 Okay, hi, everyone. So, you know the drill from yesterday. The only housekeeping thing I'm going to say is, let's keep the standing mics for people who want to raise new questions or throw fresh challenges to the audience. If you want to respond to a question that's already been raised or to something that a previous speaker has said, then just stick your hand up and we'll get a roving mic to you. So hopefully that will lend a bit more continuity to some of the discussions. Okay, we've had loads of really good food for thought. Some of the gaps and needs people have identified have been recurring throughout the entire conference, including things like multiple calls from moving away from surveys and associations to more calls in effect and functions, need for better and more animal models, larger longitudinal studies, more ecological metaphors have run rampant. We've talked a lot about succession and resilience and how we can use those principles to try and make healthy communities more resilient and how to disrupt current pathogenic ones. But I wanted to start off with a question that came through the email address that we put out, which hasn't really been talked about today and I was hoping some of the panellists might be able to address this. It's about the issue of informed consent and it comes in three parts. Do we need to change how we protect subject privacy and confidentiality and would changes to human subjects policies like say the introduction of a de minimis risk category significantly benefit the field? Two, how do we do informed consent on uncontacted peoples who we heard about this morning and are those people truly informed? And three, are there difficulties in obtaining informed consent, are difficulties in obtaining informed consent major barriers to carrying out microbiome research in children, which we've heard a lot about recently? So, Marie, did you have any thoughts on those issues? Well, I guess the informed consent for the uncontacted is for me. So, we adhere to the country policies. So, for example, Brazil has decided not to contact the uncontacted. They just overfly them in helicopters, count them from the helicopters and Venezuela has decided to contact them, send them and try to give them health service. So, you know, it's not in our hands as a scientist to criticize or take parts that you may agree with one or the other. Each one has their pros and cons. The contact issue and how to ask people whether they want, usually the contact is done to voluntarily offer help from the government, usually the health ministry. So, there are in the case of the Yanomamis, which are, I think, probably the only uncontacted peoples in Venezuela at least. There are Yanomamis who are health workers already. So, they are the first ones who get off the helicopters and talk to the authorities of the village. It's very common that these peoples have heard about medicine, even if they have been uncontacted, and they are very open to medicine because they have learned the reason why medicina is so famous, they even know the word, is because it works. So, basically the first contact is by another Yanomami in their own language, of course. Everything has to be in their own language. And then, if they accept, and usually that requires meetings of the authorities, and then they give a village consent, and the protocol is similar even to with the contacted communities. So, there is not an individual informed consent and, of course, no signatures, obviously. But it's a process that it's done in agreement, and as much as we can, at least in Peru and in the community, and in the Yanomamis that are from the higher-in-all commissions, we try to bring posters and explain what we do, what is a microbe. It's not an easy task. We have to use a lot of imagination to show graphically and use the translators of their own ethnic group to try to explain them why is it important to study what we are studying, and always get their approval. The individual approval is personal. It's a mum that doesn't want to participate. We don't force. But typically they are very open. And, of course, everything is done under the umbrella of the ministries of health in any country. So we have to understand that our informed consents in the U.S. are not applicable to the rest of the world necessarily. Thank you very much. Does anyone else have any views on that or any other questions? The comment about IRBs often comes up when people ask me about microbiome research. I'd just like to do a poll here just for the fun of it. Who here has an IRB to do microbiome research on anybody? For how many people is this the first IRB that they ever had to do? So still a bunch. And how many people here who are not doing IRB-regulated research haven't done it because they're worried about the whole IRB process and heard nightmares about it? So, well, okay, fine. That's kind of a loaded question on the last one. I think I've had people who have come and said that. And I think I was just trying to figure out what the rationale is. Do we need to change how we protect subjects privacy or confidentiality? Because I don't think there's anything intrinsically different about microbiome research, in my opinion, than any other human subjects research that we do necessarily, except that perhaps from the technological standpoint or stuff, it's a lot easier to, quote, unquote, get involved in it, but you get kind of hung up on the whole IRB because, for many of you, it's the first time you've done an IRB because normally when you think of human subject researchers, you think of drugs, clinical trials, and devices. So I don't know if that has anything to do with it. It's more of a question than trying to figure out if we really need to change our IRB procedures to do microbiome research specifically. So I don't certainly have any solutions to offer, but also just to, I don't know, making some other, I don't know, call them aggravating observations. I just was, as somebody watching this process for the first time with the HMP and especially with the demonstration projects, I found it very startling of the sort of non-uniformity of what happened with IRBs, just depending on kind of what institution you were at and how risk averse they were. And it just struck me as very strange that lots of people could be funded to essentially go after some of the same questions and they'd be faced with different levels of risk averseness. And I sort of imagined that if there was some process where there could be sort of just some greater uniformity about how people respond to this, but this is obviously a common problem for any area of medical research. It could be true for cancer research, et cetera. Do we have anelci person here? Because historically there's a reason that they're called IRB and they're institutional rather than being some monolithic government or centralized board. That, Kirsty? So I just want to comment and I know a number of us have had discussions around this for different reasons, but to add to Vince's questions, how many people here are chairs of IRBs or involved in their IRB as a reviewer? So the first thing I'd say is if you're not a reviewer on your IRB and you're frustrated with the IRB process, I've never been at an institution that doesn't accept volunteers to sit on the IRB. So it's a really great way to improve our ability to move through high throughput analysis protocols in constructive manners. There are a number of things that have happened in the last 18 months on a federal level to try to enable more conversations between IRBs. And so we've seen that first at the CTSA, but those are some federal regulations. But one of the reasons the IRB process is very different is because different states have different definitions of what constitutes a child, for example, when you become an emancipated adult, how it is that we take care of vulnerable subjects. And so it has to really be left up to the institution because they're trying to do the work in the local setting that they're a part of. And that's actually a very inherent important aspect to LC research. And I think it's important to remember that when we engage in studies with subjects, these are relationships that we form with these individuals. And it's a trust relationship. It's not just a banking specimens and taking data. They are actually working in the public trust. And that's an important relationship that we preserve. And so when we think around issues of confidentiality and privacy, those are the one-on-one type of relationships we have. In general, IRBs continue, and we've just had this discussion at a federal level, continue to frown upon the idea of basically trolling for subjects, which means using the electronic medical records to survey large populations of individuals in healthcare systems, contact them, and engage them in research. And so I think we have to be cautious as we're thinking about subjects of banking to make sure that we're not doing that. In general, we do give consent, and we do look at issues around who consents for unrestricted future use and who does not, who allows us to re-contact them and who does not. And there are very clear racial and ethnic differences, and many of us have published on that before, and I think we will continue to see that. So I think when we think about engaging people in a trustful relationship to consent them for research, we have to keep in mind all those different variables, and that there are state laws that restrict how we can do this from a uniformity process. Thank you very much. Does anyone have any other questions, other topics? Excellent. I have an extension from that. Is there any, the speakers today feel there's value about talking about your research to the general public? And if so, have you done so? What was the venue and how were you received? No one has talked to the general public? Well, I sort of do for a living. But is there a value in scientists talking to the general public about their research? How do you feel about that and have any of you done it? It turns out Baltimore has a group called Baltimore Underground Science, and I have the opportunity to speak to them, and they're trying to do that. They're trying to get scientists to speak to the general public, but have any of the speakers here? Did they've done that? Well, maybe I could say something. I was not the only one, but we were contacted. You guys did a great job in spreading the news about this meeting, and I was, and Martin Blaiser and David was contacted by local TV station to give our, you know, take and views on the microbiome and the importance of it to the public. And even though I don't speak very well English, I said it was very important. I figured out they probably will just subtitle me, and it would be possible to communicate. But the idea was exactly that. NIH tax, a tax dollar in the system, you need to communicate that to the public, and it was very important. And it was this show is called Biosantery and will be broadcast across Washington and some affiliates. So I think it was a great job that you did to link the media with us so that we could spread the news. So I've spoken with the press on numerous occasions, and I think it's always been good. I think the public is interested in what we do. It does impact their interest and their health. We've had a lot of news media recently with the FMT trials that are ongoing at our institution. And I think that this is something that not only educates the public, but also brings awareness of the new kinds of things that we can offer from microbiome research that's being done. Yeah, I can entirely recommend talking to journalists when you get the chance. My experience is also, especially with the C-section study, that's a lot of female journalists call me from different parts of the world to ask me about that problem and what are we studying and why. So I'm always happy to do that. Also, we were filmed last year in the expedition to Peru by the Smithsonian Institution Channel, and I show a little part of the documentary there, but they cover as much of the field trip and the baby. That is also divulgation. I think it's very important because that's how we can, in a very efficient way, try to press policy makers to recognise the importance of certain issues and sometimes take action support or make legislation, et cetera. So I think it's very important that we keep divulgation to the lay citizen. Did we have a question from that corner of the room? I just want to make a comment in the same area. I totally agree that we do need to encourage everybody in this room to start interfacing with the public, whether it be through written articles in the general press or if it's through radio interviews, et cetera. Again, with policy makers in mind, I'm reminded of the genetically modified organism debate really in Europe where it's really not driven by science, it's really driven by the other side that's really taken a very negative view of genetically modified organisms. Since we're going to be putting bacteria now into people for therapeutic reasons, and I think in some cases, the ability to genetically modify these in safe ways is going to be important. We have to start that dialogue and start educating the public that these things aren't frank and foods, they're not necessarily dangerous for us. There are things that we have to do to make sure that they're safe, but we need to educate not only policy makers, but the public to not be afraid of these things because they are going to be beneficial in the long run. Indeed, it's quite easy to overestimate what the general public knows about this field when most of their experience where there's been through ads for yogurts and similar, the sheer depth and breadth of what we're finding out, I think is worth talking about. So one way to do that is to borrow something that NIH used to do, but because a budget cuts is falling behind, is set up a speakers bureau where people volunteer with specific subjects they're willing to talk about. It's on the list and they can be invited from everything from high school science classes to rotary clubs to talk about what they do, and you're not mandated to go when you get invited, but maybe the Human Microbiome Project could set up something like that which would encompass people from all over the country and offer people in various areas throughout the country the opportunity to hear about the work. So the one comment that I'll make because I've had extensive interaction with the public in terms of the field of microbiome is I think one of the key things that it's like speaking two languages, so it's the one thing we have to keep in mind when we speak to the public in that when you are among your fellow scientists and we are after precision and new knowledge that when you go out and you speak to the public outside of your field you're looking at information that's presented as if it were in a textbook and that creates a problem with communication sometimes that I'm going to argue sometimes we don't come across very clearly to the public because a lot of times the general public doesn't understand what scientific debate actually means and you know it is the natural part of vetting ideas and it does not necessarily mean we don't have a clue what we're doing which is usually what it's interpreted as unfortunately it means that you know the information is at a stage where we don't quite have all the details yet but we know where we're going and so unfortunately what I think can sometimes happen to scientists when they speak to the public is the message is muddied and it's I think really important is sometimes take a step back and ask yourself the question when you do talk to the public what's the concept you want them to walk away with and then you can be a little soft around the details but the concept has to be correct and go from there so I think it's critically important that we interface with the public for multiple reasons but we also potentially one service that could be done for everyone here is in a way to learn how to interface with the public because it's critically important there's a new question over that so in addition to the knowledge for the public I'm Bonnie Choubert from the NIHS in the epidemiology branch and we have a number of people watching this via video cast from our institute and one question that's coming up is the logistics of sample collection and incentive for study recruitment and there's a lot of people that have presented some really interesting studies and have some great samples and we're wondering if you have knowledge about some key incentives for people to get involved as well as the logistics of sample collection including mailing in their samples rather than clinic visits we do that actually we have packets that we send to the patients for home stool collection and they put on ice packs but it depends a little bit on what your question is and there are some people who are going to be getting together with this idea of trying to create standards for population microbiome studies and the problem is sample collection depends on a what your question is and how are you going to try to address it for example a fecal sample that is put immediately into an ice pack and then shipped via FedEx and then makes it in his aliquad and put it into the freezer is good for certain types of analyses but not other types of analyses are you doing you know are you trying to ask say for volatiles are you just trying to get DNA out so you can do 16S surveys et cetera et cetera so again that gets back to the whole idea of the team science because it's kind of hard to just say you're going to dive into this and follow some standard protocols to allow you to do this type of research because it really involves from the beginning with people asking some very basic questions about what is the overall biomedical question what types of things do we think might be able to address it and then kind of build up your logistics from around there I wish there was just the magical sample kit that would allow us to do proteomics and metabolomics 16S do metatranscriptomics and I don't know we can name anything else that we want to do on it and get all the appropriate clinical metadata put it into the really great program that'll analyze all these data weight them appropriately and spit out the answer and it goes on your slide and that's figure one for your nature or six for your nature paper I don't remember which one you put that one in one or six but it's not quite it's not quite that streamline yet and I don't think it'll ever be any more than it is in any other scientific endeavor so okay another question of that I have a comment I have a comment about sample preservation and along the needs aspect of our discussion I really feel strongly that we need to think more about preserving live microbes when we do these studies and there are several reasons for this we talked about not really understanding what's happening in the dynamics of these microbial communities we don't understand what they're resilient to and what it even means what perturbations we're talking about there was a comment about 30% of genes not being annotated and we also talk about using these microbes as probiotics so to figure all of that out you need live microbes at the end of the day it's just a sequence not likely to do it right so it would be really really amazing if every sample we collect in sequence we also figure out a really cheap inexpensive great way to preserve the live microbes so when someone sees something really interesting in that sequence sample you can go back and say aha you know that gives me a really interesting idea I can now go pull out those microbes and see if that idea is right or wrong or if you know my hypothesis makes any sense and otherwise I feel that we're generating tremendous amount of very valuable samples and if we're just extracting DNA we're sort of missing the more interesting part of the story okay does anyone have a quick any quick response to that before we go to the people who are waiting behind you no? yep I think that's a great question and the challenge at least for the gut really comes down to anaerobic conditions I think and storage under anaerobic conditions so so that's something that is never going to be as easy and again it may always depend on the question that gets asked and we can probably collect 10,000 samples for DNA with the same amount of work that's collecting 50 samples anaerobically well that's the current state of the art right but you know I'm not sure people and there are a lot of people doing dry sample preservation all kinds of cool technologies where you know they claim they can do magical things right so if NIH or we collectively told them look this is a real problem and if you could solve it it would make tremendous impact maybe they can maybe the tools are already out there it's just nobody's looking at it so I we've been working with Tom Schmidt and maybe Tom you might make some comments because I know you've looked at this issue with regard to the samples that we've provided to you we've had reasonable success in storing the samples at minus 70 in terms of being able to revive strains for cultivation it's difficult to provide a value an exact percentage of how many organisms are retrievable after freezing or if it's being selective I assume that it is but in general freezing has worked well sorry these are for stool samples yes okay thanks judgment of that yeah just a a couple of comments hopefully for discussion so one builds on the statement just made about 30% of the genes that are annotated saying very well studied genomes like E. coli have no known function I would actually argue that it's much higher than that we really don't know the biological functions of many more part of the reason too is that the annotations that are in GenBank right now are frequently wrong so if you're somebody who's new to the field and you take the function that comes up on your PFAM or interprosite and says hey this is what this gene does if you actually start doing some functional analyses you're going to find that many of these annotations are wrong so that's something I think that is a field we need to figure out a way to clean that up and it's a it's a hard problem the second comment and we've been talking about a lot of new technologies big data technologies big data initiatives and this is a little bit of a self survey comment so there's this disclaimer because I think this is a very important technology we overlook is that we don't really have genetic tools for most of these organisms that we are going to now start studying in the gut and I think it's an important thing for us to development I think you know Sarcus has talked highlighted what you can do with a genetic genetically adaptable organism and I think a Pete Turnbaugh if he would be able to knock out his genes he'd be able to answer his question quite quickly but unfortunately when I've asked you know program officers in my case we're trying to engineer probiotics can we submit grants that are just focused on developing genetic tools for probiotics the answer has been a pretty resounding no if you want to put a one small sub-aim in the midst of a bigger project that's taking on a disease then that's okay but it's really something that you really have to do on the side we've been successful but extending this to other bacteria it's going to take investment it's going to take time and the identification of new vectors et cetera so I know that multi-omics tools are cool but I think using some old school stuff could really help us out great thank you just before we go do you have a response to that to his first comment so he commented about making sure that we have that we're able to store some of the bacteria samples that we get at UNC one of the things that we're doing is that we're collecting mucosal biopsies and we're actually getting isolates from them so that as we move into functional analysis I think it's very important that we think about having isolates on hand so that we can then begin to ask some of these basic questions mechanistic questions so I just want to to respond to that thank you gentlemen there okay all right well my name is Michael Hurst I actually have a website fecaltransplant.org where I share the story about how two years ago I used fecaltransplants to effectively cure myself of ulcerative colitis after coming within three days having surgery well since that time I've gotten a lot of responses from people who have written me and sometimes shared their experiences and their stories and there seems to be a lot of variation in how people make this work or how it sometimes partially works and various obstacles they run into one thing I was wondering was how from the general public side can we share our insights and experiences in a meaningful way with researchers so that then they can do research off of that or perhaps provide answers from ongoing or finished research projects so from I'll give you my opinion here which is that in research there are there's multiple levels of interact there's multiple levels of interaction that from the public up to big science big funded science and also therapies and part of that also involves regulatory agencies in congress and things like that I'm going to argue that one of the problems that we can face as researchers is that you know we hear in general researchers are optimists otherwise you would have left the barn long time ago and so but and so you know I would say that you know we like to hear anecdotes of things that you know so anecdote defining that as in a single event okay and so not as in it's a story that I don't believe it's a single event and so those are positive things that move things forward but to move from single events to the research where we're at there's a lot of hurdles involved and I think one of the disconnects that certainly I have experienced and I have seen is that when is realizing that as we go to do research so for example there's there's a story of a number of years ago when the NIH is going to make a big push to actually looking at various lactobacillus or other based other types of probiotics in trials and stuff like that they got the money together is all going to be funded and then that fell flat on its face when it ran into regulatory hurdles and so as scientists we don't deal with regulatory hurdles we live with them and so where do so regulatory hurdles are there a regulation I should say not hurdles but regulation is there for protection and that protection comes from an idea of what the public wants which then goes through your representatives goes through things like that and so I would argue that the way that you can help us is to become more involved in the discussion because we talked about how can we talk with the public how can you talk to us well there's people in the middle and that's so talking to your congressman your other local representative things like that so basically getting a scientific discourse going because one of the things that can be problematic in this country at times is a lack of scientific discourse that starts from the public and then goes to our level Thank you Gary Ed Lita has asked me to try to steer the conversations back towards gaps needs challenges so if we could do that we're going to revisit this topic again tomorrow when we hear a bit more about chemical transplants but the gentleman over there is on the microphone so we've heard over the past couple of days about how the cost of sequencing the cost of gathering proteomic data everything is falling but the cost of enrolling subjects and gathering specimens maintaining specimens and the metadata is rising as a result of some of the HMP projects many of us have have specimen archives and data sets that are invaluable and could be used for decades to come the legacy of these projects be terrific if the legacy could include some way to preserve these resources for similar and even dissimilar projects and there's actually a related question that came through by email about whether people are actually reusing publicly accessible data sets what the obstacles are to doing that if they are doing this which data sets they're using and how are they using their data so does anyone have any response to that? One of the hopes when they set up the normal cohort of the HMP is that a lot of people could use these as controls and so I had a postdoc who had a project where they had a bunch of samples of convenience and were ready to go and needed some controls and I said well let's go get the HMP control data set he came back about four days later like looking like he hadn't slept at all and was saying Vince you've got to help me out here and so we eventually got it we figured out how to do it we got it we were able to use it it served its purpose well but I think this has been brought up already and the suggestion has been already there for Owen and for others that it's not the easiest way the processes aren't easy to necessarily get it out have you had a similar sort of situation trying to get at these and also getting the metadata trying to figure out which ones are really appropriate controls for the patient samples that I have Just comment on that and then we'll go to code to see I'm about to say probably the same thing Owen was is that it's I think it's important to distinguish in that case between the data and the metadata and the samples I hope what you just described was the metadata for which we've now Owen and others have several times raised the challenge that is dbGaP which gets back to the issue of subject privacy and consenting and a whole quagmire that hopefully is not the case with the data themselves No, it wasn't the data but it was able to link it to the dbGaP metadata the de-identified data set too so it shouldn't and we already had an RV so yeah that's you're right, it was that but in order to get to the data we had to decide which ones we wanted and for that we had to go to dbGaP scan the whole thing and go through the metadata figure out which ones are appropriate controls for our patient population and then get the data once we figured out which ones we wanted getting the actual sequences was not trivial but relatively easy and I would contend that's an issue of two things one what's the appropriate way to consent individuals such that we can share some amount of metadata which for the healthy cohort we can't essentially because of the consents and two what are the standards and again protocols we need to organize that metadata or samples for that matter Do we have a comment from the middle of the room? I just want to amplify off of one thing that I was getting from what Phil said was also about sort of biosample availability we are creating these incredibly precious resources and so maybe I'll do it this way I'm guessing this is a no-brainer how many people in the audience would actually view using somebody else's sample if it was available as being a good thing it would be useful in their research so how many people at this point have biosamples that they would like to share with the community so I would argue that there'd be some value to there being some type of common repository or I'm sorry a resource that helped people get access to those that seems fair to me based on that so I just want to echo that in that when we're collecting these samples not only the biosamples to collect the dietary data we pay our human subjects a lot of money so that we can get very detailed diet journals the entire time they're in our study I'm a registered dietician I train undergraduates to interview them weekly to make sure we're recording this data but you can also do it in a less expensive manner the last section was wonderful with some of the surveys they were doing the in-hane surveys are very useful for those kind of things so I think it would be wonderful to be able to share these biosamples our fecal samples but making sure that we include dietary information in that conversation if at all possible as well so we can make it more useful great thank you so one more comment then and we'll go to another question I maybe need to differentiate what Owen said about the other side is about providing samples that we have and whether we'd like to do it there's sort of two parts to that one is whether we have any sort of concern about someone scooping us but I think the main thing is how you actually do that if you have one sample and you're concerned about freestyle or whatever or you don't have a person who can do that kind of thing there isn't an ad gene for samples like this so whether we'd like to do it or whether we raise our hands or not is actually a little bit more of a subtle thing than whether we're willing to share versus able thank you I guess I was just going to add one more thing with regards to making data available it may be useful to look at the women's health initiative program which for 10 plus years now makes both data as well as specimens available and to think about if there's anything in the context of that structure that may be useful to apply to HMP data right new question yeah so um I kind of want to take it back to the diet issue here for a second so you know we've been talking about having a central repository for mice and being able to have mice that start with the baseline got microbiota that we know about and understand but I'd like to push that even further and say that we need to have some type of defined controlled diet for those mice as well as for humanized notobiotics because we saw some nice data today where you saw where one community was maintained on a specific diet but not on another and the mouse chow I'm using in my facility is not the same as what you're using in yours so there needs to be some more consensus on what defines a controlled diet so we can decide what is really maintaining a transplanted gut microbiota and things like that so I don't know how you all feel about that but I think you know doing this cross discipline things and including more registered dietitians and people with nutrition background is really really important for these studies Great question anyone have any response to that? There's a debate over that this idea of having completely genetically identical mice on identical chow in an identical cage on identical can't be corn cob bedding because that will change but you know identical bedding and things like that I agree that that allows us to kind of be able to compare our results but as we are all scientists we all look at a protocol and the first thing we do is pull out our pens and that's you know and you scratch out step 14a right that's what we do but I don't think that's necessarily a problem and it was brought up with Phil if we keep track of what is the difference I think the variation you know we like genetic variation if we can account for the variation and go back when we see an interesting result and then try to tease it out there's science in that too so I understand the desire to have standards and everything like that but at the same time I think good record keeping allows us to keep track of variation that'll expose more science I don't know again it's a debate both ways and I can see depending on what you're doing which one you would fall down on All right any more views on the variety versus standardisation debate or new questions no okay well we might finish five minutes early it's been a long day thank you all very much for your contributions see you tomorrow