sometimes it's Different for people that have only been In like TV shows and they get like this movie With like an all star cast and it's just They don't They don't do as well as everyone else And then you're looking at the rest of his Career and it's just not I mean he's worked a shit ton Like I've been scrolling for a while And I haven't gotten to the end of his IMBB So he works a lot, but I don't know I feel like he was the weakest link in the movie It's two very, very alternative Opinions right here on EFAP Who'da thunk it We'll have to judge him when we next watch the movie Rex Yeah, yeah Apparently YouTube has added an applause function On video, so it's only fitting that I ask Please clap Well that's in there for a while An applause function I had no idea Yeah, so apparently only like 3000 accounts Got it, and so when you click it It's like a way of like Super chatting a video when it's not alive And so It's not alive Like you know a live stream When it's just like a regular video But then it pays Or you pay like you super chat them $2 And so They're testing it out On 3000 accounts And I think they just added like another 2000 So that's how more people are finding out about it And they're like adjusting it So they change the button And now they're making it so you can Pay different prices It's not just the $2 And they're going to try to add it to mobile Because I guess now it's only for Topper androids But it's going to be a feature I think that they're going to use on Every single account Not just the ones that Have it right now So it's just another way For them to make money which I think is smart Because right now on just regular videos It's only through ads and they like To fuck with everyone's monetization I like that It's like you know struggling to find ways to make money When they fuck with everyone's way to make money It's like just Quit monetizing all of our videos For no reason how about that Yep By the way someone said Rags all the Barbie movies You like have the same director and the ones You dislike have a different but consistent Director as well Interesting I had no idea The plot thickens It's saying It's interesting Did you know That there's a poll on IMDB For the best Jesus hairstyle And the one that's winning right now Is Robin Williams from Jumanji Oh Really? Okay You'd think Obi-Wan You know I just assumed I don't even see him on this list yet Wow I know What's going on in this world But Captain loves on it From the Mask of Zorro That is not Jesus No he looks kind of Jesusy Was Jesus blonde? Well if his hair went from blonde To brown and he has a Jesusy Look about him He has that kind of Obi-Wan Kenobi kind of You know aesthetic Yeah but Obi-Wan pulls it off better I'll stand by it He kind of looks like Obi-Wan Kenobi From Attack of Fones The version of Obi-Wan Kenobi Yeah he can't be as good as Obi-Wan Kenobi But he's pretty good Man Starvation Room 11 hours I know Oh boy Don't you dare complain Mr Bobby side tracking Listen My energy ebbs and flows My chi Right it grows stronger When I was suddenly rejuvenated With the mention of Barbie as princess Popper Of course Won't take a goldfish's opinion on it Says the guy who got offended on behalf of a goldfish Earlier this stream No I just said I think that it's un I had goldfish when I was Young and the idea That they have short memories has always baffled me Man that goldfish Every time you walk in the room He'd be like oh hey that's the dude who gives me food And you bet your ass they remember that So don't 10 second memory Me with that bullshit They know where that food Comes from Oh that's true all animals Food Oh it's the food giver It was as good of a pet As a goldfish could be I suppose Pretty low bar for a goldfish But he's a good goldfish Jupiter ascending Jupiter ascending has shone been in it do it Someone mentioned Jupiter ascending earlier There's a chance that movie looked goofy as hell Also Why I messed it a video on Jupiter ascending Invite him on If he's up for it He was more than up for doom annihilation Because he knew that was going to be good Jupiter ascending Yeah maybe Neither Halloween nor Christmas Pagan Christmas comes from Catholics Wanting a holiday to fill holiday time And December 25th had some Theological SIG Not JC's birthday though Halloween is a Synthesis of two Christian festivals around the 1800s I have no clue Where either of them truly come from Halloween is based off Pagan's thing This person believes it is not I wouldn't know I do not know the history of Halloweeners or Christaminers So the day after Halloween November the first that's all souls Day which is a Christian thing So I don't know if Halloween was Created as a Almost like a fat Tuesday sort of Thing where so Mardi Gras fat Tuesday that's the day Before Lent starts Ash Wednesday so that's where you get All the that's where everyone has a feast And because you have the Lent fasting and everything like that You give up stuff for Lent so fat Tuesday Mardi Gras that's when You want to get rid of all your extra food You want to use it up You want to party and get it out of your system And really have a big old blowout Celebrate and have a big old bash Because you know that Lent's coming up And then after you got Easter after Martin Gras Martin Gras Yeah, maybe, maybe not, I don't know Hi rags I'm glad you like my voice over in EF100 Trailer though I have mixed feelings about You doxing my true identity Jonathan Frakes Well, is it Fact or fiction? Who knows I don't like that He downgraded from being like, you know The guy in control of a Starship, you know Whatever he did, mysteries of any kind Um It was called A Beyond belief, factor fiction Whoa And I don't know what else Jonathan Frakes did What's interesting is that William Shatner is the host of a show on Discovery Channel now Cause I was at my folks house And it was just playing in the back And I was like, damn, William Shatner looks Great for his age He brought it up in catch up too I think Yeah He's got to talk about Jonathan Frakes So we're talking about another Star Trekman Yeah I thought you guys didn't watch Star Trek Well, I'm familiar with T and G, to a degree The original series, some of Voyager I know who Jonathan Frakes is And I know that he's Riker And I know that he takes Control of the ship whenever Picard Can't, is that the case? He's number one There you go, that's what I know E.R. is Steins Gate Zero Any good? I've heard it's unnecessary And dumb I, again I do not know I would assume that is correct though I'm just going out on the limb there And uh, Metal, do you plan on playing any other Yakuza games? They're quite fun I don't know if he is Um I'm pretty sure he liked it quite a bit And for now Mario characters Mario is 5 foot 1 Luigi, Wario and Yoshi Are 5 foot 9 Peach and Daisy are 6 foot Rosalina is 7 3 And Waluigi is 7 7 Peach is 6 foot Rosalina is 7 what? 3 Oh my god God, alright Wait, what? Mario character hides, Rosalina is 7 foot 3 How tall is Waluigi then?  Here we go Again, she eats candy for meals Okay Well then have um Have like honey glazed ham I don't like ham Turkey? Cranberry sauce? No Mashed potatoes?  Or do you just stand out in the sun for an hour every day and soak up your nutrients?   Yeah yeah French bread Do you like wheat bread? No Wheat bread's a little too adventurous for you? It's not adventurous it's just disgusting Wheat bread is disgusting? Well what about what about banana bread?  And If I'm like dipping it in soup But I really don't like things that are sour Focaccia? I'm just making it Rye? What about Do you like pita bread and sandwiches And stuff? I'm allergic to pita What other bread is there?  No But it's not because I don't like them I just don't really Like I'll never Go out and have a bagel I'll get something else What about just biscuits?   I don't know Why not? I don't like the texture The texture is the best part of the English muffin Because she toast it and they're great What about Texas toast? I don't think I know what that is I don't think I know what that is I don't know what that is What about pumpernickel? That does sound made up No it isn't I'm sure it does sound made up People would often confuse I'm going to help you with this All the rest that you're going to ask me The answer is like 99.9% No Chewbada Alright then When you go to Olive Garden Do you partake of their Unlimited breadsticks? I don't go to Olive Garden What? Do you like baguettes? No, they're too dry Do you like brioche buns? Keith has a google list now I'm sure of it I worked in a restaurant You just named two B's in a row I assume you've got an alphabetic list Rags, I don't like water You don't like water I am the pickiest eater And drinker on the face of the planet What do you drink other than candy bars? Melted candy bars I do I do drink melted candy Put them in a blender Arisa smoothies No, but when When there is a golden corral I do take a bowl and a straw to the chocolate fountain How much do you weigh? Because apparently your diet is chocolate I weigh like 100 pounds When I'm soaking wet How?  When you're just around a house? I do have mio I don't like the taste of water But when I put it in, it makes it taste like colloid And I hate coffee, so I have caffeinated mio I put that in So it's like drinking fruit punch But it has caffeine Explain to me what you don't like about water It tastes bad Okay, so let's be Let's just, we're clear Water can have a lot of different tastes It does, yes I guess Definitely There's no gas about that When I go visit my relatives In Albuquerque Their tap water is disgusting over there I love my tap water Dammit, here in Arkansas Say what you will We got delicious as fuck tap water And it's good When you drink it both ways To and from school It's good stuff But yeah Water can be definitely different based on What brands you get and where you are But water in its entirety I don't understand that at all What, that it doesn't taste good?  Yes, but when it's just like cheese And then the meat and then the taco That's something Here we go, we do it Okay, fast food What's your favorite, do you do any fast food I do, yeah I'm expecting she does all of the fast food No, I do Ideal fast food, like your favorite It depends on what mood I'm in But I like Well, yeah Again, it depends on what mood I am And I am in the mood for burgers I'm in the mood for ice cream I am So I like Taco Bell McDonald's and Wiener Schnitzel And then the only thing I get from Wendy's Is the So I think As far as burgers go I think Wendy's has the best of like the low tier Fast food places Dude, what about Chick-fil-A I've never had it Intrigued Suspicious But that's because where I grew up There were no Chick-fil-A's And so then when I moved down to Southern California A few years ago there's some But the line is just so long That's the same over here There's always a line at the Chick-fil-A Always a line at the Chick-fil-A Yeah, it's just not worth it That place is a well-oiled machine I mean it's good, but I wouldn't like wait in line For it I'm not a big fast food guy But I would say that There's like an upper tier and a lower tier fast food And Chick-fil-A's in the upper tier fast foods Well, I wouldn't know Then at the very bottom you have like Orbeez, McDonald's You know, I have sort of Wombos We don't have Wombos here We don't have one I would say the worst fast food place I've ever been to though Probably Hardee's I would rate I would rate McDonald's Above Hardee's I don't think I've ever even seen one We have Over here in Russellville We have the original, the first Waterburger, and it is delish Oh, Waterburger?  Someone said In-N-Out I've had In-N-Out I've had In-N-Out It's overrated Someone said Arby's is god tier No, Arby's is just like But Hardee's is When Someone says Subway, I don't need Subway It's not the food that appeals to me Sub sandwiches are not my thing But I've had five guys before Delicious Love five guys I had the Italian night club whenever I would Go there I would do five guys runs For the guys I worked with At the hotel Sometimes we'd do a We'd do a food run and I'd be like Yeah, I'll go do a food run I'd get orders and I'd go Well So So the original Waterburgers Feltner's Waterburger up in Russellville And we go through there every once in a while When we're taking trips And it's really good Feltner's Waterburger is delicious But it's not anything like the chain Waterburgers It is specifically its own thing But it was the first one But even the chain ones are pretty good Their milkshakes are particularly great Do you have Brahms? No Yeah, so We're never going to get to the superchats We're not We already got a tie Actually we're getting to order a cap But it's okay because we'll always get to them eventually We're actually closer to the end than the middle So that's something That's good Anna, Diabetes is infecting your arteries with sugar You must resist I'm a mutant and I'll be fine So when Someone in chat was like Brahms is the bomb Yeah dude, Brahms is Brahms is great, Brahms is good stuff Like me I love me some Brahms Fuck Mary Kill, H-Bomber Guy, Jack St Quentin Reviews Kill all of them No, we're not allowed to do that Fuck Jack St He's not The other two were fucking hideous Fuckin Jack I I mean H-Bomber Guy's got the best Career prospects So maybe marrying him I don't care, money, yeah I guess I Well it's him or Quentin Reviews Rex I feel like Quentin would die first Like Like a heart complication Or something Potentially suicide You're even shocking Ea with these comments Don't give me that Okay I don't think this is from you Yeah I Fuck Jack St I would marry I guess I'd Marry H-Bomber Guy He comes across as the most Responsible of the three Because Quentin is just Like a fucking slob Like I wouldn't want to Live with Quentin Of all those three I especially would not want to live with Quentin No just look at him Like the way he dresses and the way he doesn't Groom and just the man makes plushies of himself Like at what point You're just like enough Yeah, baller tell her about that Well you got A company To make a plushie of himself It didn't work out Oh what Well I don't know like he just The first time I saw it Was with She-One-Head Of course She-One-Head didn't find it hard to sell 400 plushies of herself But Quentin tried and it didn't work out Oh man Let me get you a picture of Oh my god I just looked at a picture of it as I was speaking And it made me just It made me pause You can Check out The Quentin Reviews plush That doesn't even look like him I mean I can't remember who said it It reminds me of Golden Freeman But like Look this isn't even How much is this Yeah I'm not even able to sell this I don't know man It says he met his goals though It says 400 out of 400 I don't know But he got up to just under 200 And it's possible that 200's enough For them to just go ahead with it Yeah Cause hitting 400 On the dot First I'm shocked that 200 people were interested honestly Maybe it was like Cause they wanted a voodoo doll of him I imagine probably Probably bought a few of themself Yeah he probably Move it to everyone in his family For Christmas in their stock And he's like here's a doll of me Chat needs to see Quentin doll Okay hang on Quentin doll It's weird though cause I'm not sure How long it would take me to guess that's Quentin If you had told me Oh I wouldn't have even I don't think I The only thing that gives away from me Is the Garfield icon on his t-shirt And that's only if I think about it For longer than just assuming it's like A weird medal Does Quentin have a unobrow though?  Never heard of it I've not played Factorio But I've seen a decent chunk of Factorio It looks neat Factory Management building system thing I hear it's popular A lot of weirdos Play games like that you know Very market Uh If E.R. is still here when this is red You know that she's not L You'll know what I mean Have a good night All right you are not L What does that mean? That means something from an anime to me But I don't know what that means to you You didn't explain to me the context Because I saw that like Four hours ago when it got sent And I wanted to ask but I was like I'll just wait What does it mean? Well I mean L is a character from A Death Note if you know anything about that Which character is it? I haven't I think I tried watching that like years and years ago But I got too busy with school So what does it mean? It's safe to say that you are not L But most importantly it's he in Spanish But what does this mean? He in Spanish No It looks like Oh is this the kid that gets the book and goes crazy?  Oh wait hold on He does only eat sweets So maybe that's the connection I'm making Is this a good character? No Character who only eats sweets It's very irresponsible Oh he's a psycho? I don't know if they're an alien who doesn't have Anything bad happen from it So is this an insult Or is this a compliment that somebody is trying to give me?   No I don't You don't have a driver's license? Well I mean in Britain Everything is right next to each other So Do you know how to drive the car? No I don't drive What? Driving the car is really Cars are really simple to drive I know but he lives in the UK Which means he's going to have to learn how to do a manual Well my car is manual And I'll only buy manuals I don't want to drive an automatic Mine's a six speed I love driving manuals Like it's fun I enjoy it Having that control over the car Better gas mileage Generally parts breakages is cost less Because you just singular components They're just more engaging and fun to drive To shift And to transition smoothly from one gear to the next It's really really rewarding to drive You pay attention And you feel like you have a lot more control over the vehicle It's really rewarding It's very satisfying It's very satisfactorial It's very satisfactorial There you go But I love driving a manual Mine's a six speed And if I ever get another car Which maybe I will or maybe I'll just keep Up keeping this one I'll always have manuals And if I have spawn god forbid Then they're damn it they're learning how to drive a manual Well You know how to drive both and I prefer automatic You're a grown up and you don't know how to drive a car What does that mean I'm just like Do you know how to drive a fucking I don't know Why do I need to know how to drive a car Because you're a grown up like what happens What does that mean Okay what happens if like the terminator Is coming after you wouldn't even know how to drive The car to get away from that I'll use my laser gun No you won't have one Oh that's not fair Well Mauler if ever I need to teach I could teach you how to drive a car In like 10 minutes The actual driving of the car is super easy The hard part is The rules of the road Knowing what all the signs mean And like lefts and right turns And stuff like that's the more difficult part Yeah I don't know if you Like have you been to everything Like in walking distance Yes I've been to Britain and you know what happened I got stuck in your guys damn Traffic and I was Falling asleep and I kept Hence why you should just walk everywhere No here's the problem so Me and Boyfriend went to Europe For my birthday last year And we were in Switzerland And we went to Germany then we had to fly back To the UK and then from the UK We had to fly back to the States But something got fucked up With our like Flight and whatnot so they switched us From one airport to the other So we had to get from We flew into one that was On the other side of London And we had to drive from that airport All the way to Heathrow Which was like an hour drive during rush hour Traffic to get to our plane To get back to the States And I got in the car And I forgot that You guys drive on the wrong side of the car And on the wrong side of the road And so when we're on the freeway And I would wake up and I'd be like Oh my god there's nobody driving this car And we're on the wrong side and like having Like Oh my god I think I might just die Kind of moments and I absolutely Hated it your traffic was terrible I don't Ever want to be in that situation again But it was very far From one airport to the other so Like don't What happens if you want to go somewhere If you're going from one airport together Like If you're going from one airport to another Then why aren't you flying What do you mean? If you're going from one airport to another airport Fly Because we couldn't Because it was There's different airports on Like there's one airport on The side of London And then there's another one on the other side of London And so there was no Flight from Berlin Which is where we had booked our flight To go back to the states And so What the airport or what the flight Itinerary person did was they made Us go to this other airport And you can't fly from that airport To the other airport because they're only an hour Apart So we had to fly to that airport Get a cab from that airport And then go to the other airport that was Across London And it was just like the worst So When I I went to Washington DC We didn't Drive We used buses and we used the tram over there To get around to places So if I Lived in DC Fuck me if I ever end up living there It's a hell of a place to visit but I'd never live there Then if I needed to go Downtown or anything It would be buses and trams You wouldn't need to drive You wouldn't need a car Here in Arkansas Everybody owns a car or two Or three Just depending Because everything's kind of spread out And everyone just drives Public transportation won't get you Like everywhere you need to go And I like that I like having a car I wouldn't want to use public transportation Or rely on any of that And then maybe you just Don't need to Have a car because you use Public transportation or use the subways I know but what if you want to go somewhere What if you just want to take a drive What if you want to go to the ocean How do you get to the ocean if you live in the middle of the Freaking country and you don't have a car You fly Okay, let's say you live You rent a car Car rentals are not expensive To Nashville I rented a car to do it They're They were surprisingly cheap But if you're in Arkansas And you want to go to the ocean You probably Ain't driving If you are that's a hell of a long drive You're probably flying to a specific place How long would it take you If you've gotten your car right now To drive to an ocean The closest ocean As I don't know if it's Let me check I'd have to check The last time I was around an ocean Was Galveston and I don't know I don't think that's the closest though, let me check It's probably around It's probably in Louisiana As the crow flies it's Probably North of New Orleans Somewhere around Lewisburg Or Laplace I don't know It would probably be How long do you think it would take you To drive there? It would probably take me 9, 10 hours 10 hours maybe 9, 10 hours And you would rather fly There than drive that?


Well, I've really enjoyed those parts of the media I've been able to be at and especially that last talk and following up on the radio analogy, I feel like since I left academic medicine that some of what I've been doing is working with biologists who are trying to fix radios and trying to keep them from having it blow up when they plug it in. And maybe the radio in this case is the patient. And we're all working to the same end, which is to really bring these amazing insights from biology into advances that can benefit patients. So I'm going to talk at a conceptual level, but most of the concepts, because this is a very thoughtful field in general, you've already heard about, so I apologize for that. But I'll sort of do it at that level going all the way from how do we go from the biology to the products and what are some of the observations that I've made in working in this continuum that might be helpful in working together. So I'm going to start with where I see as a non-microbiome person, although I've sat in a few meetings about microbiome and had many discussions about it, but how does it look from somebody who's not directly involved? From a clinical and FDA perspective, just some reminders that it's important to remember that sometimes what seems like it works really doesn't, and sometimes what makes sense isn't that sensible, and sometimes what looks safe isn't. Talk a little bit about, you've heard a couple of discussions that have touched on causation because I think our thinking about our observational science should drive what we move forward, and we need to be very careful about that. And there are some, it was really fascinating to me to think about this talk because there are some things about, obviously the microbiome isn't a drug or a vaccine, and when we think about manipulating it, the normal concepts applied to how we think about clinical development and clinical intervention need to be readjusted, or at least considered, and that leads to what are unique aspects of the products, points to consider as we do clinical development, clinical trials, and then in general, how can we work together to move this field forward? And I'm really impressed actually by the maturity of the presentations I've heard from basic scientists in terms of understanding sort of the connections that need to be made to have this work, i.e., a sophisticated understanding about causation, and a sophisticated understanding about interventions and how complicated they are. So in terms of where do things seem to be, while I really, as an infectious disease physician and former basic scientist, I'm thrilled that this is, I believe that the concepts of microbiome are really, are a breakthrough in terms of understanding what a human being is, really. We also see, as in so many areas of science, a huge data explosion triggered both by a conceptual shift but also by technology and bioinformatics. And we're seeing, I'm seeing this in so many areas and it's almost tried to say it, but we have so much information and yet we really don't have much understanding of most of that information, and one of the problems that I've been seeing is that there are less and less people who can actually understand the full implications of that information. So anyhow, the excitement and enthusiasm are legitimate. We've heard a lot about the gaps in understanding at this meeting. These include things like what really is normal and what isn't, what are the dynamics of change, what is the, how does the inventory of the microbiota relate to functional status? And I really like the concept, several people have advanced that it's really what are the inputs and outputs of this community that may be most important for the human host. However, we can't forget that some of these organisms may also function as traditional bacteria. They may trigger receptors. They may do other things beyond their metabolic products, so we don't want to forget that. We're seeing lots of disease associations and we don't know if they're causative. I'll get into that a little. Animal data, some of which you seem can be quite exciting and suggest that manipulating the microbiome can impact disease or risk factors. I won't go into the successful intervention in C. diff, but clearly there's some promising clinical observations and that's been one of the most, I would say, remarkable ones as a physician who has taken care of people with refractory C. diff disease. This is a real problem and this is a real breakthrough, so that's fantastic. There are other areas that sort of are less focused on, but utility, for example, in predicting disease, could we predict disease based on the microbiome component when we just heard that, in fact, the genome may drive the microbiome, which then may drive the disease. And can we utilize the microbiome to modulate response to drugs and vaccines or to better understand them? So I did want to mention a couple of the cautionary tales, more as a framework than as any negativity, but there are a lot of examples of things where the best scientists in the world are totally convinced that something works and physicians are convinced that something works and it doesn't.  This got to the point that there were demonstrations that clinicians and patients were demanding payment for this procedure, which is basically getting your own bone marrow harvested, getting your entire bone marrow ablated, and then re-infusing your own bone marrow. It's a pretty toxic procedure with some finite mortality rate, and there were story after story of people with long-term survival and metastatic breast cancer that seemed to substantiate that this was beneficial. And finally, and I think this was a breakthrough in how we think about effectiveness in medicine, payers said, okay, we're going to pay for this, but we're also going to, I think CMS was involved, we'll do this in the context of also funding a study for those people who would be willing to enroll in a study. And a big controlled study was done, and lo and behold, there was no benefit of this procedure. So you had thousands and thousands of women get these autologous transplants, spend lots of time in hospital and bone marrow transplant units, and actually end up having more mortality and morbidity. So that's a cautionary tale. Also, this whole thing about markers that really seem to make sense to us don't always predict disease. So there's premature ventricular contractions, which are a sign of an irritable ventricle, which is a sign of predilection to sudden death, and is fairly predictive of it. But there are drugs that have been studied where that was chosen as the endpoint suppression of that ventricular ectopy, which is believed to then trigger sudden death, where that ectopy was suppressed, but actually sudden death increased. So again, the biology is sometimes more complex than we want to think. Now, when we get to biologics, which are either made from or of living things, obviously, as everybody in this room is where product safety becomes a particular concern. And things done with the best intention have had some problems. Fortunately, they are very few and far between. We have a, you know, generally a very responsible industry, and we have a strong regulatory agency. But actually, the entire FDA was pretty much founded because of a horse named Jim, as when it was realized early in the last century that plasma could be protective against infectious diseases. Horses were immunized against infectious diseases. And a diphtheria antitoxin was produced in a horse named Jim. There was a proliferation of all these companies making these anti-seria. And this turned out the horse had tetanus at the time that this was made. And this was transfused to a large number of children. I can't remember the numbers, but maybe 20 children died of tetanus from receiving this diphtheria antitoxin. And that led to the Biologics Control Act, which actually came before drug regulation. Also interestingly in terms of the NIH FDA tradition, the Biologics Control Agency was off and on part of NIH over the years, an interesting bit of history. And then a very interesting thing that David Relman had called to my attention, and I was also aware of, though, is that in the 60s and 70s, there was enthusiasm for replacing bad bacteria on the body with good bacteria. Kind of simplistic notion, but not totally unrelated to what we're talking about here today. And less virulent strains of staff were used to reek the idea of being to replace the more virulent ones and prevent serious staff disease in children. And quite a number of children, I think, was about 5 percent of those treated, then developed infections, some fatal, with the Staphylococcus that was transferred. Another point I always like to bring up is that having, this gets to that ecosystem idea, but even more individually, every part of that ecosystem is finely tuned. I mean, we're an amazing machine. So healthy biology, and especially with respect to immunity and inflammation, is a balance, a constant balance of modulating factors that allows us to be resilient when we're challenged from one end of that spectrum or another. So immunity and inflammation versus tolerance are balanced. Clotting is balanced. Yet many of our medical interventions are blunt. And so one example is one of the greatest therapeutic advances we have is TNF blockade. It's revolutionized the lives of patients with rheumatoid arthritis with inflammatory bowel disease.  And obviously, if we clot too much or too little, we have problems. So we need to consider that altering the microbiota could have similar implications. But on the other hand, it could provide an opportunity, especially with people going into it, like all of you seem to be doing, understanding its subtleties, to get the porridge just right and not have it be too hot, too cold. Now, a little bit about observation and causation. I'll go through this quickly because I think everybody's pretty familiar with this. But just to say that looking at observational data can be very tricky, things are traditionally assessed such as the strength of the association, its reproducibility, whether there's a dose response, which may not be very relevant to the microbiome, and whether it's biologically plausible. Of course, the biggest problem is what we call confounding. That is, are there other factors that we can't measure or correct for that are responsible for the association? And confounding can itself, many people don't realize this, lead to very reproducible results. So just because somebody finds constantly that the microbiome is associated with X disease does not mean obviously it causes the disease, because if there's consistent confounding factors like diet or something else, you will still have a consistent finding. And the most extreme example that I sometimes use is, does the Starbucks in neighborhoods cause higher income in a dose response relevant way? Okay. And if there was ever an observational area subject to confounding, certainly the microbiome is it, it's very complex, everything influences it. If it influences everything else, things like socioeconomic status may influence it, although I haven't seen studies of that, but I suspect they've been done and I'd be interested in that. And the other thing I wanted to mention is I see all these wonderful dendrograms and all this incredible data, but I used to see this when people were dissecting the immune system and they had all these T cell subsets and you could, in the clotting system, you could explain or hypothesize a role for anything being up or down-regulated causing virtually any disease. And I think systems biology has both given us tremendous insights, but it's also made it possible to propose biologic plausibility for nearly anything. So we have to be a little careful of telling stories and then believing our own stories. So taken together, I think for microbiome interventions, these will make controlled clinical trials very important. Now there are some unique issues in microbiome manipulation and implications, including parallels that I really like and I've heard here to ecosystems. I wanted to mention a few other ones. In reflecting on this, that how reminiscent this is of ecosystem issues, I also realized that we at FDA, et cetera, frequently see these and in clinical medicine in other domains. For example, states of health and disease are frequently not binary and their establishment or treatment may require multi-step process. We just heard about hit and miss kind of things. Well, late in the course of a disease, an intervention which could have been effective early on may not be effective. And this goes against how we normally do clinical trials. We normally treat severely ill patients first because they're more desperate for cures. They have a higher potential benefit, but they in fact may not get the benefit. Interventions in the microbiome particularly may or may not persist. So the fact that something doesn't work may be not so much that you didn't have the right idea, but that the intervention itself doesn't accomplish that change in the biome. And then the most important outcomes, whether positive or negative, may be long term. So people are looking at chronic disease in many of these cases and obviously those are very hard studies to do. Now, I think one of the areas where the investigator and innovator community comes into contact with FDA is the products and their characterization. I wanted to say a little bit about that. These are really unique products. There's a need for defined and characterized products. As we've heard from several people, there's a need to define do we need these mixtures, these complex mixtures, can we hone them down and what are the tensions between that, between a viable ecosystem since that's what it is, and reductionism and how we approach that. I mentioned the potential for adventitious agents and I will say that sometimes one man's non-pathogen can be another man's pathogen, so we need to think about that. Genotype versus phenotype, what's necessary for the desired effect, the stability of organisms and mixtures, both as a product and in the patient. So based on these issues, the kind of information FDA typically wants to see is the source, the history, the genotype and phenotype, the antibiogram, the stability of these products. And we do take a risk-based approach to that, so for early clinical studies, you need less data when you're exposing less people, depending on what the source is, you may need more or less data. So we have guidances, there's a guidance on live bacterial products that can be helpful, but I wanted to emphasize that guidances are just that and we really encourage people to come in and talk. And if something seems unworkable or you have alternative approaches, please propose them. What about clinical trials? How do we decide whether to do them? I think this is almost like anything else. Is there strong evidence of causality? Do we have a mechanism of action that supports the proposed intervention? Is there evidence for safety and efficacy, whether in animals or humans? Important one to think about and we've seen lots of problems in other complex products like cell therapies. Can you reproduce the therapy in the future? And that gets again to characterizing the intervention or the product. If you can't, you're subjecting people to risk without benefit. And if you can't, you're also very frustrated because we've seen a lot of things that worked one time and that they couldn't be made to work again. Specific issues, I mentioned fine-tuning the intervention, product characterization, what other things. One interesting point is the challenge in population selection and this could be a benefit. If you can identify this dysbiotic subgroup that needs the intervention, you may be able to get away with much smaller clinical trials than if you just tried to treat everybody with obesity or everybody with inflammatory bowel disease. Monitoring the effects on the microbiome both to establish a dose response or an intermediate endpoint. And I think importantly for development of biomarkers, it raises the complexity and importance of appropriate sampling and data analysis plans. I also want to mention there's a unique opportunity in terms of biomarker and diagnostic development and that building good data collection and assays into studies could allow us to define biomarkers and provide disease insights. And I mentioned long-term follow-up and I know I'm tight on time so I'm going to zip along here. So what you really want to do is think through early on and I'm always surprised at how often even sometimes very sophisticated product developers collect all this data and then really decide what they want to do. I think you have to learn from your data and you could change your intention based on the data but it's a good idea to have a sense upfront what the candidate patient populations and indications would be, the criticality of ensuring the ability to reproducibly produce and characterize the relative product or intervention, the study and relevant disease models, careful consideration of safety issues, and then design stage clinical trials with relevant endpoints. And please consider sampling and assays for candidate biomarkers and doing, you know, in multi-center studies, central labs with well-validated assays can be very important in this. I think our current clinical research enterprise in the United States probably loses as much useful information as it actually collects and analyzes. I think this is emerging science that we all can and should learn from. So I'm delighted to be able to be here and encourage this field and this interaction, hopefully inform it a little. We know we are ourselves complex ecosystems. We have both vulnerabilities and resilience. We don't want to fix the resilience. We want to fix the vulnerabilities. I think the promise of recognizing this reality reminds me of the recognition of our broader global ecosystem and environment and the need to support its balance and offers great potential benefits. For all these reasons, it should be based on the best science and a healthy respect for the complexity of nature. And personally, and I think in general, we're optimistic about the impact of microbiome science and welcome a really constructive engagement going forward. Thanks very much. So we have time for some question. Hi, thank you. That was terrific talk. I'm with the Office of Dietary Supplements, Cathy Camp. And I wondered if you could address some of the issues that we face with things such as probiotics that are actually regulated as dietary supplements versus drugs and their use as targets to the microbiome, particularly with infant formulas. Thank you. Thanks. Well, I don't have particular expertise in the area, but I think as one of the speakers had said on the first day, and you're probably an expert on this, FDA has somewhat limited oversight over dietary supplements, except when something goes wrong. So manufacturers are required to support, report serious adverse events, and FDA will investigate those. And I think it's safe to say that there haven't been a lot of serious adverse events from the commercially made probiotics. That said, if they, my understanding is if they use ingredients developed before something like 1994, they get no actual pre-marketing review at FDA. So essentially they can be out there selling these probiotics without an unbiased review of the data. So I think it's a little bit of a buyer-beware situation, but I'm not aware of a lot of harm. The flip side of this is there may be opportunity. We've seen that some of the clinical trials have been done with some of these commercially available preparations, some of which have shown some interesting results, for example, in infant diarrhea. I think one of the things I've heard a little, we worked with NCAM on this issue a few years ago at NIH, is it would be great for these companies to bring forward more information about their products to engage the research community. Some companies have been very willing to provide researchers with information on the manufacturing and content of their products, but in many cases researchers have a hard time knowing what an actual product is. I will say not to impugn any specific product, but in some cases when products have been looked at it's been found some of these do, but others don't contain live organisms etc. So I'll leave it at that. Maybe I have a quick question. One of the issues is a lot of the whatever you want to call them probiotic or other different product that are derived for the microbiome is that they don't really fit one category. They can be devices, they can be food, they can be drugs. Is there any plan at FDA to kind of centralize maybe a an entry point for us who are developing or thinking about those things to guide us through the complex FDA structure? I think that's a really good question because it is a complicated system and I want to point out it's that way not because like we like it, but that's because the laws are different in those areas and companies decide how they want to submit their products. I think in general your entry point is the center for biologics because what we're talking about is using a microorganism or an intervention and if that's wrong they can help you elsewhere but for a medical indication to treat, diagnose or prevent disease and that becomes a medical intervention and does engage a pre-market review process. In some cases that might not be the case or for example a trial of an antibiotic to alter the microbiome might be with the drug center but we I'll bring that idea back and we can consider you know certainly we can look at our web interface for example and try to improve or try to put up a page that might make it easier to enter and navigate the system and the other thing I would offer is you know people can contact my office too because I mean there's always this this concept of which you bring up which is curing disease but what about maintaining health what does that fit? Well the you know I think maintaining health in terms of objective measures i.e for example one of the things you might want to do is have a resilient microbiome so that you prevent diarrheal disease or prevent atopic dermatitis that still comes under prevention of disease and in general we would encourage that kind of engagement. There are these things called structure function claims so when you and that's what the dietary supplements use and that those are those sort of interesting things you'll see in advertisements like this will help your immune system or this will help your joints and again that's related to the what the law is and our staff do their best to sort of keep an eye on that but you can see there's a very I think for credible scientific purposes in general you're talking about preventing treating or diagnosing specific illnesses. One last question and we'll go to Greg. I'm Gilman Gray from the Child Health Institute thanks very much. I enjoyed your overview. We're interested in the oligosaccharides in human milk that have antibacterial or antiviral activity especially two fucacil lactose. Do you see any future in honing down on specific oligosaccharides that may have biological activity and adding them to formula or giving them in a pill? Are we are we going down the wrong road here because we're kind of interested in doing that? Yeah well I don't feel like I know the science there enough to comment on it but what I would say is as a concept I think that if it is scientifically sound that is a really good direction to go in other words if we recognize simple interventions that can accomplish or aid or a bet you know what we see the microbiome as a whole functionally engaged in those are a really good idea. I could you know again if I don't know if you've been in contact with folks but if you sent me an email I could try to get you connected to people with expertise in that specific area. There are in the food area there's an issue where if a company can file a petition with the FDA for what's called generally recognized as safe to sure if they can show based on scientific literature etc experiments that a certain substance is safe that actually is often if that's approved by the FDA it can be allowed as an ingredient but obviously that doesn't answer the question then of is this effective in what you're trying to do which is you know prevent or ameliorate disease in children. Yeah so ours is really a medical model and we would have to go through the FDA and get all kinds of clearances to pre clinical testing and all of that right and we need gram or kilogram quantities of it right now there are only most exist in microgram quantities. Yeah what I what I can say is it is hard to develop drugs particularly if there's not commercial interest behind it but if there's promising information you know NIH may have ability to help if you have business partners they may have ability to help. There's tremendous we've seen tremendous power in the patient advocacy community to bring together groups who can try to help move products forward and one of the models we're trying to put forward at FDA is to try to help you with that so you know if to try to help lay out a pathway help identify what the issues are rather than just have you come in and feel like you're having to meet you know commercial requirements now the flip side is there are safety issues you know many active pharmaceutical ingredients come from all over the world there's a lot of issues about quality and safety of the supply chain so those are important things to consider too. Great I'll take you up on your offer you'll be hearing from me thanks so much. No you're very welcome. Well let's thanks Dr. Goodman for a great talk. I'd like to welcome everybody to the next session this is the first of the translation sections and this one is on the body microbiome access I'm Carl Baker I'm program director for or for keratinocyte biology and diseases in the division of skin and rheumatic diseases of NIAMS and I'm going to be chairing the session this morning. I'd like we have a very full session so I just like to remind speakers to stay on schedule so that we can have a little bit of time for questions. So the first speaker this morning is Ted Dynan who is from the University College Cork in Ireland and he's going to talk about the microbiome brain and behavior.


I've been asking the Holy Spirit, what are you saying in this season? What's one of the things you want to communicate to your church? And I'm telling you, I heard very clearly the Holy Spirit speak. It's time to gather again. It's time to gather again. There's a very dangerous trend, and I hope you're not caught up in it, a very, very dangerous trend that really has been catching on in many parts of the church. This idea that we don't need to gather, this idea that we can have a superficial connection with the body of Christ and expect to thrive spiritually. I understand that Christ is our source. I understand that we all have the Holy Spirit. 1 John 2, 27 tells us we all have the anointing, but the truth of the matter is this, God always intended for his church to gather together. That's the design. That's how he created his church. That's what he intended for his church, that we gather together. You cannot replace the gathering of the saints with an online connection. Now, this is coming from someone who has an online ministry. If I didn't love you, if I didn't care about you, if I just wanted to be self-serving, I would say, you know what, yeah, you don't need your pastor. You don't need those people. You know what, you're probably more anointed. You probably know better. They're probably all religious and compromised. They're probably all dry spiritually.  You're the only one in the group who truly is anointed. You're the only one who actually wants the deeper things of God. And I would tell you those lies to flatter you so that I could benefit from it. Look, as I said, I'm in online ministry and we are seeing a fruitful season, a very fruitful season. So this isn't coming from an old wine skin who's complaining about change and who doesn't like the way things are going. I believe in online ministry. I believe this new wave of communicating is powerful. It's useful. It's a great tool, but it is by no means a replacement for gathering with one another. You can't replace that personal touch. Only in gathering can we find true accountability. Only in gathering can we find true relationship. You see, if we just connect online, then we get to know one another's personas.  People can't hold you accountable if all they know is that projection that you created online. People can't truly connect with you if you're at a distance. The physical gathering together of the saints, that is needed. Let me show you something in scripture. This is found in Hebrews chapter 10. I'm going to read verse number 25. And let us not neglect our meeting together, as some people do, but encourage one another, especially now that the day of his return is drawing near. That is scripture. How are we supposed to lay hands on those who are sick if we're not gathering in person? How are we supposed to together feed the hungry, clothe the naked, how's the homeless if we're not gathering together? It's the gathering of the saints that makes the difference. Now, we've all heard the clever sounding excuses like, well, I am the body of Christ. Well, no, you're not. You are not the body until you gather. It's only in our gathering that we become the body. It's only in our gathering that we experience the union that God intended for us to experience. You need a pastor. You need fellow believers.  You need personal connection. That's how God intended it to be. Now, when this pandemic first started to affect the church as a whole, what began to happen is people started to isolate themselves. Now, isolation is the breeding ground for fear, for strange doctrine and for bitterness. And so, as people start to isolate, they start to get bitter. They start to get weird. They start to become confused. They start to become fearful and cold. That's just a reality, even prideful. In fact, the enemy can use flattery to make you isolate. And he does that often.  And later with that religious system, come out of them and we kind of get this idea in our head, yeah, the people in my church, they're all cold. They don't get it. They don't understand it like I do. My pastor is not as powerful as this guy or this girl online. My pastor doesn't do it like the online people or all these things that sound like good reasons to disconnect. But the truth of the matter is those people online, those people on television, those people on radio are most likely not going to share a meal with you. If you go to the hospital, they're most likely not going to be able to come and visit you. You experience a family tragedy. They're most likely not going to call you. So we have to get this out of our minds that the more spiritual we become, that the more isolated we become from the body of Christ. Now, I understand sanctification. I understand being set apart. But being set apart and sanctified is not the same as being isolated. And we can't confuse the two. We have to stop pretending or acting like fellowship with other believers is somehow a contamination to our great spirituality. I mean, if we are really supposed to isolate from those who are not as mature as us in the faith, then how is anyone else supposed to grow if we're hiding that gift? You see, I've seen it happen to where people come into a church. They want expression right away. They want their gifts to be used right away. They want to be put on the platform right away. When people insist on them being known before they're platformed, they say, oh, that's religious. And then they'll go to some ministry online or television or radio or some online group that will tell them, yeah, you're gifted. They're religious. You should start now. And really what's happening is people who want to skip the process are finding a platform and they're able to do it because of online ministry, because of the way online ministry works, because of the way online connection works. Anyone can have a platform, whether they've gone through the process or not. Anyone can have a platform, whether they're accountable or not. Anyone can have a platform, whether they have a spiritual covering or not. And spiritual covering is biblical, not for control, but for guidance and protection and accountability and strength. And so what's happening is the enemy is telling people, you're the remnant. That's why you're isolated. And while thinking themselves the remnant, they actually become the rebellious because they're disobeying God's command to connect, to fellowship, to gather. They're using clever sounding, spiritual sounding excuses like, well, I'm just so anointed. I'm so gifted or nobody understands my anointing. And these are not healthy excuses. People online will even tell you, your pastor's not anointed like me. Your pastor doesn't do it like me. Your pastor doesn't flow on the gifts like I do. Your pastor can't take you to levels I can take you. That's dangerous. The moment people start talking like that, run the other direction because that is not the spirit of God. That is not of the Holy Spirit. Now I understand that many of us have experienced church hurt. So we call it church hurt or offense. And I want to speak to that a little bit because I think that's important too, because I don't want to be dismissive of the fact that there is such a thing as spiritual abuse. There is such a thing as leadership being too controlling and legalistic. There is such a thing as emotional pain that we experience as a result of relationships in the church. That's a fact. In fact, I did a whole message on how to identify a cult, how to know you're in a cult and not a church. So I believe that that's a reality and I don't want to be dismissive of anyone's experience or negative encounters. But we have to really process this from a biblical perspective. I'm not saying that you weren't legitimately hurt. I'm not saying that you weren't abused or emotionally wounded. That happens. What I am saying is the fact that people hurt you is not a good reason to dismiss God's design that will help you to fulfill your destiny. Now I don't want to condemn you, but I do want to bring some truth to light that will help you to process some things. Yes, people say things. Yes, maybe you went to a church, they all gossiped about you. Maybe you went to a church and the pastor was controlling, manipulative. Maybe the pastor abused you in one way or another. Maybe someone on leadership abused you in one way or another and nobody did anything about it. Maybe you didn't quite connect. Maybe you felt like an outcast. Now, there's two ways we have to look at this. One, we have to acknowledge that it's possible. I'm not saying this is definitely the case with you, but at least process it to where it's a question in your mind. At least let it be a question in your mind. The question being, did they really do something that was so horrible that I had the right to leave or I had the need to leave? Or was I reacting poorly to a somewhat negative situation? Was it their actions that caused me to leave and disconnect? Or was it my perception of their actions? Were they really religious and controlling or did I just not like the fact that they wanted me to go through the biblical process to be proven before I had a platform? And that's a big one because a lot of new believers, a lot of young believers, a lot of believers who never matured do use that as a point of accusation against leadership. In other words, they'll say, I have the gift of prophecy or I want to flow in deliverance or I want to flow in the gift of healing or I want to flow in this or that. And they haven't proven themselves. Nobody knows who they are. They're not accountable to anyone. No one knows their lifestyle. Nobody knows if they're living clean. And they expect to just come into the church and just be allowed to do whatever they want, pray for people during the altar call, pray for people during the worship, go up and give words to people while the pastor is preaching and so forth. And maybe it's not even that disruptive necessarily. But the idea is, biblically speaking, that a leader or someone who ministers in that way should be known and publicly proven before they are released to do so. Now this has nothing to do with evangelism. This has nothing to do with witnessing to your friends and neighbors. This has to do with ministry and edification and leadership and influence within the church. And the Bible does give a set of criteria for that. Now, sometimes people will look at that situation and because they weren't platformed when they want it to be platformed or because things in the service didn't happen the way they wanted it to happen, they dismiss that church and say, oh, that church is religious.  And I'm thinking, okay, they don't do deliverance enough or they don't do deliverance as often as you want to see it. Or they don't do healing enough. Okay. They don't do healing enough or they don't run a healing service like you want to see it. Oh, they don't, they don't allow prophecy to flow. They don't allow prophecy to flow or they didn't allow you to prophesy. See, there's a major difference here. And so we have to ask ourselves, why did we leave? Why did we disconnect? Why do we feel hurt? And we have to have the maturity to at least assess ourselves to see if in fact maybe we didn't quite process things correctly. Maybe it was ego that made us leave because we weren't platformed or released in the way we wanted to or as quickly as we wanted to be released. Or maybe someone did say something offensive, but they didn't mean to. Or maybe things were a little stuffy. Maybe you were a little rejected. Consider possibly, I know this is going to sound harsh, but consider possibly maybe you did come off a little weird. Maybe you were a little odd. And that's why maybe who were uncomfortable to connect with you? Maybe you weren't being relatable. Maybe they caught on to something that maybe you didn't. That's a possibility. I'm not saying that's definitely it, but at least consider that as a possibility. Now, once you've considered those possibilities that it could be on you, then we move into the other possibilities that maybe it was a bad situation. Maybe someone was mean. Maybe someone was inappropriate, but maybe it wasn't to the level to where you should have disconnected from either that church or even the body of Christ as a whole. And of course, we should never disconnect from the body of Christ as a whole. Ask yourself, was I maybe being too sensitive? That's a tough one. I know this is not easy. This is not easy. And there's nothing wrong with being sensitive. Nothing at all. People talk about the fact that sensitivity is a part of who they are. And that is a fact. You know, there are some things about you that God doesn't want to change. Rather, he wants to capture. For example, I'm an overthinker by nature. And because I'm an overthinker, I see the details in everything. And if I'm not careful, that can make me anxious and stressed out. I can feel pressure that no one's putting on me. And I'm looking at all these little details and I'm processing them. Sometimes that can be a negative thing. I over think or I think in great detail, I should say. Now, in some settings, that's good. When I'm writing a book, that's great. When I'm studying the word to deliver a message to you, that works out great because I see all the little details and I see all the ways that I can simplify it and present it in a very sequential way. You know, one, two, three here it is, right? That works great. But when I'm driving, that doesn't work so great because I see all the details. I see all the possible car accidents waiting to happen. So I get all tensed up, Steve, you can testify to this. And I get all tensed up and he could cut me off. Maybe he's going to miss his exit and try to cut across traffic. That person might slam on their brakes. That person's tire looks a little weird. That guy's on his phone. That person behind me keeps coming too close. It doesn't look like they're stopping in time. Right? I'm aware of all these things. And that can make me very tense. Right?  So my attention to detail, God doesn't want to change that. He wants to capture it. So you may be a very sensitive person. Good. That means you're compassionate. That means you notice when other people are hurting and nobody else notices them. You notice when people look like they're being left out. You notice when people look like they're being rejected. You notice when people look uncomfortable or sick or tired or disturbed in any way.  You're drawn to pray for them. You're drawn to talk to them. You're drawn to make them feel welcome. Right? That is your gift. So your sensitivity is not a curse. It's a gift that God doesn't want to change. He wants to capture.  You do allow it to go a little bit too deep in the heart. So maybe the people were a little unwelcoming, but maybe they perceived you as maybe just a little odd or maybe you're putting off signs that you don't want to be talked to. That could be one thing too. So it doesn't always all fall on the other individuals. Sometimes it falls on us too. And we have to ask ourselves, did I take that too harshly? Did I take that too close to the heart? Was I being unreasonable by cutting everyone off because of the circumstance? I mean, we are the family of God. And in families, there is tension. The closer you get to people, the more tension you'll experience. The closer you get to people, the more of the negative you start to see in them. That is a part of growing together that happens in marriages, business relationships, friendships, any relationship where you're drawing closer to someone, you begin to see flaws no one else gets to see. And they are positioned now to hurt you in ways no one else can hurt you. But that's where grace comes in, isn't it? That's where love and forgiveness and understanding love covers a multitude of sins. And in that way, you can capture that sensitivity, not change it, because you can't change how sensitive you are.  But you can capture that sensitivity now and say, okay, Lord, I acknowledge that what they said to me was wrong or hurtful or the way they left me out was wrong or hurtful or how they tried to control me or maybe pressure me that was wrong and hurtful. But you know what? I'm going to forgive them. I'm not going to look for an apology. I'm not going to wait for them to come to me. That may never happen. They may not even know they offended you. And you allow to some degree, some level of leeway for these people who will hurt you, because everyone will hurt you. Now, I am not advocating for abuse. I'm not saying you should allow people to abuse you. But I am saying that we should make room for people's mistakes, because there will be mistakes. People will hurt you.  Why? Because you're connected. It's a deeper connection. But realize, tension comes when you begin to draw nearer to people. That is why no marriage, no friendship, no business partnership can survive without grace, because you get to see the uglier side of people, the closer you get. You get to see the really dark stuff that nobody else even knew was there. And that's why it's a privilege to know someone, because we have the privilege to offer grace for those areas. Again, let me stress this. I'm not talking about abuse, but I am saying there's a spectrum to these things. Not every offense is a reason to say, that's it. I'm leaving. And if you have a pattern of leaving churches, if you have a pattern of leaving ministries, if there is a consistent sequence of you going to a place, loving it, finding a few flaws, getting a little bitter, allowing someone to offend you, and then leaving, if that's a pattern and you've repeated it two, three, four, five times, then that goes to show you that you're not approaching this properly. And I say that again, because I love you. I'm not condemning you. I'm not trying to attack you, but this is important that it's brought to your attention for your own good. Otherwise, you're going to go through that cycle again and again and again. You'll never find the perfect church. I heard one preacher say it was a little mean, but he said it and it was true. He said, if you ever find the perfect church, don't go there because you'll ruin it. And I thought, oh, that's true. If I found the perfect church and I went there, I would totally ruin it because I'm flawed. And that's just the reality. You're not going to find the perfect church. You're not going to find the perfect body of believers. You may not even agree doctrinally with everything the church believes. So you may go to a church and the pastor believes, maybe there's like nine out of 10 things you all agree on. And there's one doctrine that's not a major central tenet of the faith. And okay, maybe there's some disagreement. Let it be. But find people who can connect with you. By the way, you're not even supposed to be leaving the responsibility of your own spiritual growth in the hands of another individual. That's between you and the Lord, your spiritual growth. You go to church for accountability. You go to church for encouragement. You go to church to serve.  So that is why you gather. And as long as you have the right perspective on that, that you have a spiritual leader to guide you and to counsel you and to give you wisdom, not to control you, but to guide. Once you understand these perspectives, then because you put fewer expectations on others, you're disappointed less often. And that is how it should work. Grace, grace, grace, covering one another, because people will hurt you. Let me just break the news to you. I've been preaching for several years and I'll be preaching for several years more. Eventually I'm going to say something that you're going to go, hmm, I don't know how I feel about what he just said. I don't know if I like that. I don't know if I agree. I just ask you to give me grace. Eventually I may see one of your posts where I go, that was a little odd, but you know what? Grace. And again, I'm not talking about abuse, nor am I talking about allowing someone to be in your fellowship that doesn't hold one of the primary tenants of the faith. Of course, we all have to agree on the deity of Christ, his bodily resurrection, his heavenly ascension, the basics, the tenants, the foundational truths. We all have to agree on those, but beyond those, there's room for grace. There's room for forgiveness. Let me show you this portion of Scripture. Matthew 18, I'll start at verse 21. Then Peter came to him and asked, Lord, how often should I forgive someone who sins against me seven times? No, not seven times, Jesus replied, but 70 times seven. Therefore, the kingdom of heaven can be compared to a king who decided to bring his accounts up to date with servants who had borrowed money from him. In the process, one of his debtors was brought in who owed him millions of dollars. He couldn't pay, so his master ordered that he be sold, along with his wife, his children, and everything he owned to pay the debt. But the man fell down before his master and begged him, please be patient with me, and I will pay it. Then his master was filled with pity for him, and he released him and forgave his debt. What a wonderful thing. Verse 28, watch this now. But when the man left the king, he went to a fellow servant who owed him a few thousand dollars. He grabbed him by the throat and demanded instant payment. His fellow servant fell down before him and begged for a little more time, be patient with me, and I will pay it, he pleaded. But his creditor wouldn't wait, and had the man arrested and put in prison until the debt could be paid in full. When some of the other servants saw this, they were very upset. They went to the king and told him everything that had happened.  Shouldn't you have mercy on your fellow servant just as I had mercy on you? Wow. Then the angry king sent the man to prison to be tortured until he had paid his entire debt. That's what my heavenly father will do to you. If you refuse to forgive your brothers and sisters from your heart, whoa, convicting, convicting, forgive as we've been forgiven. I'm not talking about allowing abuse. I'm not talking about having fellowship with people who are in heresy and denying the fundamentals of the faith. I'm talking about grace for fellow brothers and sisters in Christ. I'm talking about grace even for your leaders, your spiritual leaders, who we all need. We all need spiritual leaders. I think sometimes we look at preachers and we don't see the behind the scenes. We don't see that the preachers we follow, at least the ones who are biblically sound, also have spiritual leaders. That's the way God designed it. It's the body. It's togetherness. It's union. The scripture talks about making allowance for one another's mistakes. What does that mean? It means being prepared to forgive before you're even offended. Forgiveness is not something that you do when someone offends you. Forgiveness is the condition of your heart long before you're offended. Forgiveness, you give before it's even happened. It's living in that state where you're ready to let things go. Not compiling a list. Not compiling criticisms. Not putting everyone through a system to see if they passed the test and allowing them to be connected with you based upon whether or not they passed that test that's going on in your head. But being ready to forgive, which means we will be offended. Jesus said 70 times seven. That means again and again and again. Why do you have to forgive someone more than once for one offense? That's because sometimes it's not the offense but the memory of the offense that reoffends us. And then we have to forgive them again once we've remembered it. We forgive them. We move on. It comes to memory. Seeds of bitterness start being sown and we have to remember in that moment, 70 times seven, not just for what they did, but for the memory of what they did. That's the choice. So again, I say this because I love you and I care. I'm glad you watch us online. I'm glad you enjoy this ministry. But start gathering again. Get back to church. Connect with the body of Christ. Connect with a spiritual leader. You need a pastor. You need leaders. You need fellow brothers and sisters in Christ. And you need to be leading others. We all need those connections. We all need mentorship, friendship and discipleship. I have mentorship pastors, leaders who pour into me, who hold me accountable, who rebuke me, who correct me in a loving, gentle, but necessary way. I have my friendships, people like Steve, people all around me who are my friends who can be real with me and tell me when I'm getting odd or getting out of line or becoming moody and mean. These are people who love me, who I can go to for prayer. We all need that. And I have people I'm discipling, discipleship, people who I can bring the word to and train and guide and pray with. And yes, even lovingly, though I don't enjoy doing it, but lovingly correct sometimes, we all need that. Don't listen to people who try to pull you away from that. That's a spirit. That's a spirit. And you'll notice that people who try to pull you away. And I'm not talking about anyone in particular. So don't think I'm talking about your former pastor or that church used to go to down the street or the person who's at your work. Because sometimes I think people take what I say and they use it as ammo to attack the people in their lives. I'm not saying this so you can attack. I'm saying this just so you can be aware.  Or I'm more gifted in this area than your leaders. Or your leadership, your church doesn't do it like I do it. They don't have power like I have. They don't know what I know. They just don't get it. We're the spiritually elite. They're not. Again, that's not the remnant. That's the rebellious. It's trying to pull you into isolation through flattery. Wonderful thing. I'm glad you enjoy this ministry. I'm glad you receive our content online, but this isn't going to cut it. You have got to gather with believers. And I know it's scary. Look, I'm not trying to be dismissive of the pain you've felt.  And remember, that's not an insult.  That can be difficult. That can be painful. That can be scary, but you have to do it. You've got to take that leap. Will you be hurt again? Absolutely. It's going to happen again. You're going to get hurt again. You're going to be disappointed again. Why? Because we're all human. We're all flawed. We all disappoint each other. And you've disappointed others too. That's not an attack. That's just to bring things into perspective. That's human. Isn't it amazing that when people offend us, we want justice and retribution. But when we offend others, we want grace and forgiveness and understanding. Let's extend that grace and forgiveness that we might be the body of Christ. Let's gather again. Let's hear what the Spirit is saying. Let's gather again. Father, help us do it. Help us to do it, Lord. We ask you this in the mighty name of Jesus. Heal our hearts, give us wisdom, perspective, strength, and peace. We ask this in the mighty name of Jesus. I want you to say it because you believe it. Say amen. Amen. It's time to forgive. It's time to gather.