information is busy and rich and it focuses on what was found to be a recurrent signaling abnormalities in a signaling pathway known as the PI3 kinase pathway that promotes the survival and metabolism of cells. The first important point is to say it's not one abnormality but all large number of genes were either mutated, amplified or deleted such that when you put them in a pathway diagram you can see that in small numbers of patients there were mutations somewhere in the pathway leading to a grand total of 28% of all of this cancer type having some abnormality in this pathway and some of the point mutations in a key kinase called mTOR that in this pathway are shown here and they cluster in particular parts of the protein. Important point is that from a clinical point of view, a clinical study had already been done with a drug that targets mTOR known as Everolimus and you'll note that in fact in clear cell carcinoma there was a signal. There were responders, it's not a home run, we're not curing anyone but the drug works and it's probably because this type of cancer relies and has turned on this signaling pathway which is and of course now we have to figure out well who are these responders to this drug, did they have these mutations whereas the other ones did not. Now this is mislabeled, this is a study of recent study of endometrial cancer that the TCGA did and these are about 500 samples from different patients and then you classify them by their molecular abnormalities in a variety of ways that I won't go into but the categories are fairly self-explanatory. There's what is called an ultramutated type of endometrial cancer with lots and lots of mutations due to a defect in a repair enzyme. Then there's a hyper-mutated form that's defect in a different repair enzyme, the mismatch repair enzyme and then there's two other forms that are called copy number low and copy number high meaning that there were either extra amplification of DNA here or not as many events over here. Now if you look at this classification with respect to, that's not shown here yet, I'll get to the next slide. So this leads us to the classification, what's now shown is how does this relate to the histology as a pathologist would normally do it. The pathologist sees there's an endometrial, an endometrioid type of this cancer and a serous-like type of this cancer and that's in either light blue or dark blue. You'll note that in this copy number low and these others mostly it's the endometrioid so things are lining up okay but here we have a problem. Here there's a mixture of histological diagnoses within one of these categories and in fact it would look like there's some things that are really serous by their molecular profile but the pathologist called it endometrial. Do we care about this? Well yes we do because endometrioid has a better prognosis and is treated differently from the serous type. It is given adjuvant therapy with radiotherapy is along with surgery whereas this more difficult to treat serous type chemotherapy is added to surgery where if you look at the survival of the patients classified in this way you'll see that indeed this serous type in the red curve has the worst outcome. This copy number low has an intermediate outcome and this ultramutated type at the end. These folks do incredibly well so you could say maybe all they need is surgery and nothing else but the important point again is that if we stuck with the histological diagnosis it's possible that some patients who really have this molecular serous type would have been called endometrioid and maybe gotten the less aggressive therapy and not done as well as if they had gotten chemotherapy. So now can we find new therapies for our patients based on structural genomics and here I'll highlight just one example from the pediatric target study that we've been looking at a large number of these childhood cancers shown here and this was a 10 year old boy and he had a refractory form of B cell acute lymphoblastic leukemia of course is pretty treatable except when it's not and in this case it wasn't and the RNA sequencing was done another way to look at the RNA not the DNA but nonetheless it showed that this boy's tumor had a translocation that involved a receptor tyrosine kinase known as the PDGF receptor. So fortunately there's a drug for this and it's called a matinib you may have used it or heard about it as a treatment for chronic myelodysl leukemia but it also is a very good inhibitor of the PDGF receptor and he started this treatment got immediate clinical improvement within one week there was a morphological remission in the blood and by two weeks there was essentially no molecularly detected disease and that's shown here in this PCR assay on before treatment this is the the translocation mRNA and on treatment you just can't detect it anymore. Now this is a very new unpublished work so we don't know how this individual is doing long term but it's a dramatic response and it's this kind of N of 1 experience anecdotal experience that we've been seeing with some of these targeted agents that have gotten a lot of people excited but of course anecdotes are not how we do good clinical medicine so the Cancer Institute is trying to do this more seriously and essentially the problem is how do we find the right drug for the right patient and there's two ways to approach that the first is in this genotype to phenotype that is I discover that the tumor has this mutation I have a drug I think is good for that aberrant protein made by that mutation and let's see how it works and we're not going to just do this in one patient we're going to do this in a thousand patients and to find these thousand patients that have some targetable molecular abnormality will screen about 1500 to 3000 of them in in CLIA labs to get the these molecular genetic changes we've gotten drugs over 30 of them committed by pharmaceutical companies that may target one or the other of these mutant proteins and they are going to give them to the NCI for this trial and then we're going to assign a sort of algorithm if you have this abnormality or the other you get drug A but these other abnormalities you get drug B and so on and then we're going to see how often it is that we can as I say predict the T-leaves predict the response is this a successful approach and that will go through the clinical trial design the second the second way to look for the right drug and the right person is so called phenotype to genotype here the doctor is the investigator the doctor sees this remarkable response in one individual that the same drug in other individuals seemingly of the same cancer type did not respond and so these are the so called exceptional responders and here's one celebrated case from Memorial Sloan Kettering 73 year old gentleman I think it's actually I don't know that a 73 year old with bladder cancer and and and this person had been put on and failing a lot of other therapies had put on the same drug that I introduced to you this Everolimus the target the mTOR protein and had a remarkable complete response and it was it's been quite durable no evidence of disease 24 months after starting the therapy and this is just the abdominal scan showing large clusters of tumor masses that then resolve and are still gone at 18 months so why is it that this one patient had a response whereas the clinical trial that he was in was declared a a failed trial the statistical endpoint was not met well the whole genome sequencing was done on this patient and here's a way we depict all the molecular abnormalities where all the chromosomes are arrayed in a circle one through 22 X and Y and and then these various marks refer to whether where there are abnormalities and some of them you can't see these little dots are point mutations in the genome and I've a circle circled one green dot which indicates a frame shift mutation in a tumor suppressor pro protein called TSC one and TSC one is a negative regulator of this mTOR signaling complex so when you remove the break on this complex you get spontaneous signaling and that is presumably why this patient had such a good response now with this knowledge if you go back to the clinical trial and look at the response of patients on this trial and ask whether there were mutations in this TSC one disease gene you find here this big this is the depiction of the tumor volume so going over to the left is the loss of tumor volume so this is the patient we've been talking about with the remarkable response but here's some other partial responses or actually didn't even make it into partial response but they are the ones that have the mutations whereas the ones that don't have a mutation all those tumors grew so this is now sparked more work there's another clinical trial to evaluate whether this is indeed true and so to capitalize on this kind of clinical observation we're encouraging physicians from all over the country all over the world for that matter to send us your exceptional responders that is we would like to study these unusual responses if the patient is willing to participate have their genome sequenced and then see how often we can figure out the puzzle of why we had such a clinical response so in the last part of the talk then I'll tell you about how we've approached a particular really aggressive type of lymphoma known as diffuse large B cell lymphoma and I will introduce first the idea of functional genomics and we depict this by Achilles here being felled by the arrow to his heel and I modified this to include on his shield a histological picture of diffuse large B cell lymphoma and the metaphor is so rich I can't believe to tell you but if you remember the Iliad then the shield of Achilles which is described in several pages in that book basically if you read and understood the shield of Achilles you would know how the world works and worked at that time. There were depictions of the various cities and there were depictions of wars and there were mountains and rivers and oceans so same way we feel that if we can understand in a molecular way this cancer then we will find this vulnerability that we can target therapeutically. So the way we do this is do a generic screen of course genetic screens have been done since Mendel and famous people studying fruit flies and we just couldn't do that with the cancer cells because of course we can't breed our organism of choice the human at will so but we have new techniques that allow us to do genetics without heredity in a way and what we do is we have tools called small hairpin RNAs that are able to surgically inactivate a particular one gene at a time and in so doing we can see what that gene does for the cancer cell and that's depicted here so we have a library of these SH RNA vectors each one in different color targeting a different one of the 24,000 human genes and we introduce that large B cell lymphoma library into a cancer cell line so you can see that every cell growing in this flask in my laboratory would have a different SH RNA and therefore have inactivated a different gene so this is the beginning of a genetic experiment you have genetic diversity in a population of cells you now apply a selective pressure and the selective pressure is simply can any cell in that flask grow and proliferate and survive for three weeks in culture so you'll note that in this population of cells one is missing right and presumably that is because this SH RNA this turquoise SH RNA knocked out an essential gene in that cancer cell that it cannot live without and therefore it is depleted from the population and so then all we have to do is compare the population of SH RNA vectors at the end of the experiment to that at the beginning of the experiment and figure out what the essential genes for proliferation survival are so these are our so-called Achilles heel screens important point to make is that it's not at odds in any way with the structure genomics I just got telling you about in fact what we find over and over again is when we perform an Achilles heel screen and then look within the pathway we've identified as essential pathway somewhere in there in that pathway is a mutation that tells us why that pathway was active and so this is the goal finding these essential cancer pathways so diffuse large B cell lymphoma I'm sure you've all had some experience with it in one way or the other is the most common type of non-Achilles lymphoma it's a aggressive but obviously can be treated and the cure rate currently with CHOP chemotherapy regimen plus Rituximab is on the order of 50% so great 50% much better than other solid cancers but we're trying to figure out something to do for the other 50% and this leaves us with a large number of deaths every year 10,000 in the United States alone and so we thought that perhaps the problem was that by looking into the microscope and describing the cells as large and diffuse in spread maybe that was just not sufficiently accurate to perceive the differences that were leading to different responses to chemotherapy so we used molecular profiling to find subtypes of diffuse large B cell lymphoma and the molecular profiling the available technology to me 10 years, 13 years ago was not this fancy next gen sequencing but rather ability to profile the levels of messenger RNAs of various genes within the cell so-called gene expression profiling and the way we usually depict this is if a gene is very active and there's a lot of messenger RNA tumor is given a red color and if there's very little expression of gene you get a green color and black is somewhere in between and then what you see in this diagram are lymphoma biopsies probably a couple of hundred of them each in a different column from a different patient and then we have a number of genes probably about 200 genes here and you can see that in tumors of this variety which we call the activated B cell or ABC they have this signature of genes being very active and these genes being inactive and just the opposite in the germinal center type GCB you have a different signature of gene activity and these different activities didn't just arise from from know where they're actually a signature of the type of normal B cell from whence this lymphoma derived so as I mentioned one of our goals was to figure out which of the patients were doing well with chemotherapy and which weren't and it certainly is the case that these ABC tumors are the bad actors here we're only curing at best about 40% of the patients with our chop chemotherapy whereas the germinal center type is coming in at about 75% so we're not done worrying about the germinal center type but we've spent most of our work in the lab on the the activated type so how do you know that this is reality well that is maybe there's an infinite number of ways to use all this complex data to to divide up tumors and why is this the right way to divide them up well I've shown you that there was some clinical differences so that's one thing to hang your hat on the other thing to hang your hat on is that then you look in those tumors classified as ABC or GCB ask what are the genetic abnormalities which mutations which deletions amplifications of genes which structural genomic changes are found in one type or the other and what you find is that all of the abnormalities shown on the left side here are only found in the activated B cell type whereas all these others on the right side are only found in the germinal center type so this Yin Yang appearance tells you that these are pathogenetically distinct diseases and why are they distinct as I mentioned these tumors come from a different starting point a different normal B cell and probably because of that different start point then it has to take different steps to become malignant and the way that we think about how this particular ABC malignancy arises is boiled down to a very simple molecular wiring diagram what we noticed very early on that was that there was one signaling pathway within the malignant cells known as the NF Kappa B pathway which was seemingly stuck on in the on position in all these tumors and this is a key pathway that in any cell type will prevent cell death so of course that's one of the hallmarks of cancer that the cells don't die appropriately now NF Kappa B does another important thing to a B lymphocyte it turns on a transcription factor called IRF4 which propels that B cell down the differentiation pathway to becoming a plasma cell and if it went all the way down to the end then that might be the substrate of multiple myeloma a plasmacitic neoplasm but it wouldn't be this ABC diffuse lymphoma so instead there's a second block having to do with a loss of another transcription factor known as blimp 1 and these cells pile up in a differentiation stage that's normally only transiently present so this plasmablastic stage is probably no more than about 12 hours in the life of a B cell but perhaps now this abnormal accumulation in this stage allows for further oncogenic changes to lead to the full malignancy what we wanted to understand though was why this NF Kappa B pathway that was promoting the abnormal survival of these malignant cells what was the cause of this normally this is turned on in a B lymphocyte in response to exposure to an antigen in the environment and it gets the cell activated but we didn't know that there was any antigen here so this pathway was on all the time why was that and in particular what upstream signaling pathways lead into the key regulatory kinase in this pathway known as ICAP B kinase that turns on NF Kappa B and what we discovered which I'll take you through in a step by step fashion is that it is the B cell receptor signaling pathway that is important and the B cell receptor pathway of course is arguably the B cell receptor is arguably the most important receptor to a B cell without it you can't even make a B cell from a bone marrow progenitor cell you have no B cells and then even if you had those B cells and when you were exposed to an antigen, a pathogen, a virus there would be no response because it's the receptor for those antigens this is the key receptor and it does many many things for the B cell that promote its survival and proliferation so what we discovered in our genetic screen initially was that there was a signaling complex downstream of the B cell receptor and upstream of ICAP B kinase involving three proteins card 11 malt 1 BCL 10 and if we inactivated any one of these three proteins by that SH RNA technique then the cells died our cell line models of this type of lymphoma so that was our first clue that this entire pathway which had been worked out previously by immunologists was important then we started sequencing the tumors and found that in 10% of the tumors of this variety there were mutations that affected the card 11 adapter protein and these mutations were really fascinating because they created mutant proteins that spontaneously turned on the NF Kappa B pathway if they were put into another cell so these were the oncogenes if you will within these cells but note that 90% of the cases did not have any mutations in card 11 yet we had other cell line models that with with no mutations of card 11 but still if I knocked down card 11 they die so something was was turning on wild type card 11 so we surmised there must be some signal upstream in this pathway that was tickling card 11 and turning it on and in fact in our genetic screen we had already observed a strong dependency of those cell lines on Bruton's tyrosine kinase which I'm sure you remember as important to even make a B lymphocyte the the boys with this X linked inherited disease don't have B cells and suffer from infections and and and and other things so this is important kinase that links the B cell receptor to the downstream NF Kappa B pathway but then we started sequencing oh there must be mutations in BTK so we sequenced that and there were no mutations in any of our patients we sequenced all the other kinases in the cascade no mutations and finally tumbled to the fact well maybe it's just at the the source of this river right maybe it's at the B cell receptor itself so we went and knocked down components of the B cell receptor and the cells croaked so the and turned off this NF Kappa B pathway so these cells depend on the B cell receptor but why well in 21% of the tumors we found mutations in in two of the components of the B cell receptor known as CD79A and CD79B this seems to be going in and out this microphone sorry and and I'll take you through these appear to be gain of function mutations and and and but but they're not perhaps as strong as that card 11 mutation I told you about and we'll get into that so how does B cell receptor signaling work well this is sort of the cartoon version and this is what you would find in an immunology textbook that there are the two immunoglobulin chains that interact with antigen and then there's a signaling chain CD79A and B within the cytoplasmic part of CD79A and B there's a series of amino acids a motif known as an ITAM motif and this is the signaling motif that's important and what happens is some Sark family kinases phosphorylate the tyrosines there recruit another kinase known as sick and then a lot of downstream signaling occurs so mutations in CD79A and B occurred in 21% of the patients with this ABC type of lymphoma and essentially never or very rare occurring in the other types of lymphomas that we decided so this says that this type of B cell receptor signaling is a key part of the pathogenesis of the ABC lymphoma and not these other lymphomes again highlighting the molecular differences between these sub times so what are the functional consequences of those mutations in the B cell receptor well here's the cartoon that I showed you and what we found the mutations first what were they well they were fascinating in that they affected one single amino acid this tyrosine a proximal tyrosine in CD79A and CD79B in the vast majority of cases and basically you could put any other amino acid in there one case actually deleted that tyrosine any of those appeared to be functionally the same type of mutation now at a lower frequency we found deletions in the other signaling component CD79A that surgically took out the ITAM region of CD79A so what do these do why are they selected for well the first thing to understand way to understand this is that one of the consequences of engaging the B cell receptor with this red antigen this foreign substance is like all receptors it will then be down modulated off the cell surface in an endocytic recycling and thereby terminating the response well we discovered that if you have a mutation in CD79B this endocytic recycling is blocked so the so the receptor simply stays at higher levels at all times on the cell surface and thereby promoting signaling. The second mechanism that we discovered had to do with a negative feedback for B cell receptor signaling so all receptors both turn on signaling and then have ways of turning it off because if you didn't this would be pathological and in this particular receptor there's a kind one of the Sark family kinase is known as LYN that phosphorylates another protein CD22 and recruits a phosphatase that takes off those phosphotyrosines and turns the receptor back to its native state and what we found that in tumors that have the mutant form of CD79B that kinase although active is much less active and does not engage those negative regulatory elements so two ways we get more B cell receptor at the surface and it's more active. Now life was fine at that point but the molecular biology and genetics of cancer doesn't have to be simple and so we had in our genetics screen an equally important survival pathway that seemed to emanate from a signaling adapter known as Mighty 88 and it also turns on the NFKB pathway very strongly. Well and in 39% of our tumors we found activating mutations in Mighty 88 that make it constitutionally able to turn on NFKB. So what is Mighty 88? It's a very famous receptor for immunologists because it is the adapter rather for the toll like receptors that are involved in innate immunity. They just see danger somewhere in the environment. They see a virus with a viral RNA or a viral DNA or they see a lipid from a bacteria and they alert the immune response. These are the so-called pattern recognition receptors and they utilize the signaling adapter Mighty 88 and they are powerful receptors just like the B cell receptor that turn on the NFKB pathway, P30 map kinase, engage a number of cytokines, IL-6 and IL-10 and interferon. And this is becoming this particular mutation, one of the, I call it sort of the RAS oncogene for late B cell malignancies. So here is the frequency of this mutation within various mature B cell malignancies. Here's our ABC lymphomas coming in at 29% with one particular mutation I'm showing you. But there's a primary central nervous system diffused lymphoma that has about a 40% occurrence of this mutation, a cutaneous type of diffused lymphoma with a 70% testicular diffused lymphoma, 80% and a type of indolent plasma cell neoplasm, Walden stones, macular, and anemia. 90% of individuals with this type of cancer, the tumor cells have this one particular point mutation. But at a lower frequency chronic lymphocytic leukemia which is of course the most common leukemia, 3% of those cases have that same mutation. So we need to understand what this guy is doing. So on the face of it it would look like you had two parallel pathways leading to NFKB. But we had a drug, first of all, that targeted one of those two pathways, the B cell receptor pathway. And that drug is known as Ibrutinib. And so we were, we, what? Ibrutinib. Good to write this name down because we are all going to be prescribing this drug or hopefully not getting this drug, but it is, it is an unbelievable drug and it's going to be active, it is active in multiple B cell lymphomas but I predict will have activity in autoimmune and inflammatory diseases. So we hooked up with a company that makes this called Pharmacyclics and forged ahead, worrying a little bit about this pathway, the Maudi 88 pathway, whether it would somehow mitigate the effect of this drug but nonetheless decided to go ahead with its study. The drug is fantastic in how it works. It makes a covalent bond in the active site of the kinase and thereby inactivating that protein kinase for its lifetime.  And it gives you great selectivity. There are only 10 kinases encoded in the human genome that have this particular cysteine to which the drug attaches in that position. So as you should be aware these kinase inhibitors of which there are many, many of them are multi-kinase that hit lots of different things. This one is more specific. It does seem to cause any problems with infections but it's an excellent question. In the lab this was highly potent in this dose response curve in killing some of our lymphoma cell lines that rely on the B cell receptor but had no effect on some other cell lines that don't. So we started a clinical trial across the road in the clinical center with my colleague Wyndham Wilson to test this out in sort of an extension of the company's phase one trial. And this is a 52 year old woman whose tumor by molecular profiling was of the ABC type and had a mutation within the B cell receptor CD79B. She had had all the patients I'm going to tell you about are relapsed refractory category. They have on average had three prior therapies usually two or three. And this woman had had two chemotherapies and had had a complete response to each but in each case relapsed. And then started taking a brutinib by mouth. It's a single white pill you take once a day without any discernible side effects. By week eight she went into a complete response shown here. Here are some abdominal tumors. The others are her kidneys of course. And these abdominal tumors in this PET scan overlaid on a CT have gone away at week eight. And she is our star. She is our exceptional responder. She is now out 3.3 years living without any sign of disease taking this drug once a day by mouth. No infections. No discernible side effects. So this is a remarkable way to get your cancer treated. It's like a blood pressure pill. Here's another lady that had a 59 year old same ABC tumor. In this case though she did not have a mutation in her B cell receptor or in my D88. She had had a stormy course. She had what's called primary refractory disease where the tumor never responded once to chemotherapy. And she came to us in extremis. She had a very rapid rise in her LDH, an indication of tumor volume in her serum. Then she started getting a brutinib and you can see this dramatic fall in the LDH. Here's her tumor that was there by imaging when she arrived. She had so much tumor in her abdomen that she couldn't eat because her stomach was being compressed. And here's what her scan looked like after three weeks. So this is a tumor that never budged with chemotherapy that seemed to melt away here. It's great. I saw her at this moment. She was doing fine. And then about two weeks later the tumor came roaring back. And so she had some form of resistance. And so it's not all roses here. It's the beginning of a new type of therapy. So to take a serious look and get away from anecdotes, we did a clinical trial, phase two clinical trial, multi-center around the country led by Wyndham and myself. And this enrolled 70 patients, all relapsed refractory. Here we took all patients of all molecular subtypes and determined whether they were ABC or GCB by profiling. And then they started getting this same drug at the same dose. And we've now finished the clinical trial. And here are some of the survival curves where here's our lady that is our exceptional responder at the top. And here are a number of other individuals, some of which are still on study with these arrows. And now this is a little old slide. About two or three of them are out past the year. But you can see that many of the ABC tumors that are relapsing, but at a longer time point than the GCB tumors. And this is another way to depict the results. This is the waterfall plot looking at loss of tumor volume. And you can see we have a lot of complete responses here and partial responses and most of them are in the blue ABC type rather than the GCB type. So overall our response rate was around 40% in the ABC type with counting both complete and partial responses, whereas only 5% of the GCB type responded. So this is evidence that in response to a targeted therapy there's a need to know about this molecular distinction between these subtypes. And this translates into a statistically significant increase in progression of free survival. And in overall survival, our overall survival in the ABC type is 10.3 months and the GCB type 3.3 months. So you know, it's a benefit to these patients. Obviously we need to add something to this single agent therapy to make it really work, but it's certainly a start. So can we understand which of the ABC patients are responding and which are not by looking at the mutations that I've been telling you about in these various pathways? Sort of. So if you look at tumors that have a mutation in the B cell receptor and the numbers are small here, that 6 out of 9 of those respond, so a somewhat higher response rate than in patients that have a wild type form of the B cell receptor. While that's significant and indicating that the mutations are important, I want to emphasize that 30% response rate in patients without a genetic cause is an important signal and tells us that there may be non-genetic ways to turn on B cell receptor signaling in these cases. And to drive that home, here's one other clinical vignette, one of our patients, a 48-year-old gentleman with the ABC lymphomas. By our sequencing, had a wild type B cell receptor in Mighty 88, had relapsed from several agents, went on therapy, went into a complete remission. Here's a thoracic tumor that went away at week 10. I believe he had a four-and-a-half-month response to this drug and then relapsed. Important point is that we sent the tumor off for some very deep sequencing by a company called Foundation Medicine and they found using their next generation sequencing something we hadn't found by conventional sequencing. They found at a 5% level in that biopsy, in that patient, there was a mutation in the B cell receptor that we had missed because of our techniques. And that when we looked at that tumor, here's before treatment, this looked like a wild type sequence. But when we started looking at the tumor on therapy in the pressure of a brutinum, now you see this sort of noisy line. This is another subclone that is that rare subclone that didn't show up very well. Here there's a second band. So there is a rare subclone that says that this tumor has something to do with the B cell receptor. Siggling, there's a mutation in the B cell receptor. But remember, the whole tumor went away. It's a complete response. But only 5% of the tumor had this mutation. So you don't need the mutation to be responding. But this is obviously telling us something important. Now what about the other mutation? This, well, yeah, right, good question. This is, the first one is on study, but before a brutinum treatment. The second one is three days of a brutinum, only three days of a brutinum. So within three days we start selecting out this subclone that has a higher level of B cell receptor signaling. All right, what about some of these other mutations? Card 11, if you remember, the wiring diagram is way downstream of BTK. So you might say this might be a resistance mutation. Numbers are small. Only had two patients. They didn't respond. Not going to make too much out of that. What about these MiD88 mutations? Would they somehow circumvent the ability of a brutinum to work? Well, not really. You had responses if you were mutant or wild type. But the picture got much more interesting when we asked whether they had concurrent B cell receptor mutations. And in four out of five patients that had both the MiD88 and the B cell receptor mutated, they responded, whereas zero out of seven patients that had only the MiD88 mutation responded. And why is this? Well, we think it has something to do with the fact that genetically there was an overlap amongst 155 tumors, and about 10% of the ABC tumors had both mutations. And that was more than we would expect by chance. So we think that there might be a synergy between these pathways in some patients, whereas the zero out of seven response over here may say, well, maybe there's another way to become this ABC type of tumor that has nothing to do with the B cell receptor will not respond to a brutinum. And we need a new therapy over here. Okay. And since the hour is late, I'm going to sum up saying that a brutinum, the latter part of the talk, is showing you this irreversible BTK inhibitors inducing a high rate of response in previously refractory tumors that the mutant B cell receptors have a more frequent response to this drug, but you don't absolutely require that. And here I will highlight some recently published work on this drug, a brutinum in chronic lymphocytic leukemia, and in mantel cell lymphoma to a New England journal papers you may have seen where there is a 70% and 68% response to this brutinum drug. And by genomic sequencing, there are no mutations in the B cell receptor. But those malignant tendencies are responding to this drug. Same sort of thing, this sort of non-genetic dependence on the B cell receptor. I didn't show you this for a sake of time, but a brutinum combines very favorably with a lot of other drugs, including conventional chemotherapy, leading to a lot of combination trials that we're now setting up at the NIH and around the country. And to sum up the whole talk, I would like to emphasize from the research point of view that we can combine this next gen sequencing, find the structural genomics of cancer with a functional genomic study of the essential pathways, getting some good computer scientists involved to deal with this avalanche, this big data problem, and arrive at these essential cancer pathways. But going forward in something I'm going to be focusing on in my new job is that the patient will be at the center, and we will be wanting to do all of these genomic studies in the context of clinical trials where we have the outcome and we can relate the response or not to the prolactinum molecular abnormalities. And very soon, coming to a hospital near you will be the following paradigm that the patient will show up. They'll then undergo some sort of genomic profiling of sequencing the DNA or looking at expression levels and profiling. In that way, there will be some phase of data interpretation. Then you'll make a decision to employ a particular drug based on what you found. You'll image to see whether there was a response. If and when drug resistance occurs, you'll have to get a fresh biopsy, figure out whether there were any new mutations that occurred in that tumor, and then if you find an actual mutation, employ yet a different drug. I don't think this is science fiction. I think this will be reality in the very near future. So just to sum up, I just really want to give most credit to Wyndham Wilson, who helped lead all of these clinical trials with a brute nib with me. Thanks very much. So how will this incredibly arrogant science find its way into the clinic? How will oncologists learn from this and use it? Well, it's already happening, and for better or for worse. So I'll take this opportunity. So for, I think, about $4,000, you can order a test from Foundation Medicine, and there may well be other companies, so I'm not endorsing just that one company, but they will sequence over 200 genes for you and find all sorts of abnormalities. Then you can see, oh, well, there's maybe a drug targeting this particular abnormality. That goes under the rubric of this N of 1 type. I think that may work sometimes. I showed you some examples where it does work. It may fail more times. We just don't know. So I think one of the virtues is that we have the data available if we want to do that, but we still need good clinical science to see how informative that data really is. Thank you so much for this talk. I've been waiting for this a long time. But I want to give you another concept to reverse things. And that is that Stage 3 and Stage 4 of rheumatoid arthritis is a disabling disease with an increased incidence of lymphoma. Yes, it is. And so for the methotrexate failures, the treatment options are an anti-TNF drug, which may increase lymphoma. And with the problems of big form, we don't know if it increases lymphoma or if it is there. Or we can use adipatocep, which is a told receptor, or we can use rituxin. And so how about thinking about using genomics to determine aggressive therapy in rheumatoid arthritis based on your genomics? Who are recording? Could you bear a phrase to the question? The question is, can this way of turning the crank on molecular view of disease be applied in this case to rheumatoid arthritis? And it's certainly what I've been trying to promote for years. The problem, the cancer is special. We know where the disease is. It's where the tumor is. Rheumatoid, where is the disease? What should we profile? Can we look at the blood? Well, maybe not. Maybe the relevant cells are not floating around the blood. Maybe they're in the joints. You've got to get a joint biopsy. Did you hit the lesion that is informative in the joint because it's all spotty? Not so simple, but not impossible. So I think there, and of course there's an underlying genetics, you can always look at the germline component. And I will emphasize what you said or restated is that there is indeed a genetic increased risk of non-Hodgkin's lymphoma in patients that have rheumatoid arthritis. There is a genetic component that we have yet. It's about a two-fold relative risk, but it's there. So there could be, and as you've seen, because the B-cell receptors can be, B-cells can be involved in both these autoimmune disease and these malignant diseases, the same receptor pathways could be used. And we don't know yet, and it'll be fascinating to see how a brutinib works in this patient population. So some oncologists won't let us use an anti-TNF in a patient that has pre-existing lymphoma and rheumatoid arthritis, and some will, you know? And do you think it's so hard? Well, I don't, because TNF is hooked up to, in so many different ways, and depending on other things that are going on, can either promote the survival or the death of cells. It's way complicated, and you have to be talking about which immune cells, which subset are you talking about. So I don't have any deep insights there. I think that this is, I mean, it's not every patient that gets these lymphomas. I mean, as I've understood, they're pretty darn rare. It's hard to even collect a series. So they're reported. They probably happen. But as you alluded to, we don't have a real study of what anti-TNF induced lymphoma looks like. I'd love to study it. I just don't have the tumors. Yeah. So that's exactly what we want to do. So the Cancer Institute has, I'm sorry, the question was we've had decades of, let's say, empirical trials. I mean, they were a new drug tried in cancer that didn't work. And can we salvage anything by the molecular analysis of tumors? Well, fortunately, we kept a lot of those tumors in tumor banks. And now one of the things I would like to do is turn this heavy-duty technology on those older tumors and see if those two patients out of 45, which is what their experience was in that bladder cancer trial, which was a failed NCI-supported trial, now we can see, well, those were the two. And now if we, you know, because when you get into common cancers, if there are one or two percent of patients that have a target of a lesion, you want to know about that. And so we have to care about cancer in all of its heterogeneity so that when we've done our clinical trials, we haven't, we've lumped everybody together. So we couldn't possibly have seen it. The example there is KRASM and colon cancer, I guess. Absolutely. One more question, and then we'll break. Yeah. One more question just to ask, and think about it again, some more clinical. In the future, is a clinical trial at the age of electronic medical residents? There's been some recent articles saying that if you use a registry-based real-time study, is that something that you're looking to have? Yes.  That's what I've been doing for all of the work that I described in lymphoma. These were not patients on a trial. These are patients that receive standard of care at good academic institutions around the country, and we just got their tumors, figured out what their response was, and made sense out of it. I would say that there's still a need to conduct things properly, but there might be a proper way to know with electronic records that a patient had actually received a particular regimen, you know, hadn't stopped early. You know, there's problems with doing what you suggest, but it's not at all insurmountable. And it could well be, and a vision also that we have is that genomic profiling will become so inexpensive that patients will just get it as a course of their care. And then what we would like to do as researchers is if the patients are willing to donate their cancer information, we would then like to just take the data, we need their tumors at that point, and take the data and then look at not just 10,000, how about 100,000 patients, how about a million patients, and then really understand more that way. Are you able to do expression studies in preserved tissue? Yes, that's very exciting new development. We can do perfectly fine RNA sequencing from formal and fixed tissue. One of the best lectures we've had here in years. Thank you very much. Thanks.


silent so we can be fully present this morning. Now let's get musically present by turning to the words for in gathering him which you find inside your order of service. What must appear to some of you or feel to some of you as if it's the 10 o'clock service here at First Unitarian Society where independent thinkers gather in a safe nurturing and early environment to explore issues of a social spiritual and ethical significance as we try to make a difference in this world. I'm Steve Goldberg a proud sleep deprived member of this congregation and I'd like to extend a happy hello to those who are watching at home or listening at home and a special welcome to any guests visitors or newcomers. If this is your first time at First Unitarian Society you'll find it's a special place and we invite you to join us for fellowship right after the service out in the commons. And if you are accompanied by a youngster today we welcome youngsters but sometimes they might prefer to enjoy the service from a another spot a private space. We offer a couple options for you one is our child haven in the back corner of the room and then we also offer some comfortable seating just outside the doorway in the commons. This will be a great time to silence those pesky electronic devices that you just will not need for the next hour so thanks for taking care of that. And speaking of taking care of each other it would be a shame and shame on me if I would forget to acknowledge the wonderful volunteers who helped make the service run smoothly today. So our appreciation to Mark Schultz who's handling the sound system. To Patty Witte who greeted us so warmly upstairs. And Smiley who is serving today as our lay minister. Thank you Anne. Thank you to Helen Dyer and Doug Hill our ushers. To Sharon Stratish and Gene Hills who are hosting the all important coffee and hospitality hour a little later today. And Betty Evenson who makes sure that the vegetation here up on the stage is vibrant and green. Just a couple announcements here for you before we begin the service. You know that we have been encouraging pledges for our annual campaign. And somebody not I won the 2016 17 annual campaign gift basket. Her name is Kirsten Sieber. Congratulations to Chris Kirsten for pledging and for winning. I didn't win but I did get a heart on my name tag because like Kirsten and many of you I completed the pledge form. And if you haven't had a chance to do that yet please take advantage of extra pledge forms that are available in the Commons after the service. The other announcement is that the magic number today is 68.  Cabaret is now scheduled for May 20th. But you'll have a chance to experience a night in Italy on Friday May 20th right here a night in Italy Italian food gourmet food Italian music I don't know what gourmet music but Italian music and while the food and music will be Italian the auction items will be strictly Unitarian in other words Unitarians will be donating the auction items. It's a very important fundraiser for the place we love so well the place called First Unitarian Society and we need your help to make this night in Italy a very special experience for everybody on Friday May 20th only how many days from now 68 they're paying attention already Michael that's good. Today's sermon in fact is a result of a cabaret auction item so cabaret is the kind of thing that keeps on giving even after the evening itself is over. Speaking of things that are beginning or ending we are about to begin our service so please sit back or lean forward to enjoy today's service I know it will touch your heart stir your spirit and trigger one or two new thoughts we're glad you're here. Come into this place that is made holy by our very presence. Come in with all of your vulnerabilities and your strengths your fears your anxieties your hopes and your love here you do not need to hide you do not need to pretend you do not need to be anything other than you are or are called to be come into this place where we can touch and be touched heal and be healed forgive and be forgiven come into this place where the ordinary is sanctified life is glorified and compassion is realized come into this place together we make it a holy place I invite you to rise in body or in spirit for the lighting of our chalice and if you will join me in reading the words of affirmation that are printed in this morning's program for every disappointment from which we have new growth from every disillusionment after which we have a relighting of hope from every disaster after which we have a resurrection into new life we light this chalice and now in the spirit of that new life please turn to your neighbor in exchange with them a warm and friendly greeting please be seated well the ranks of our young people seem a little thin today but if we do have some young people that would like to come forward for the message for all ages we would invite you to do so I feel like you're like these adults that sit in the back in the supposed Paul of Tarsus said where two or three are gathered so it looks like some of your friends oh you've got you've got a blue heart looks like some of your friends didn't realize that daylight savings time began today and they're probably still at home in bed but here your parents got you up and brought you to church right so today is when daylight savings time begins and so we're gonna have more light at night and less light in the morning at least for a while yeah today is also March the 13th and it's the birthday of someone who was born almost 300 years ago in England and this man's name was Joseph Priestley and Joseph Priestley was a Unitarian minister a long time ago in England which is way across the ocean long long way from here and Joseph Priestley was someone who really is given credit for spreading Unitarianism in England and then also kind of helping it to get started here in the United States he was a very very highly respected man and a lot of important people came to his church where he preached and included in those people were the grandparents of a very famous scientist who was named was Charles Darwin Charles Darwin's grandparents came to the church that Joseph Priestley served now Joseph Priestley was a Unitarian minister but actually he's famous more famous because he was a scientist too he did he wrote a lot of things about religion and Unitarianism but he also wrote a lot about science he studied electricity you know the thing that makes our lights go on and off and because he was so interested in electricity he made friends with a guy here in the United States who was also interested in electricity and his name was Benjamin Franklin and Joseph Priestley and Benjamin Franklin became really good friends and they would correspond they would write to each other across the Atlantic Ocean and through Benjamin Franklin he got to know two U.S. presidents John Adams and Thomas Jefferson and became friends with them as well and when really late in his life Joseph Priestley got into some really bad trouble in England for his political views well the people in England didn't like him anymore and he thought to himself I can't stay in England so Thomas Jefferson our third president wrote to him and said Joseph why don't you come here and live in the United States and that's exactly what he did but he's basically remembered today as a scientist now when Pete when he was alive Joseph Priestley was alive people didn't get paid for doing science okay there were no professional scientists and so what happened is is that a lot of the people who like to do science and do experiments and explore the natural world well they were actually ministers because back then ministers had a lot of extra time on their hands don't we wish today right a scientist were very very curious people and Joseph Priestley was very very curious about the natural world and how it works why things happen the way they do like what is it that causes the rain to fall or how is it that fish can breathe underwater we know that don't we because they have these things called gills you know to help them breathe underwater yeah and the thing about it is though is that scientists couldn't just go out to the store and buy the equipment that he needed to study all these things so Joseph Priestley if you look up there made his own equipment this is an example of one of the things that he made to help with his scientific experiments now one of the things that had really kind of puzzled people confused them for a long long time was why if you were to do something like this lighting a candle and it's doing just fine so I put a glass over the top of it what's happening to it it went out didn't it and people would see that happen and they couldn't exactly figure out why it was that when a candle is put under a glass like this it didn't keep burning because they didn't know anything about air okay they just thought that air is just this nothing that's all around us right it's the space between things and they didn't understand anything about the fact that air is not empty air is full of what gases different kinds of gases so there's nitrogen in the air 70% of the air around us is nitrogen and there's methane and there's carbon dioxide and then there's also what we breathe and keeps us alive oxygen oxygen and what Joseph Priestly did is he he keep the device he came up with this experiment where he could measure the air in the glass and what he found out is that when a flame was under the glass and burning and then it finally goes out or if you put a little animal under there like a mouse and the mouse dies under it that only 20% of the air is used up in this glass and that 20% is the oxygen that the flame needs to stay alive and that all of us need to stay alive and so he discovered that there's this 20% of the air that's made up of this gas that we all need to live the gas is oxygen now this led to a lot of other discoveries that Joseph Priestly made about air and about gases but then there was one experiment that he performed that he said was the most important experiment he'd ever done and it's the one that made him the absolute happiest and this was an experiment in which he was able to somehow combine carbon dioxide with plain old water in order to make carbonated water which allows us to drink what water and soda pop Coca-Cola 7-up all those good things and if you get older maybe beer so anyway Joseph Priestly was the one who kind of came up with this idea this artificial way of making carbonated water so that we could have soft drinks to drink so the next time for a very very special occasion when your parents give you a little coke or a little 7-up you remember to thank our good friend Joseph Priestly because he's the one that invented this so he spent the last few years of his life here in the United States in a little town in Pennsylvania and while he was there he began speaking at a little chapel a little Unitarian Chapel and it was really one of the first Unitarian churches in the United States so here in the United States he was very important as one of the very earliest Unitarians and also a person that got people really excited about this whole new science the science of chemistry anybody here interested in being a scientist at some point in your life yeah so this is someone you're probably gonna learn about because he's very important in the history of science I didn't see him because I'm not old enough to see him he's been gone a long time well thank you for listening and we're going to now sing you out to your classes with our next him please be seated and so we continue with a selection from the historian Frederick Turner the holidays that divide our calendar were meant to remind us of something important something we shouldn't forget the word holiday after all means holy day religious holidays such as Passover and Easter they seek to transmute the memory of ancient suffering into the promise of better times to come at the center of the ritual is sacrifice whereby we acknowledge by some smaller act of voluntary loss the greater gifts that enable all of us to exist at all but from time to time civilization demands the creation of a new holiday a holiday to celebrate a mystery or to call humanity to some new self-awareness and we need a new holiday today because we need to be reminded that the great works of humanity the very best that we can do entail a heavy cost not only to ourselves but to the world we inhabit as a species we cringe at the thought of the price that we pay to live in civilization that we kill animals for food that we raise forests to provide ourselves with shelter that our cars and our factories darken the air both as a society and as individuals we are compelled to commit certain acts that make us ashamed after we have thought about them shame which is nothing other than the discovery of self figures in the foundational myth of nearly every culture on earth self-knowledge is human kind's most distinguishing attribute and our bodies inform us in a way that no other animal knows when we are caught in the ludicrous contradiction of our competing selves the blush hot feeling around the neck and cheeks arisen from the memory of something you did last night or even 20 years ago and yet that hot flush of shame when recognized and when accepted can serve as a prelude to a strange fresh moment of transformation of epiphany both for the individual and for society for this we do require some a ritual that enlarges the essential paradox of our humanity and so I propose the creation of a new festival to be observed on the first Monday of August a month without a national holiday and its name will be blushing Monday and on this day we will recognize our destructive nature and we will celebrate our creativity and our lunacy the mood of the day will be shockingly mixed deadly serious comically manic cynical idealistic horrified and joyful we will accuse ourselves forgive ourselves celebrate the absurd joy of mortal conscious living everyone on blushing Monday has to dress and act in the most embarrassing way that he or she can imagine everyone must say the most embarrassing thing that comes into his head the thing that everybody thinks but nobody says either civilization is worth the cost or humanity is obliged to purge itself from the earth and because we have not chosen the latter option we owe it to the world to give thanks on this particular day for its sacrifices thank you so much meeting house chorus the text to that anthem is known as the prayer of yellow lark and that's one of my favorites and it's wonderful to see that it's set to music and now we say goodbye to any number of our choir members who are preparing for all music Sunday which we will be observing next week and if you're confused about the time change today just be aware of the fact that next week's services are at 10 o'clock in the morning and 3 o'clock in the afternoon so we hope to see many of you for this fantastic presentation of Dona Nobby's Poetry next week well I recently finished reading a fascinating history of the Vanderbilts at one time one of the wealthiest families in the world starting with virtually no assets no capital Cornelius Vanderbilt better known as the Commodore he created a transportation empire in the decades following the Civil War and the Commodore son William he expanded his father's network of railroads and steamship routes and the Vanderbilts social and economic influence helped to define the gilded age of the late 19th and early 20th centuries subsequent generations of this family spent lavishly building a half dozen mansions along New York's Fifth Avenue huge estates in North Carolina Long Island and New Jersey they commissioned the world's largest private yachts they decorated their various homes with medieval tapestries and old masters and the Vanderbilts entertained ceaselessly this in fact became their work this was a requirement of their lofty social station and it was also a competitive contest that they engaged in with their equally wealthy peers now naturally only the right people were invited to these elaborate soirees European nobles powerful politicians and others like themselves who had more money than they knew what to do with in describing those who belonged to this privileged set a reporter observed that its members quote devoted themselves to pleasure regardless of expense having read that comment one wealthy New York socialite corrected the journalist no she said we devote ourselves to expense regardless of pleasure an incident took place once at florham Florence Vanderbilt Twomley's 1200 acre estate in New Jersey and it reveals the ethos of America's privileged elite in this particular era Mrs. Vanderbilt had invited several dozen guests to spend the Labor Day weekend in her 110 room house emerging from breakfast after the weekend Monday morning these visitors were surprised to find their bags all packed and waiting for their owners near the front door surely madam does not expect us to leave today one guest asked the butler this is Labor Day this is a federal holiday all businesses and offices are closed today the butler bowed slightly and left to convey this concern to the lady of the house returning shortly he announced to the gathered guests begging your pardon Mrs. Vanderbilt says to tell you that she has never heard of Labor Day this was of course an earlier era and with the stock market crash of 1929 and the widespread pain caused by the Great Depression such posturing came to be seen as callous and utterly inappropriate overt displays of wealth and privilege had become in fact a cause for shame but not so much today for we are living in what some observers have described as a new gilded age one in which the conspicuous display of wealth and the use of great substance to tilt the political playing field have once again become common practice shortly after the recession of 2008 hundreds of millions of dollars were withdrawn from the nation's Treasury withdrawn to bail out some of the nation's largest financial institutions including the prime instigators of the mortgage meltdown and out of those taxpayer funds top executives in these very firms claimed huge bonuses for their work feathering their own nests at the expense of the recently foreclosed Jennifer Jacquet teaches environmental studies at New York University and she argues that shame can become for us an extra legal weapon in the fight against corporate greed and malfeasance even if no specific legal statute has been violated egregious instances like these of exploitation and influence peddling can be called out and Jaquette would target repeat offenders who seem to have scant regard for the public's well-being or for the health of the environment if shaming can benefit the community she says why not use it in ways that the community finds acceptable and that shaming can provide a powerful incentive to modify behavior was attested in the state of California when that state threatened to publish the names of its top tax delinquents on a website before that threat could be carried out by state officials California had received more than 400 million dollars in back taxes the communist witch hunts that shook the nation in the early 1950s afford another example during those years as we all know Wisconsin senator Joe McCarthy gained a nationwide reputation by lodging basically unfounded accusations against functionaries in the State Department the Pentagon and other government agencies and for a time McCarthy was the most feared man in Washington if not in the United States but eventually he carried that crusade just a step or two too far and so at a nationally televised Senate hearing on June 9th 1954 an army defense attorney named Joseph Nye Welch rebuked the inquisitor have you know decency sir at long last have you left no sense of decency this episode succeeded in drawing a curtain of shame around Joseph McCarthy Wisconsin's junior senator and he left those hearings disgraced with much diminished power and with his departure a dark page in American history was finally turned over examples like these highlight the difference between a society in which shame can serve a constructive purpose and where it cannot the Vanderbilt's lived in an era in which the very wealthy lived lavishly and spent shamelessly often paying their employees less than a living wage and eventually and in keeping with changing social and cultural norms behaviors like this that one excite once excited admiration they had become a source of resentment and disapproval and sure enough America's wealthy learned to live less ostentatiously at least for a time similarly Joe McCarthy playing to the public sphere of the Soviet Union initially he enjoyed widespread support for his anti-communism efforts but eventually eventually those fears began to dissipate and McCarthy came to be seen as a persecutor rather than a savior public shaming hastened that man's downfall but what about today is shame still a part of our national conversation and does it to any degree deter public officials from acting inappropriately in ways that offend community standards or democratic values well not so much corporate leaders of stupendous wealth receive tax breaks and subsidies worth tens of billions of dollars while at the same time they promote policies that push middle and low-income Americans even lower on the economic ladder one is tempted to ask members of that plutocracy have you no shame have you at last no decency and when it comes to shamelessness what are we to make of Donald Trump whose scurrilous attacks on entire categories of human beings have become red meat for a large segment of disaffected Americans mr. Trump for whom shamelessness seems to have become a criterion of strong leadership has even incited his supporters to acts of physical violence in recent weeks does contemporary society need a renewed sense of shame Robert Karen is a psychotherapist who practices and teaches in New York City and he says that compared to other cultures he's familiar with we give shame rather short shrift people hear our strange about shame Karen's Asian students tell him you're strange about it so amitya etzioni a well-known spokesman for communitarianism has called for a revival of shame he says it can become an effective means of altering behavior and promoting the common good and so etzioni advocates publishing the names of men who solicit prostitutes of placing identifying labels on the license plates of those convicted of DWI of requiring serious troublemakers to wear special identifiable clothing like any tool etzioni argues shame can be abused but that does not make it wrong in principle but if not wrong in principle it is in fact often wrong in practice and whatever benefits it might confer we are probably right to be suspicious of this powerful and potentially disabling emotion but let's step back for a moment now and just ask ourselves what what what is it we're talking about here what is this shame how is it triggered what should we do about it well we can be begin answering that question by drawing a necessary distinction between shame and guilt the two terms are often used interchangeably but they are not at all the same thing according to Robert Bly we experience guilt when we have done something wrong recognize the need to atone for it shame on the other hand is the conviction often unwarranted that as a person you are an utterly inadequate being on this planet Barbara Flanagan agrees with that assessment guilt is an internal reaction to a moral transgression it is linked to doing something wrong and it presumes a measure of personal agency responsibility shame she says lacks that moral dimension it is the experience of feeling bad about oneself but not for having transgressed a person experiences shame not for what he or she does but for what he or she is one's very identity as a worthy person is called into question and exposed for everyone to see so unlike Jennifer jacket and amitya et suyoni houston universities brunet brown has serious reservations about the utility of shame it is often she says a cause for destructive behaviors and if shame once served a beneficent social purpose it no longer does according to brown an individual's negative behaviors can often be traced right back to unacknowledged shame it is she says highly correlated with conditions like addiction depression violence and aggression so when we think again about those fervent supporters of Donald Trump this kind of rings true because surveys indicate that many of Trump's followers have lost significant social and economic ground in recent times they may have slipped from the middle class to the lower class this is the same demographic that now leads the country in substance abuse and in suicide feeling inadequate and ashamed of their own ability to capture the American dream these are folks who need to find a scapegoat a person can respond to shame in one of several ways brunet brown says you can move away from it stuff it down keep it a deep dark secret you can move toward it which may mean ingratiating yourselves to others becoming an overcompensating people pleaser or you can move against shame by attacking those thought to be responsible for it shaming and hurting them in turn and this is the message that mr. Trump seems to be delivering when he promises I am going to make you great again I'm gonna make America great and again the unspoken subtext is only I can remove that painful shame living with active conscious shame can be very very distressing especially because one really doesn't know exactly what to do about it how to dispel it by fessing up to a moral transgression at atoning for it one can assuage the guilty conscience but since shame has to do with one's identity not with a particular wrongdoing what can you do with that other than disappear so think of the expressions that we use when we are ambushed by shame I could crawl into a hole I could sink through the floor I could just die so in this age of social media and of the internet this is important to keep in mind because there have been too many stories of impressionable teens and young adults who were driven to suicide or more rarely to acts of violence because embarrassing information about them was posted online exposed to the whole world these young people did not know how to live with themselves they certainly did not want to show their face in public anymore once you have been shamed on the internet Laura Kipnis writes you are shamed for life despite the various services that claim to be able to scrub search engines of the victims names that's very tragic kind of thing to happen to a person so is there anything that we can do to immunize people from this kind of shame to a certain extent yes and the formative years are so very important children who are raised by parents children who are exposed to teachers who help them to feel secure in themselves are much better able to deal with guilt and shame when they become adults it is so so easy to shame a person when he or she already possesses from childhood a sense of their own inadequacy their own unworthiness Francis Weller is a psychotherapist who recalls one morning when his young son came into the kitchen bursting with enthusiasm and yelling daddy daddy Weller was startled he was preparing breakfast and he snapped at his son stop that quit that at which point his son ran tearfully back into his own room Weller knew immediately that his behavior on that occasion was utterly inappropriate so he immediately went in to apologize you wanted something from me he said to his son and I didn't give it to you did I and his son responded I didn't think you wanted to be my daddy anymore that's how fast the rupture can occur Weller says and I thought to myself afterwards what would have happened if I kept on making breakfast if I had not gone in there my son would probably have been left with this thought that I just didn't want to be his father and beyond that that it was his fault humiliation Alice Miller notes was once a commonly used pedagogical strategy that teachers employed to erase what they called a child's self conceit and humiliation and shaming are still employed perhaps not as consciously not as rigorously as a classroom management tool when surveyed 85% of respondents as adults can remember one or more painful incidents in childhood and 90% of those people can remember the specific teacher administrator or coach who caused them shame much of this shaming is not meant to hurt students Brené Brown says but it does and we need to look for alternatives to using it now there are antidotes that are available to us of more mature years and Brené Brown recommended something that she calls rumbling the employment of mindfulness in pursuit of greater insight into the causes of our shame she says that those who are troubled by shame tend to ruminate a lot you know what's like to ruminate you turn these thoughts and feelings over and over in your mind without ever gaining a real sense of closure rumbling is different from ruminating its purpose Brown says is to get to the truth of the story what do I need to understand about myself what is the fictional part of the narrative and where is that coming from and when we do this kind of internal processing we may discover with Robert Karen that not all shame is the same so there is for instance what he calls class shame the shame that adheres to skin color social status sexual orientation or disability it is a divisive kind of shame used to stigmatize an entire class of individuals and it is all too visible in our political conversations today class shame and then there's what he calls narcissistic shame which leaves its possessor feeling utterly unlovable wholly inadequate and burdened with a curse as in a radical as original sin class based and narcissistic shame are both highly toxic and neither performs a useful service either to the individual or to the society we live in but in his typology Robert Karen also includes something called existential shame which he says arises when you see yourself as you really are and then use that knowledge to begin a process of rehabilitation good example writing in the New York Times recently Sally Sattel and Scott Lillian felt argue that this existential shame can assist addicts in their recovery if those addicts retain some measure of confidence that this habit that they have acquired is under their control if on the other hand the individual believes that their addiction is a disease over which they have no volitional power then that shame can become narcissistic this indelible stain and a potential cause for even deeper despair so whether or not shame possesses redeeming values well we get mixed messages the jury is still out some observers will tell us that it is an emotion just like any other and that like guilt it has the potential to play a useful role under certain circumstances if it has gotten a bad rap Jennifer Jeket says it's because the norm being enforced is a bad one and just because shame is uncomfortable is no reason for us to banish it completely others however others look forward to the eventual disappearance of shame from our emotional repertory they celebrate the de-shaming of sex as do I the decline of shame the shaming power of institutional religion as do I there are better and more humane ways of altering people's behavior better ways of maintaining a just society then by using the blunt instrument of shame these people insist but personally shame I think as human beings we're stuck with it and that being the case we would all do well to learn more about it about its etiology we would do well to learn about its potency and if necessary we need to learn how to apply it very judiciously very sparingly and always in the spirit of justice and with gracious goodwill may it be so our offering today will be shared with the League of Women Voters and they are doing yeoman service in this run-up to our national elections in registering people to vote if you are not registered to vote or if you have moved recently and need to re-register there is a table out in the commons that is staffed by the League of Women Voters and they will assist you in that process today please be generous so that they can continue this work in the larger community we gather each week as a community of memory and of hope and to this time and place we bring our whole and sometimes our broken and maybe even shameful selves we carry with us the joys and the sorrows of the recent past and we seek here a place where they might be received and celebrated and shared we would pause now to remember fondly Sally Hansen a longtime member of the society with her husband Lee who died this past week her obituary was in this morning's paper Sally spent a long time struggling with dementia and she was very lucky to have an extraordinarily committed and caring husband Lee who kept her at home as long as he possibly could and then was able to place her in a very supportive environment so we miss her but we also recognize that she was in a very difficult situation in her life and our best thoughts to Lee and to the rest of their family today in addition to that sorrow just mentioned we would acknowledge any others that were unspoken today that remain among us and we hold those with equal concern in our hearts let us now sit silently for just a moment or two in the spirit of empathy and of hope and so by virtue of our brief time together today may our burdens be lightened and our joys expanded please turn now to our closing hymn number 323 break not the circle and now with gladness for our accomplishments with forgiveness for our all-too- frequent mistakes and misapprehensions with perseverance in life's adventure we go forth we push on onward with respect for our yesterday's onward with praise for today onward with hopefulness for tomorrow blessed be and go in peace please be seated for the postlude