Harnessing the power of the microbiota to boost immunity against infection and cancer

Harnessing the power of the microbiota to boost immunity against infection and cancer

[Music] good afternoon everyone welcome to the front row uh my name is jamie williamson and uh i am the executive vice president here at scripps and uh and today’s guest uh is uh professor howard hang who’s gonna tell us about the microbiome uh let me give you a little brief bio about uh about howard so howard uh got his bs in chemistry at university of california santa cruz and he went on to do his doctoral work in chemistry at berkeley following a postdoc at harvard medical school he joined the faculty at the rockefeller university in 2007 and we were very fortunate to recruit howard here to scripps in uh 2020. so uh what’s what’s uh on on the menu for today so it’s the microbiome and howard is uh what i would call a chemical biologist he uh uses the tools of chemistry to attack biological problems but with a very chemical perspective so the microbiome of course is the set of microbes that’s associated with your body there might be microbes all over your skin and but primarily the biggest part of your microbiome is your gut flora so what’s inside your whole intestinal tract now e coli is is the classic example of a of a gut microbe uh it’s it’s really it’s one of the first organisms that was sequenced it’s a classic laboratory organism but it’s actually in everybody’s body and of course uh people are aware that e coli can be a pathogenic bacteria so if you uh get meat that’s contaminated with certain strains of e coli it can be very damaging i think uh everyone can at least relate to what happens when your microbiome gets out of whack my own first experience with a microbiome came in the mid 1990s and it turned out i had an infection of helicobacter pylori which was a major human pathogen that’s associated with your gut and no one really knew that there was this link to getting ulcers and so i did a three-course three-month course of antibiotics to to get rid of it but this is a natural bacterium that has an effect on a disease outcome i think everyone is aware of probiotics and i must say that you know initially i was pretty skeptical of you know this but it’s it’s very clear that how you feel and the contents of your guts really depends on your diet and what you eat and how you eat and as i mentioned when it gets out of whack it’s not particularly pleasant so it’s very clear there’s a connection between your gut and your health but as scientists we want to understand what is that connection we don’t want to just understand there’s a correlation we want to know the where and the why so the big question about the microbiome is how does the content of your guts affect your health and the progression of certain kinds of diseases so your your gut is filled with all different kinds of bacteria i’m sure howard is going to talk more about that but it’s basically a food fight it’s it’s a food fight in that they’re all these bacteria are you know in your gut they’re competing for resources and trying to colonize the gut and what we’re really just starting to understand now are the specific connections between what’s going on there all the nutrients inside the gut and the outcome of bacteria sorry the outcome of disease so what you’re going to hear today from howard is this remarkable set of connections and one of one of the most remarkable is the contents of your gut determine how effective chemotherapy might be and and so it’s that question it’s not the correlation of gut and health it’s the causation how does what’s in your gut actually have the effect that it does and that’s what howard is the world’s expert at and uh that’s what he’s going to talk about today so again howard welcome looking forward to your talk and i’ll join back at the end and we’ll have a little discussion so take it away howard welcome you all today to the front row lecture it’s really my pleasure to be sharing some of the work my lab has been doing on the microbiome again i’m howard hayne and i’m a professor in the immunology and microbiology department as well as the chemistry department here at scripps research uh and today i was to tell you more about how we’ve been using more reductionist approaches to really understand mechanisms how much gut microbes interact with your immune system and how that influences our susceptibility infection and how that modulates the efficacy of chemotherapy okay so just to recap what jamie already said in the introduction um you know with all the bad news we’ve had recently about how microbes are harmful to us i remind you all that um you know microbes are ubiquitous and cover the surface of our body um and are very prominent in our guts um and can be beneficial to our health and just for a little terminology here i just want to sort of highlight that we often refer to this community of bacteria viruses and fungi in our mucosal surfaces as the microbiota which characterizes the microorganisms and the microbiome is a description of the genetic material within our microbiota what’s important here is that the microbiota and the microbiome include very unique biological activity that i’ll show you modulates health and disease um jamie already mentioned a few of these numbers but um it’s very clear these days that there’s large numbers of bacteria within our surfaces in particular in our gut so for example in the colon folks have estimated that the numbers of individual bacteria roughly are comparable to the number of red blood cells we have in our body and within each of us there’s probably hundreds of individual bacterial species and if you sort of do a rough back of the envel calculation if there’s 5 000 genes or so for every bacterial species times 100 or so um you know that’s a significant number of more genes that we have in the micro ions in our in our human genome uh what’s important about these genes is that you can code unique activities small molecules proteins metabolites that can modulate our physiology and our health what’s complicated about the microbiome is that the microbiota can vary between the different locations so for example bacterial species that are in your gut may be different from those in your skin it varies significantly between individuals so myself and jamie for example got a very different composition of microbiota it varies with our age our diet our use of antibiotics but many studies now have really correlated the composition of the microbiota with physiology and disease so for example the microbiota can help us metabolize food and when dysregulated can lead to malnutrition and obesity the presence of these microbes also primes our immune system and leads us to resistance to infection modulate the inflammation and also contributes to the onset of cancer there’s also a connection between the microbes in our nervous system so um you know it’s been thought that there’s a direct connection between the microbes and the signaling to the brain and often all you need to think about maybe this is one of the reasons why we get angry um beyond this feature the microbes that i got also modulate metabolism of drugs and as i’ll show you later on today the efficacy of immunotherapy um there’s many notable examples of how the microbiota modulates human health um maybe a couple ones that i think are quite interesting or a couple years ago the new york times um highlighted this paper how um marathon runners may have different microbes in their gut and in fact they may have microbes that consume lactic acid more than others and that this may lead to you know better running performances okay beyond this example um you can also find that the microbiome has been very exciting and even has its own exhibit in the netherlands museum in new york those of you that visited a few years ago may have noticed as well this is actually a photo that i took myself when i visited the natchez museum a few years ago beyond these studies i just want to highlight a few um you know notable studies here at scripps research from my colleagues um so a few of you might have already attended my colleague reza gadiri’s seminar on how the microbiome modulates cardiovascular disease uh a few months ago and we’re also happy to recruit michael constantine’s lab as a new assistant professor who’s been studying how the microbiome modulates specific subsets of t cells in the gut and also in the skin and that this might impact um the behavior of animals in early life and tissue repair um so beyond these studies um today i’ll really focus on how the microbiome modulates cancer therapy and infection we know now that the presence of these microbes are important signals to our immune system and modulates the level of immune activity in the gut and other tissues but what’s been surprising is that the microbiome maybe also modulates the impact of our therapies that were exploring these states so cancer media therapy is probably a topic i don’t need to give a long introduction this has been a remarkable discovery in immunology the discovery of these checkpoints on t cells which renders them sort of inactive when they’re over primed um has also led to the discovery that when these t cells are not fully active they don’t sufficiently kill cancer cells but the discovery of these antibodies that could block the activity of these checkpoints can unleash these breaks on t cells and allow them to survey tissues to kill cancer cells and this remarkable discovery was noted by the 2018 nobel prize in medicine and the development of these antibodies or inhibitors of the immune checkpoints has allowed um the use of these um compounds to unleash the activity of t cells to clear cancer cells um so on the right here are actually survival curves from some colleagues of ours and sloan kettering to show the responsiveness of melanoma patients when they’re treated with these checkpoint inhibitors um to unleash the activity of t cells to clear tumors and as you can see um the discovery of the cancer debris has been really transformative you can see that the patient survival with individual combinations of these checkpoint inhibitors has significantly increased the lifespan of cancer patients what’s interesting here is a a number of patients are still non-responsive to these remarkable immunotherapies and the reasons for this are quite complicated could be the differences that has genetics between patients their immune systems their behavior and their diet but what’s been very exciting in the microbiome field recently is that there’s been a connection of how gut microbes may modulate the efficacy of cancer immunotherapy which is highlighted by the cover of science a couple years ago and this cover really highlights three notable papers by several different laboratories would suggest that the gut microbiome composition of patients influences um their receptiveness or efficacy of cancer immunotherapy in the patients so it suggests that different composition of gut microbes within individuals my influence how they respond to cancer immunotherapy and in animal models we and others have shown that actually antibiotics for example that clear gut microbiota from animals renders cancer media that be not affected so these studies suggest that specific species may be important for immunotherapy efficacy in cancer patients um and more recently uh two really notable studies suggest that if you take the microbiota from one individual and give it to a cancer patient that’s receiving immunotherapy this may actually enhance their efficacy of immunotherapy so this is schematized here on the right these cartoons suggest that some individuals that receive a non-responsive microbiota may not have no impact on the tumor growth however some individuals that have received active microbiota may actually um promote or enhance the efficacy of immunotherapy and help shrink tumors in patients and here’s actually one really illustrated graph of this feature so these are cancer patients that receive different microbiota uh transplants in the blue those individuals got a microbiota transplant from one donor and you can see that there’s no major effect on the tumor growth however the other group of individuals got a microbial transplant from a different donor and you can see those individuals actually have significant decreases in their tumor size over time would suggest that there’s something special about the microbiota of donor number one that leads to the enhancement of cancer immunotherapy so to understand uh this more deeply many labs and our laboratory as well has used dna sequencing to explore the composition of the microbiota and so to understand what species are present in different individuals you can extract the dna from the microbiome subjected to now very cost effective advanced sequencing methods for dna and this can be read out and by reading the dna out of the bacterial dna extracts you can now backtrack and figure out what actual species are in different individuals okay and so some of the data looks like this here here’s a sort of heat map of different patients or individuals that respond or don’t respond to cancer immunotherapy and on the list here the number of actual species that are associated with different individuals and you can see here by the heat map that some bacterial species appear to be enriched in response to patients compared to those are non-responsive um but one major challenge in the field and for those that are interested in mechanisms of microbiome microbiota species is which one of these virtual species is really the causative factor and how does it do that to enhance the efficacy of immunotherapy and on the right here i just want to highlight some challenges for exploring microbiomes many of these microbes are host or disease specific as you can see here on the left many of these microbes grow under anaerobic conditions and sometimes cannot be cultured in the laboratory one of the other challenges of starting microbiome interactions is that some microbes interact with each other require their growth require the presence of other microbes for growth and activity and often the activities from the microbiota may come from rare and minor species that are not very abundant okay and that it can also be challenging to isolate the territories infirmities virtual species in contrast to e coli for example we still happen to have limited genetic tools and chemical tools so these are some of the major challenges that scientists like myself and others are trying to tackle in the coming years to try to understand the functions and mechanisms of specific species okay so to do that um let me just summarize what i just said already is that the composition of bacterial species within the microbiota is correlated with our health and disease and some of these microbes may function as so-called endogenous adjuvants to prime our host immune system but we still need to know what spectral species do that uh and which are the mechanisms by which they act okay um so to address these challenges uh my laboratory at scripps uh research has taken two general approaches to explore the activity of uh different microbiota and their corresponding metabolites as jamie noticed uh noted already i’m a chemist and so some of these molecules are small molecules that are generated by the bacteria and we use chemical approaches to understand their signaling pathways and their mechanisms of action today i really focus on how we’ve used animal models to export individual microvirus species and the hopes of wishes of this work is to understand the mechanisms of action in doing so we want to be able to determine new approaches for therapeutics and develop new diagnostics and for my group in particular we want to do this in the context of infection and cancer all right um so one of the approaches we’ve taken to use animal models is to use small cost-effective animal models as surrogates for studies in humans uh and one animal model that i got attracted to uh several years ago is using worms as a surrogate for example the mammalian gut okay and so here’s a cartoon of the worm anatomy um you can see here that this even the worms don’t have adaptive immune responses they do have features that are quite similar to ours um and those of you that actually have interactive worms know that worms naturally interact with microbes in their environment in the soil and in compost and so they’re naturally evolved to interact with diverse microbes and we have actually evolved specific mechanisms to detect and engage microbes in the environment and for these reasons we thought it might be interesting to use worms as an animal model to explore individual microbiota species as a cost-effective way of exploring hundreds of different vector species that we’re now identifying okay um so um many years ago now a very adventurous graduate student to read around my lab set up the system um where we could take adolescent worms put them on a plate of specific microwater species and then challenge these worms with an infection such as salmonella type american okay so some of these assays look like this you’re the video of worms this is a worm that’s on a natural food source for um c elegans where it’s cruising around on the plate looking for more bacteria to eat okay this worm in the middle here is actually a worm that’s been exposed to salmonella types of miriam you can see here that the worm is not very happy about it and it’s kind of curled up kind of reminds me of when i choose the wrong food cart when i visit new york city um in contrast this worm on the right was first exposed to this organism in turkish specimen but now it’s still infected with salmonella technium you can see here that despite the fact that it’s been exposed and infected by salmonella it’s actually quite happy and still cruising along looking for more food to eat in fact maybe the only difference you can see that’s a little chubby okay um so using these kind of behavioral assays we can evaluate individual microbiota species but beyond these sort of movies we can also do this more quantitatively in a height super fashion so these worms are quite inexpensive and we can grow lots of them and use them in a multiplex manner in 96 well plates to explore different conditions um to evaluate mechanisms and specific factors that impact um susceptibility infection and back tracks the mechanisms of the microbiota so on the bottom panel here you can see we can barely readily discriminate live and dead worms and the right here is now survival curve of worms that are first exposed to different conditions of bacterial species and you can see here that in the black line is a normal lifespan of c elegans in this assay um the red line is c elegans that are infected with salmonella type of miriam you can see that they die more quickly than those on controlled bacteria uh on the green line here is uh worms are first exposed to in chocolate cospecium this is the worm on the right i showed you before that was crazy along just fine even though it’s exposed to salmonella um this is a very specific feature of worms that are first exposed to chocolate species and not another bacterial species such as bacterial um b-cellulose okay um so we are quite excited about this observation discovered that theseum could detect worms against infection um so what is enterococcus cesium this is part of a large family of gram-positive bacteria that are in our microbiomes and also in the environment they’re more famous for being resistant and major causes of healthcare associated infection which is quite problematic in the clinic but these microbes have been found in diverse animals and in the environment and also could be beneficial so now analyzing different species are now greater than 60 species of enterococcus that have been identified antarctica’s vacations and feces are most prominent in humans they constitute roughly one percent of the human microbiota by sequencing methods is microbes are very tolerant to broad ph’s temperature and automatic conditions that allow them to occupy different niches including in animals and also in soil but beyond being potential pathogens in the hospital setting um commensal strains or non-infectious strains of charcus are also known to be protective in fact in the states you can actually buy for florida where the major ingredient is a particular strain of entire caucus um dcm that is used at the probiotic in pets and in europe you can buy this formulation biofluorine which the major active ingredient here is in charcoal specimen as well okay so beyond being potential pathogens antarctics are potentially beneficial and as i’ll show you later associated with cancer immunotherapy um so having identified enterococcus speciem as a protective species one of the advantages of us using c elegans which it’s a really nice system for us to dislike mechanisms um so using these activity assays which are cost effective you can compare different genes between protective species of pcm versus michaelis analyze specific proteins are expressed in the protective organisms and compared to the chaos that’s not protected and these many studies that we did over the years that allowed us to discover entire calculus species produces a protein called secreted antigen a that’s sort of cartoon here and we discovered that screening engine a um when expressed neutrium uh hydrolyzes um cell wall fragments from bacteria and it produces immunologically active small molecules that then primes not only c elegans but mice and prevents them from being infected from salmonella and other pathogens so this is quite an exciting discovery and here i’ll see a couple pieces of further evidence for its biochemical activity we were fortunate to solve the structure of sag a and here is a model of the x-ray structure of seige which we were um greatly sort of facilitated by previous structures of this a related enzyme from you know wilson’s lag here at scripps research and you can see here from the space building model of sage it can really bind the small molecule very tightly in the active site biochemically we determine that psychic hydrolyzes small pieces of the bacterial cell wall this generates more active sort of so-called neuropeptides which are known to signal to host cells and activate an immune signaling pathways to promote immunity uh in vertebrates and in mice okay so those discoveries and many other experiments led to this sort of cartoon model of how enterococcus and sagging may be functioning uh in the gut where the presence of enterococcus and the expression of this enzyme cleaves cell wall fragments to prime innate immunity in the gut that provides resistance to intestinal pathogens such as salmonella and others but beyond that i’ll show you later on that the generation of these immunologically active metabolites they also prime systemic immune responses and help us clear tumors in combination with cancer immunotherapy so i’ll just show you a little bit of use of data towards infection um since um sage from intractable species acts on the host we also export other microbial pathogens um to see if they could protect against other microbial pathogens and one of particular interest is clostridium difficile this is another major hospital-acquired infection that’s quite problematic to treat um and so in studies in mouse models we showed that um if you colonize mice with saggy expressing bacteria and renders mice resistant to the pathogenesis that’s induced by clustering difficile see here not available don’t do this very well but our discovery of cellular let us do a very cool experiment which is now to express sage into these non-protective bacterial species ensure that the expression of saggy itself was sufficient to improve post survival against c diff infection okay so there’s just one piece debated i wanted to show you shows that how the discovery of a specific factor can lead to new therapeutic approaches towards infectious diseases okay um so for the remainder talk i’m going to focus on how our discovery of intracoccus um these themes and psyches expression may also prime and enhance our efficacy the efficacy of cancer immunotherapy um so back to this chart of bacterial species that are enriched in response to patients and non-responsive patients and it turns out if you look carefully in the patients that respond to immunotherapy uh antarctica dysthesia is one of these bacterial species that is enriched in several of the responsive individuals um this is a summary of one study and on the right here is a correlation map of bacterial species that are connected to the efficacy of immunotherapies and in fact in terms of the specimen was found in multiple studies of cancer immunotherapy suggesting that it actually might occur broadly um in humans um so we wondered whether uh is antarctica species expression sufficient to actually enhance cancer immunotherapy um and in this context um we wanted to ask you know for those individuals that are non-responsive perhaps in the future we could give them a saga expressing probiotic or its metabolite to then turn the non-responsive individuals to be responsive to immunotherapy so we haven’t done this in humans yet um but to model these experiments in the future we’ve actually used mouse models where we’ve taken mice that either have non-responsive microbiota or depleted of the microbiota altogether and asked whether a sague or particular bacterial species or its corresponding metabolite are sufficient to enhance the efficacy of immunotherapy amiibo so one of the experiments that a talented postdoc mcgriffin set up is shown here where he can take mice that are known to harbor non-responsive microbiota but administer enterococcus in their drinking water these are aerobic bacteria challenge them with a classic syngenic or immune competent tumor just for melanoma and then subsequently administer immunotherapy over time and that would monitor tumor growth profile the immune response of the tumors and also look at the microbiota and so i just want to show you two pieces of data from mass one of these experiments is that first of all when we administer these bacteria we don’t really change the global composition of the microbiota in these mice you can see they’re all quite similar between different experimental samples but what’s quite remarkable is on the right if you look at the tumor growth over time you can see that mice are colonized then check out the specimen in combination with immunotherapy so significantly in paratuber growth compared to mice that are given intercontinental spectators what’s quite remarkable is we can make enterococcus because active by expressing sagai in antarctica and you can see that in the blue line there that’s almost as active as antarctica species itself okay so these are quite exciting studies suggesting that um the administration of antarctic antarcticium could actually reprogram the activity of the host microbiome and make it more receptive to cancer immunotherapy so to do this more carefully matt actually did monocolonization experiments mice so these experiments we actually first depleted mice of their endogenous microbiota by giving them antibiotics and then giving individual strains where we can actually knock kerosene to where the monoclonalization of different bacterial species is sufficient by itself to enhance the efficacy of immunotherapy um and so here on the bottom are two two more tumor growth curves for similar experiments i showed you before here with the different um immunotherapy that have been used in the clinic so antibodies to anticipate or or antibodies to pdo one both of which can be enhanced by co-colonization of these mice within talk about the speciem not within turococcus michaelis but again remarkably the expression of entire caucus of sage into tarot caucus because was sufficient to turn on the activity in bacteria okay matt did a number of other studies here that i won’t have time to share but now also sure that the presence of these microbes activates myeloid cells that enhances the immune response to produce more active t cells to clear the tumors this he also showed that we see increases in tumor specific t cells in the mice and also based on the mechanism of action that i described before um be explored that the immune receptor not you was also required for this enhancement of tumor immunotherapy okay so this leads us to sort of describe the cartoon area i’ll show you in more detail here um beyond um priming the gut towards infection um on the left ear um the data i just showed you here suggests that the presence of enterococcus in the host and sage expression to generate these small cell fragments which may be getting into the circulation activating so-called antigen presentation cells or mileage cells to directly clear tumors or enhance the activation of tumor cells of t cells that also contributes to tumor clearance and this in combination really helps the efficacy of immunotherapy when administered together all right so one of the questions we wanted to ask is well based on these data you know can we actually use saga expressing sarcoids in humans and i’ll just tell you that that’s not a good idea based on what i showed you before due to the fact that these bacteria be ready to become resistant to existing antibiotics it may be problematic in the clinic and furthermore the presence can these microbes can be sort of drivers for inflammation and promote inflammatory bowel disease in the context of transplantation they may they also are known to bloom in the gut in response to antibiotic treatment and are correlated with poor survival and mortality during transplantation um so this is one of the reasons why even though there are territories are commensal species in our microbiota they’re not prescribed to be used in humans due to potential pathogenesis and drug resistance okay however one can think about getting around this problem by modifying probiotics and so jamie mentioned his introduction that many of you are aware of different probiotics that you can get as dietary supplements in your yogurts and fermented foods unfortunately for many bacterial species or probiotics their effects on human health are quite unclear but one of the things that researchers and our group has done is think about taking probiotics which may be safely administered humans and engineering them to encode interesting proteins or small molecules they might actually have defined mechanisms action so for this purpose right therapeutics is actually licensed sage uh from our laboratory and is using um sagas to engineer improve probiotics to modulate this immunity um so this is sort of schematized here on the left so lactococcus lactose for example is a probiotic that hasn’t been explored in humans and using synthetic biology approaches we can engineer actually calculus lactose to express that elegant in its chromosome and on the right here what’s quite remarkable is um now that lactic acid like it’s expressed inside we can ask whether it affects the activity of cancer immunotherapy in a mouse model um so again here bacterococcus lactose alone the parent strain in the like turquoise line here shows no effect on tumor growth in a mouse model but if you now make that strain express sage you can see in the purple line that it is almost as active as center half species inhibiting the growth of tumors in the mouse model um along these experiments we can also ask mechanistic questions about sega and where we mutate the active site of the enzyme and here you can see here in the sort of brown line here that an active version of sagate is not effective at enhancing tumor immunotherapy um suggesting that the biochemical activity that resources for is really important for the efficacy of this enzyme for enhancing the efficacy of immune therapy in vivo okay this has also led to some um you know suggestions on the lab over the years that we may be making uh sage-based probiotic yogurt um and which is i think that quite interesting and i think potential future avenue for rice therapeutics um but having been in san diego for a little while now i think one of the questions i started asking is wonder whether there’s probiotic beers and if you do a google search for probiotic you actually there’s actually this graphic that you can find on the internet which is quite interesting which is actually connected to science you can see here in this nice picture uh i guess one thing i would do here is to modify this a little bit and ask whether we can uh insert uh express again into probiotics to perhaps make a sega ipa in the future okay so all kidding aside um these engineered probiotic strains would be considered sort of drugs in the future and still need actually a lot of safety evaluation before it can go into humans okay which is something that rise therapeutics is embarking on these days okay um so to come back to this cartoon again um i think i showed you a number of experiments now in data that supports the idea that um the expression of sag a and this um of this enzyme cleaving subway fragments from microbes can enhance intestinal immunity against infection and also prime systemic immune responses to help clear tumors so one of the questions we were asking that we is may there be other saggy like enzymes within the human microbiome okay and so to do this we’ve actually leveraged a number of studies for many labs in the field you can see here highlighted in this recent this issue of nature a few years ago which is a collection of data from many many studies of microbiome analysis from different sites and individuals um and in the different disease contexts so the workflow here sort of summarizes work from many many laboratories sampling the microbiota composition uh a different tissues and different individuals in a variety of diseases including inflammatory bowel disease and pre-diabetes and others so leveraging this large data set matt could ask are there a site are there saggy like enzymes within the human microbiome and by doing so maybe there are other microbial species and they may function like interactive species so now the workflow that matt engaged here has been right by taking the sequence of the sega protein and gene you can ask whether there are other related genes in the human microbiome and on the right here is a correlation chart of the rectal species and they’re a genes that may be similar to cygae and trichocal species you can see from this chart that uh these all the other species of enterococcus um have clear um saggy orthologs that are very similar but what’s also interesting from this analysis is that other bacterial species that are highlighted on this brow we have orthologs of sarge that are quite similar as well this is something we’re now exploring to determine whether other microbial species in the human marker may function in a similar fashion okay so stay tuned for our analysis of other maybe sega like enzymes from the human microbiome okay um i just want to highlight that this is a really remarkable body of work from a really talented postdoc matthew griffin in the lab who was supported by the hope funds for cancer who’s now here at scripps research as well math paper should be online in a couple weeks it’s too bad that it was on online today but those of you that want to read more details about matt’s work can look at his paper in a week or so and that this work was also funded by the national cancer institute and the melanoma research foundation um all right so let me just contextualize what i described to you um today in the context of what we and others are interested in for how to leverage or harness um our understanding of the microbiome for potential therapy um and diagnostics so one of the first features is trying to determine um efficacy of immunotherapy um so by understanding the presence of active microbes such as we may predict whether different individuals might be receptive to immunotherapy the discovery specific genes and mechanisms also provides us additional features to explore as biomarkers for stool samples between patients to highlight unique factors that may be important determinants beyond just the presence of a micro species so here again sag a is like maybe a key biomarker in the context of therapy you know fecal microbial transplantation as i mentioned in the beginning is i think very exciting and interesting one of the challenges of these transplantation experiments is that you get a mixed community of microbes that’s quite heterogeneous between individuals and sometimes it could also harbor pathogens so the development of more synthetic and sort of well-curated microbial species such as a probiotic that’s engineered to express egg it might be more effective in the future and for personalizing these therapeutic approaches um not only is it important to understand what microbes are in the microbiota but what’s what genes and pathways in the host that may be key to understanding whether the microbes are active so in our studies um in data we i didn’t show you that not too this post immune receptor was required um so only those individuals that have a functional not to allele um would be receptive to this kind of therapeutic approach okay um and lastly i just wanna end with a few um comments and slides on potential small molecule therapeutics so by understanding the mechanisms of the bacteria in this corresponding enzyme and it’s the small molecules the metabolites produce is let us ask what about the mirror peptides itself could they be used as small molecule therapeutics that can be used in combination with the immunotherapy and so this is something we’re excited to pursue at scripps um should we repurpose existing drugs and can we develop better naughty agonists that would mimic how the microbiota actually functions and this has implications for infection inflammation and cancer as i mentioned already um okay so one um a couple more experiments i want to show you that leads us to i think a future direction here is matt actually has also tested this idea by directly evaluating these neuropeptides in mouse models of immunotherapy so by comparing an active isomer versus an inactive isomer of these mineral peptides now i can really nicely show that only the active isomer of the mirror peptide inhibits tumor growth in combination with immunotherapy as you can see here in the green line compared to the red and blue lines as controls he’s also done additional mechanistic studies to understand the cells that are being activated in vivo and for those efficient autos here this is the one of these single cell rna seq plots where you can see that specific subset of myelid cells are being activated and expanded upon the addition of these neuropeptides in the context of drug discovery i want to go back a bit more and say that um these neuropeptides were discovered quite a while ago in the context of foreign’s adjuvant uh and was developed as sort of drug derivatives in the late 90s and as single agents were shown to be effective at preventing uh cancer growth in mouse models and was eventually developed into this drug called meatpack that’s that’s administered or distributed by this company together and this is a drug that’s used to treat recurrent osteosarcoma in children so after kids have been diagnosed with osteosarcoma and the tumor is removed they’re given this drug to prevent the recurrence of the tumor as a single agent and i’ll just mention that our studies suggest that beyond the use of the single agent perhaps meatpacks should be repurposed as a combination uh small molecule or drug to enhance the efficacy of existing immunotherapies so this is something ongoing that’s actually happening in the field at the moment uh but at scripps we’re also wondering if we can prove the activity of non-two agonists by developing better generations of these drugs uh and towards this end a talented graduate student in my lab has taken advantage of structural biology studies of the nacho receptor itself done some docking studies where you can now explore different compounds that may act like mermaid peptides these neuropeptides um the parent ones have some pharmacological liabilities so we would like to develop more stable ones that can act with longer half life and vivo so to do that take you has modeled a series of dipeptides with synthetic small molecules by virtual screening and through this process has actually synthesized several compounds and i’ll show you here now that are as active or maybe more active than the original peptide itself here by screening the this panel of small molecules and cell based screens on the dose response curves are some of the most interesting computer compounds are shown on the right what’s interesting a few of these compounds are as active as removal dipeptides and we’re quite excited about this but beyond our own sort of targeted medicinal chemistry studies one of the great things about being here at scripps is we have a really remarkable community for doing small molecular discovery and in particular our collaboration with caliper this remarkable non-profit direct discovery institute that’s connected to scripps provides us an opportunity to find additional small molecules and some of you might already have noticed this really important study recently from caliper um to explore antibiotic drugs for covid by screening large collections of compounds that are that existing at caliber so for this uh for our studies we’ve actually now collaborated with tristan wilson the group leader caliper you can see kristen here and what’s amazing at caliper is that caliper has these really fancy robotics that can do high-tech screening many many compounds more than my laboratory can do and on here on the right here is a heat map of all the compounds that kristen’s team are caliph at the screen you can see every single dot on this heat map represents a new candidate small molecule that may act similarly to neuropeptide to activate the not two agonists the nature receptor what’s also interesting is their screen also identifies general antagonists of nacho for us as a way to dampen the immune system in other contexts okay um so just let me summarize here what i’ve described here today from a few different studies from my group um that these bacterial species of entire caucus which express this remarkable enzyme sage activates not to and the presence of these bacteria in animal models controls intestinal infections and in combination with immunotherapy can lead to decreased tumor growth in vivo there’s an interesting analogy of enterococcus with an existing actually vaccine called bcg which also acts via the nature pathway and bcg is an attended strain of microbacteria that has been used as a vaccine for tuberculosis because it broadly activates immune responses it’s also been explored against other pathogens including respiratory viruses and actually it’s in clinical trials um for kerbin19 recently we’ll see how those trials pan out in the years going forward but in the states bcg’s activity for priming immune response has also been used to treat bladder cancer and these contexts provides an interesting analogy to our discoveries of enterococcus sage and nacho activation and going forward um we also want to ask you know what are the sort of broad implications of saggy-based probiotics and not novel not to agonist in the future can these engineered bacteria or new small molecule agonists be paired with existing vaccines to enhance their efficacy uh towards other infectious diseases including respiratory viral infections such as influenza virus uh rsv and of course i think it was on many folks in one of these days as far as kobe 2. um so these are i think new opportunities for us to do further therapeutic development scripts which are excited to engage um and this is really one of the major reasons why i’ve been excited to join scripps research okay um so just let me close by just thanking all the people that have done the work over the years or some i try to highlight them on the way here but the those individuals are involved in the studies i described today are highlighted in red um and we were sort of um fortunate to be funded by the nih and others here they’re summarized below um you can see here for the collaborators i have on the right this is one of the major reasons i’ve come to scripps and has provided many new opportunities for new collaborations which i’m excited to further explore in the future um so i’ll just close you by just a couple take home messages um that uh i hope i showed you that the microbiota is important for host physiology um the onset of disease and our response to therapy um and that new innovative approaches are still needed to dissect the functions of individual microbial species and in doing so let’s give this new opportunity to develop new therapeutic approaches and for new diagnostics so i’ll just close here and let jamie field any questions thank you very much that was that was great it’s i’ve been following along in in q a and uh we’ve had about a thousand people on and uh and what what people were following you and it’s really interesting because a lot of the questions that people posed you answered later in your seminar so it was great that you sort of uh hit hit some of those already um you know i think one if i could aggregate a number of questions i think people are kind of interested in you know what is the path and the timeline i mean you definitely have this effect you know what to give to people so how do you how do you turn that into something that cancer patients can take advantage of i mean what’s you know what are the steps and how long is it going to be i mean i think people are wondering that because it seems remarkable and it is yeah that’s a great question that’s something we’ve been exploring ourselves so i’ll purchase first to say in terms of um diagnostics you know i think what’s important about what we’ve done is to demonstrate that intracalculus speculation is causative and it’s related species um first provides i think a very important thing for clinicians to do is to ask in their patients do they have these bacteria and if they have those bacteria you may predict that they may be more responsive to the existing immunotherapies that are around so that’s i think one of the most important um impactful things that our study highlights um going forward in terms of you know leveraging um the discovery of target like this for drug um development you know i already mentioned before that there’s some problems of using hr caucus right so we worry about that and their potential pathogenesis is problematic um but one of the things i’m excited about is like identifying other microbial species that are not prone to pathogenesis they give us other microbes as a way to supplement immunotherapy um as a nutritional supplement okay um so i think that’s an exciting future to explore other microbial species besides enterococcus okay on the um probiotic engineering front okay um you know the fact that we’ve genetically engineered probiotics makes them no longer you know nutritional supplements and now we have to go through the traditional path to the fda okay and so that’s something important for us in terms of now having the synthetic strain to go through the proper regulatory and safety routes before they can be administered and approved by the drug so this will go through the traditional passage traditional pathways of an fda approved drug and require all the safety evaluation as any other drug so that is probably in terms of timeline probably one of the most challenging things on the small molecule side of the things we’ve done i think that there’s a more traditional path of drug discovery which we’re excited now that there’s some compounds that we i think could explore um howard there a number of people were really just interested in some basic stuff about microbiome and and you know one of the questions is we all know that when we take antibiotics it you know it has a dramatic effect on your microbiome and you know what comes back how fast does it come back does it come back the same as it used to be and you know is that a time when you should take probiotics and just i know you know a lot of general facts about this and i think people are kind of interested in that relationship yeah it’s also you know this makes us it’s concerning with all microbiome and use antibiotics so there’s no doubt that antibiotics has been remarkable and we need that to fight infections um and um what’s been observed in the field is that um after antibiotic treatment the major microbial species will come back okay but every use of antibiotics kind of permanently changes the composition over time and the microbes pieces that rebounds often is connected to your diet and what things that you’re exposed to actually um you often get a microbiota transform of your pets even so um every bout of antibiotic uses will shift your microbiome a bit and it will be impacted by your own behavior and the food you eat but rest assured that a lot of beneficial bacteria do come back okay so um i don’t want to prescribe or you know give the impression that we shouldn’t use antibiotics they’re life-saving drugs for sure um so so i think um maybe um you have a lot of fans good good reaction to this talk um so so i i think i think you might have touched on this in the seminar but but so can you just eat these miriamloid peptides that get released and have the same effect or or or do you is do you need a certain species there i mean what’s what’s the yeah so the mirror peptides um are um themselves um really poor um pharmacological properties in certain half white so they get digested in the upper gi maybe yeah they don’t really um so to improve their activity in vivo you know the drug that’s developed by takeda is actually a liposome formulation that improves the circulation right so that drug is currently administered by intravenous infusion um when given to patients uh but new versions are online now that may be orally available so stay tuned for that so howard how maybe could you give us a sense for how general this is i mean he found this remarkable connection between certain species and connected the dots down to the very receptor involved in the immune response uh you know how many stories like that are there you know is this just crazy or is this a really general thing that we should be kind of looking at yeah so i think let’s say beyond our work other laboratories around you know the globe also begin to dissect the activities of individual backspiral species and we’re seeing similar themes you know other microbes may be hitting different receptors but um so more of that is coming online um i think for us the generality i think can really be highlighted by um actually the analysis of the similar enzymes in the microbiome right so by doing that and looking at sort of genetics and militarities between those enzymes we may find that other microbes may be functioning in a similar manner and i think that’s something that’s exciting and important for us to do in the future is to ask how general is this and do a lot of microbes that display or the only specific rare species that we pick up today i have an interesting question so if you’re at home and you’re curious about the state of your microbiome what is there in terms of home diagnostic um well there’s been actually quite a few sort of microbiome sampling you know i think there are kits you can buy that you can actually you know um uh take a sample of your own microbiome um dna sequencing is cheap enough that you can you know find the appropriate laboratory or clinician to actually do sequencing and actually it’s quite inexpensive to do that and um so those of you that are in san diego know that um they know that rob knight who’s at ucsd has initiated the human sort of the american microbiome project that’s just sampling the microbiota from different people not directly connected to disease necessarily but just to see how diverse and broad microbial species are um so that’s another big approach um for sort of home sampling i guess if you will right okay um howard i think we’re coming up close to the end and i did want to touch on a more general topic so so i i guess i want to ask you how did you become a scientist that’s a good question how did you how did you get to where you are i mean you know it’s you know i i recited your your academic pedigree but you became a scientist you know before then and how did that how did that happen yeah so i guess you know i have to say that you know i was not one of these kids that was really fascinating with science at a very young age and i kind of struggled with what i was interested in but when i got to college you know i just fell in love with organic chemistry and that’s what for me sort of connected uh me to science and the love of small molecules and how they function and over the years you know the molecules have gotten bigger and more complex complex and um you know i just got interested in how molecules interact with biology over time and that over the years led me to infectious diseases and microbes and modulating the immune system so you know i think i was very lucky to have some great mentors and teachers at uc santa cruz that really got me interested in chemistry so you didn’t have a chemistry set in your basement when you were i i did not okay so i was kind of a lay bloomer but now i’m hooked yeah yeah terrific um so uh i do i did want to just share one other little personal thing uh with with howard uh with with the with the audience uh howard does have some outside activities um and uh so i i hope you can see this but this is this is uh howard at torrey pines uh in last december i think was new year’s eve and uh i’m the photographer because i was too chicken to get in the water that day it was too big but this is a pretty nice shot and uh howard and i do enjoy uh surfing pretty regularly together so it’s not all science all the time but i guess all the time we it’s most of the time and we do talk about science when we’re sitting there in between in between waves so yeah anyway it’s it’s great to have colleagues like howard at scripps research and uh so thank you all for tuning in i just wanted to mention again and remind you that the next front row is jeff kelly which will be wednesday september 15th 1pm thank you all for coming uh this show is required uh recorded and you can get it at the front row in the website so thanks for participating and thanks howard for a terrific lecture thank you everybody for attending bye everybody [Music]
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Harnessing the power of the microbiota to boost immunity against infection and cancer

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