A New Class Of Living Medicines

June 22, 2016 7:08 AM

Hacking Gut Bacteria Could Be The Future Of Medicine "In new research, biologists and medical engineers at the Massachusetts Institute of Technology are doing just that by reprogramming gut bacteria to act as “living therapeutics” that can correct the metabolic dysfunctions underlying certain ailments." [...] “Synlogic is programming these probiotic microbes to consume ammonia or phenylalanine,” Collins explained in a statement. “They are reaching levels that are expected to be clinically meaningful, which is quite remarkable.” Ultimately, Synlogic is looking to create synthetic biotic treatments for not only rare genetic disorders but also for a range of ailments with metabolic components, including autoimmune diseases, cardiovascular disease and central nervous system disorders.
posted by OnceUponATime (19 comments total)

There was an interesting segment on "psychobiotics" -- a fairly ugly neologism for trying to treat psychological problems by influencing the but microbiome -- toward the end of this episode of the BBC's Science In Action podcast. Still at the stage of "seems to work in mice, tantalising preliminary data in humans", and I haven't had a chance to go and read the actual papers yet, but it's very interesting stuff at first glance.
posted by metaBugs at 7:24 AM on June 22, 2016 [3 favorites]

THE CORPORATIONS WANT TO PUT GMOS IN YOUR BODY!!!1
posted by biogeo at 7:50 AM on June 22, 2016 [4 favorites]

But seriously, this is pretty cool, and probably what actual nanotechnology enhancements will look like.
posted by biogeo at 7:51 AM on June 22, 2016

Its important to keep in mind is that in the last 20+ years of extremely active research, no one has yet to demonstrate that they have a culture of anything that will actually positively affect the health of either healthy or sick volunteers when given live that doesn't also have the exact same effect when given dead. The cultures just don't typically survive very long in the gut as its like sending sheep that have been domesticated in an Erlenmeyer flask away from predators, viruses, or competition to a sack full of hardened wolves who are there because they are the survivors of a deathmatch that has lasted as long as their human host has been alive. Paradoxically though, even dead many probiotic cultures have been show to possess statistically significant if small positive effects on either or both healthy and sick volunteers. The most plausible theoretical model for why this is the case posit that probiotic cultures, live and dead, serve as especially effective food for feeding the cultures you already have. The field of using live probiotics to treat sick people took a massive hit when a Dutch trial demonstrated that when probiotics were given to patients with acute pancreatitis who were sick enough that the bacteria flourished, the treatment killed a bunch of people.

For genetically engineering gut microbes with advantageous traits to be a thing we will need to use bacteria that can compete with the wolves in our guts that we already have, which means undomesticated cultures, and we'll need to have some assurance that those cultures won't hurt people without domesticating them. The only logistically feasible way I see around this conundrum would involve genetically engineering temperate E. coli phage like lambda, viruses that infect a ubiquitous gut bacteria that we understand really well. Essentially, all "live" phages can go through what is called a lytic life cycle when they infect a cell, shut down host metabolism and substitute their own, replicate their DNA, construct and pack viral particles, and then lyse the cell for the new particles to hunt for more cells. This is obviously extremely lethal, which is great for us, but some phages (known as temperate phages and somewhat analogous to retroviruses) can also go through a lysogenic life cycle where instead of shutting down the hosts' metabolism, they turn off their genomes and wait. This creates what are call lysogens, sort of a phage/bacteria hybrid, where the phage hides and lets the host replicate it with its own chromosome when it divides. Now these temperate phages have an interest in their bacterial hosts doing well and sometimes have exotic genes, which get expressed independently of the host lethal ones, that often contribute to host success in weird situations ^{(SAFETY CAVEAT)}.

I think for this field to move forward we'll eventually need to construct temperate phages that will be able to integrate into their host genomes but lack the machinery to get out and produce a productive infection, something we've been able to do since the 50s, and provide them with a genetic payload that will have some use, which is now possible with current technology. This way an engineered temperate phage consumed by a patient will modify the patient's own healthy microbiota to digest phenylalanine, or release anti-inflammatory compounds, or produce a diagnostic dye should some compound be present - such that fluorescent green poop means cancer or whatever.

^{(SAFETY CAVEAT)} In nature genes carried by these viruses are responsible for all sorts of things like most of the photosynthesis that happens on Earth, but also a whole lot of our bacterial diseases. Thus, for example, cholera isn't really caused by Vibrio cholerae like you may have heard but instead by the CTX-φ and TLC-φ phages. Vibrio are, for the most part, planktonic marine bacteria content to scavenge for low levels of organic substrates in the oceans and leave us well enough alone. However, when infected by the temperate CTX-φ and TLC-φ phages, Vibrio cholerae suddenly gets a pathogenicity cassette of DNA with a type IV pillus and the profoundly nasty cholera toxin. Vibrio cholerae is like the pleasant dude who rolls around on the back of a truck in a jumpsuit picking up the garbage in front of your home, CTX-φ is the agent that turns him into a poison-syringe/grappling-hook wielding madman looking to feed off of your guts. These viruses would have the theoretical capacity to use the escape mechanisms of a wild virus already present in one of its hosts to escape, and maybe plausibly take virulence factors with it, but the temperate viruses already present in the gut already have that potential.

posted by Blasdelb at 7:55 AM on June 22, 2016 [46 favorites]

I was hoping you would comment, Blasdelb, and now I'm just hoping I can better understand your comment if I re-read it a couple more times. :-)

It seems like the Synlogic engineered bacteria have already been tested in mice -- wouldn't they face the same kind of "wolves" in mouse-guts as in human-guts?

You don't think we'll be able to put gut bacteria to work until we can put the gut bacteria that are already in us to work, rather than trying to replace them with new ones?

I guess I am imagining a dose of really strong antibiotics followed by an enema... Thinking that's probably what they are already doing with the mice?

My kids have PKU so I have a special personal interest in whether this is just hype or is the really interesting and novel development it seems like it could be (and not just for PKU.)
posted by OnceUponATime at 8:09 AM on June 22, 2016

"There was an interesting segment on "psychobiotics" -- a fairly ugly neologism for trying to treat psychological problems by influencing the but microbiome -- toward the end of this episode of the BBC's Science In Action podcast. Still at the stage of "seems to work in mice, tantalising preliminary data in humans", and I haven't had a chance to go and read the actual papers yet, but it's very interesting stuff at first glance."

Another mefite memailed me a while ago to ask me to look into it for them so they could better understand how this review, which is a great start, relates to their kid,

The adoptive transfer of behavioral phenotype via the intestinal microbiota: experimental evidence and clinical implications
Intestinal commensal bacteria or their products may be used to treat CNS disorders.
There is growing interest in the ability of the intestinal microbiome to influence host function within and beyond the gastrointestinal tract. Here we review evidence of microbiome–brain interactions in mice and focus on the ability to transfer behavioral traits between mouse strains using fecal microbiota transplantation (FMT). Transplantation alters brain chemistry and behavior in recipient ex-germ free mice, raising the possibility of using FMT for disorders of the central nervous system, and prompting caution in the selection of FMT donors for conditions that may include refractory Clostridium difficile infection, diabetes and inflammatory bowel disease in humans.
•Behavioral phenotype can be transferred via the intestinal microbiota in mice.
•Changes in behavior in recipient mice are accompanied by changes in brain chemistry.
•Investigation of the intestinal microbiome in central nervous system (CNS) disorders is warranted.
•Donor screening for fecal transplants should exclude CNS and psychiatric illness.

If anyone would like access to it or any of the other linked research, please feel free to memail me with the desired paper, an email address I can send a PDF to, and a promise not to distribute that PDF further. If you then came back to the thread with questions or things you learned that would make me embarrassingly happy, but no pressure.

I hope the subject will be a lot more clear over the next year or two, looking through the authors names in the references of this review it seems like a lot of people who used to be doing probiotics when that was more exciting are now studying this, and their papers have been publishing pretty astonishingly well, so it looks like we can look forward to more work being done. Behavioral/neurological microbiology was beginning to be a thing back in the '90s before it kind of fizzled out with a lack of results that could be described as both exciting and solid, at least beyond a few clearly demonstrated but very narrow conclusions - like how you can treat some brain disorders in mice with antibiotics in ways that don't make sense otherwise.

The germ-free and SPF mice results that the article discusses aren't so convincing to me as Germ-free, and even SPF mice, are pretty sick critters - so showing them acting weird because of general microbiota related ill-health could for most of those papers just as easily be explained as a trivial finding. Microbiota are intricately involved in mammalian metabolism, almost like another organ, and so saying that starving critters act weird is maybe not so novel even if it does help to establish the case for everything else. The various papers showing that you can turn crafty, cautious, misanthropic, and anxious Balb/c mice into dumb, trusting, and cuddly NIH Swiss mice and vice versa by switching out their flora, however, make a pretty strong case that there might be something to this field that we didn't catch in the '90s. The various human results that the article talks about are also a lot less convincing with the methodological problems the authors are careful to either explicitly or obliquely refer to. Overall though, I think those authors make a pretty decent case for the only two conclusions they actually make, that some serious caution related to potential neurological and psychological conditions in fecal donors is warranted because we might just be playing with fire (that is, in addition to poop), and that someone should probably put together some better designed studies seeing how fucking with the microbiota of people with neurological and psychological disorders affects things.

There is a lot of crazy and woo around all of this, like how the modern anti-vaxx movement is built around Wakefield's clearly fraudulent connection between the gut and the MMR vaccine, as well as various diets that all lack clear evidence. However, the basic idea that some neurological disorders can be positively or negatively affected by the microbial composition of the gut, and thus diet, is all more than essentially plausible - even if there is no clear evidence pointing to any particular neurological disorder being affected this way, or microbial composition that can have such an effect, or diet that can cause that composition. A solidly convincing and useful case should require a clear demonstration of at least the first two, which modern sequencing should be able to either demonstrate or not. The effects of something like that being found are kind of fun to think about though, psychiatric facilities would need to get a lot more particular about poop, the ethics and logistics of fecal transplants for both C. difficile problems and psychiatric/neurological disorders would get really weird really fast, and "splashback" would turn into a simultaneously dead serious and hilarious epidemiological concern.

The logistics alone surrounding modifying bacteria, which would have the potential to transmit through populations if effective, would disorienting enough without even considering the profound ethical questions involved.
posted by Blasdelb at 8:10 AM on June 22, 2016 [12 favorites]

Let's start making our gut bacteria express CRISPR and really get the reporters talking.
posted by maryr at 8:15 AM on June 22, 2016 [2 favorites]

"It seems like the Synlogic engineered bacteria have already been tested in mice -- wouldn't they face the same kind of "wolves" in mouse-guts as in human-guts?"

"You don't think we'll be able to put gut bacteria to work until we can put the gut bacteria that are already in us to work, rather than trying to replace them with new ones?"

All I seem to be able to find are abstracts that aren't specific about the strains of mouse used, whether these are mice with healthy microbiota we're talking about, or how long they managed to productively colonize the mice - but experience with humans doesn't point to colonization with active bacteria being a trivial thing to accomplish using domesticated strains. Have you found a more complete reporting of what they've accomplished so far?

"I guess I am imagining a dose of really strong antibiotics followed by an enema... Thinking that's probably what they are already doing with the mice?"

This is essentially what is done with fecal transplants, which involves taking complex undomesticated cultures (a euphemism for poop), from healthy donors and implanting it into people with various kinds of serious bowel complaints.

During the domestication inherent to maintaining a culture in a lab, bacteria will pretty rapidly lose their metabolically expensive defenses against phages, mechanisms for interacting with their hosts immune systems, and mechanisms for interacting with bacteria they're not clonally related to as they evolve to succeed in the lab environment where none of these things are an issue. If the goal is to treat healthy mice, and thus eventually healthy humans, that don't need to be maintained in a constant state of dysbiosis in order for the treatment to work, this the domestication of strains then presents a challenge. I'm not sure what Synlogic's plan to overcome this challenge is, but I'd be curious to find out, Tim Lu isn't the kind of researcher I'd expect bullshit from.
posted by Blasdelb at 8:38 AM on June 22, 2016 [2 favorites]

Tim Lu isn't the kind of researcher I'd expect bullshit from.

Mouse shit, yes.

I'm so sorry.
posted by Mooski at 8:46 AM on June 22, 2016 [3 favorites]

I maybe understand an eighth of what is being said here, but being married to somebody with gut disorders/allergies/immune issues, I'm obviously very interested in what might come out of this research.
posted by emjaybee at 8:50 AM on June 22, 2016 [1 favorite]

Have you found a more complete reporting of what they've accomplished so far?

Not really, but their website has a few hints. It says:

When administered regularly, a therapeutically engineered EcN will blend with the existing flora and make up a small portion of the overall microbiome without specifically colonizing in the gut. Just as other groups of bacteria in the microbiota carry out specific and essential activities, a therapeutically engineered EcN will also fulfill an essential metabolic function that is programmed into the organism. (Synlogic uses EcN as one of the chassis for building its synthetic biotic medicines).

And it also says "synthetic biotics shift metabolic functions from a diseased organ to a stable, non-colonizing fraction of the microbiome."

For the application that's most of interest to me, it says: "SYNB2010 is highly effective in reducing levels of blood phenylalanine and has demonstrated robust activity in validated rodent models of PKU. [...] Synlogic is rapidly advancing SYNB2010 into development with the goal of filing an IND or equivalent to initiate clinical trials in people with PKU in the next 12-18 months."

I don't know how well that addresses the issues you're raising. I can't tell whether they're explaining their solution, or just claiming "Yes, we've solved that problem" but doesn't it seem like they're at least doing the latter, with this whole "Stable, non-colonizing fraction" thing? And if they're really moving to clinical trials in people so soon, one hopes it must have been a pretty realistic rodent model they were working with?
posted by OnceUponATime at 8:51 AM on June 22, 2016

I guess maybe "administered regularly" is a clue, there, about how they keep their innocent little cultured sheep from being wiped out by the wild wolves.... They just keep sending in more sheep?
posted by OnceUponATime at 8:54 AM on June 22, 2016

THE CORPORATIONS WANT TO PUT GMOS IN YOUR BODY!!!1

This cutting attack on people skeptical of corporations and GMOs would probably be more devastating if corporations weren't the ones pumping food full of antibiotics, necessitating things like gut bacteria transplants.

Also, glad to see science has finally dumped healthy skepticism in favor of unbridled faith.
posted by entropicamericana at 8:56 AM on June 22, 2016 [2 favorites]

In all seriousness, this is amazing stuff - I remember as a kid seing a filmstrip (remember those?) talking about how how powerful adrenalin was, demonstrating by dosing a cat with a small amount and the next frame was the cat looking like it was ready to kill the world.

From that point on, I guess I internalized the idea that all any of us were was the sum of a really, REALLY complex set of chemical reactions. Now it looks like gut flora may play a huge part in which of those chemicals get into the mix - the idea of taking control of even a small part of that is exciting as hell.
posted by Mooski at 8:58 AM on June 22, 2016 [1 favorite]

Also, glad to see science has finally dumped healthy skepticism in favor of unbridled faith.

Finally? Do you even remember the '50s?
posted by Apocryphon at 9:40 AM on June 22, 2016 [1 favorite]

entropicamericana: "This cutting attack on people skeptical of corporations and GMOs would probably be more devastating if corporations weren't the ones pumping food full of antibiotics, necessitating things like gut bacteria transplants."

When people talk about "pumping food full of antibiotics" what we're talking about is the practice of feeding meat animals, dairy cows, and egg laying hens antibiotics to treat infections and also to bulk up meat animals as large doses of antibiotics mysteriously cause animals to bulk up more quickly. It is super illegal to put antibiotics in food, or to give animals antibiotics in such a way as any meaningful traces of those antibiotics would end up in food. However the practice still has incredibly serious implications because routinely providing agricultural animals with massive doses of antibiotics will produce antibiotic resistant strains of bacteria in those animals that could then spread zoonotically to directly agricultural workers and spread the genetic cassettes responsible for antibiotic resistance into the environment. At the moment antibiotics are being used agriculturally in the kinds of vast quantities that could be reasonably expected to alter the prevalence of antibiotic resistance environmentally, and thus indirectly impact human health in really big and important ways by spreading that resistance to human pathogens we'd then no longer be able to treat so effectively.

It is important to keep in mind however, that the risks involved in the use of antibiotics in agricultural animals are very dependent on the antibiotic being used, where drugs with wider mechanisms of action that don't generate resistance or drugs with no safe application in humans probably shouldn't be banned. There is also the easily nebulous but important distinction between therapeutic and 'prophylactic' uses, where it makes no sense to keep large animal vets from treating a prize racehorse or a rural family's one cow for disease but the large operations that are the plausible problem can always ensure that their animals get sick in order to fatten them up with antibiotics. The FDA and USDA have thankfully been getting a lot tougher about negotiating and enforcing the unfortunately nebulous distinction between what should be ok and what shouldn't over the last couple of years, which has benefited my own field as farmers look to phage for alternatives to the antibiotics they can no longer use. However, the lines that need to be drawn between what is ok and what isn't are going to necessarily be difficult to distinguish in a way that isn't really well served by overly simplistic activism. I have yet to see anything written by the press for the general public that even attempts to honestly tackle the genuinely complex question of which antimicrobials should be banned from which agricultural uses and in which contexts. We genuinely need an informed public eye acting as a watchdog to keep the agricultural industry honest and healthy but, like with so many other complex regulatory issues, eyes that compulsively see danger everywhere are no longer actually watching.

The kinds of problems that necessitate things like gut bacteria transplants have nothing to do with the problems associated with shitty uses of antibiotics in agriculture though. Fecal transplants are actually relatively scary for a lot of complex reasons relating to how poorly we understand the fire we're playing with, and at least in the US they're generally only allowed for addressing problems that are just plain much scarier. The classic example that convinced the FDA to lift its short lived moratorium on any fecal transplants are C. difficile infections. They can happen spontaneously, and likely have since pre-history, but are primarily seen in already sick patients who have needed antibiotics for extended periods of time. While it is ordinarily out-competed by healthy microbiota, as a spore forming organism capable of growing slowly, C. difficile is pretty well adapted to persisting through antibiotic regimens - causing it to show up in these patients when we kill off everything else. When allowed to grow however, it creates a hideous spiral where patients need to be on antibiotics to control the growth of C. difficile but those very same antibiotics prevent the growth of healthy bacteria. It is difficult to overstate how awful these infections are, the smell of C. difficile consuming a human gut alone is ...overpoweringly unfortunate. What fecal transplants do is break the cycle by hopefully replacing it with an already healthy one.

Fecal transplants are also being explored in Europe, where regulators are in general a lot less cautious about the significant unknowns, for all sorts of other gut complaints - but none of them plausibly have anything to do with the problems that can be associated with agricultural uses of antibiotics.

entropicamericana: "Also, glad to see science has finally dumped healthy skepticism in favor of unbridled faith."

For any kind of active management of the metagenomes of our gut microbiota to have any hope of producing productive effects and not hideously awful ones, we will need the kind of healthy skepticism that our regulatory apparatuses have gotten remarkably good at over the years having learned from what doesn't work. However, we'll also need at least some measure of it from the general public. We will need eyes that are actually capable of watching and learning, rather than either the knee-jerk trust or compulsive conspiratorial thinking that seems to always dominate discussions about complex regulatory issues.
posted by Blasdelb at 10:10 AM on June 22, 2016 [13 favorites]

entropicamericana, I apologize that I seem to have caused offense with my admittedly stupid throwaway joke. Please allow me to clarify the point behind it.

This is a promising advance in new potential therapy for otherwise intractable human diseases. But because it involves genetic modification of bacteria, I think we can safely predict that there will be a knee-jerk anti-GMO response against it. This is unfortunate, since as is the case with GMO foods, this political opposition will come at the cost of real people's health and wellbeing.

I have no interest in defending corporations or the use or misuse of science by capital, but I do want to note that it is scientists who have provided one of the louder voices to call attention to the costs of overusing antibiotics in agricultural production. I'm also not aware of any evidence that agricultural overuse of antibiotics "necessitates things like gut bacteria transplants." The real risk is the evolution of antibiotic-resistant strains of bacteria which we can't treat when they cause infections, and quite possibly the additional effects of antibiotic compounds and their metabolites at microdoses as low-grade endocrine disruptors.

On preview, I'll stop there since Blasdelb probably covered everything else I was going to say.
posted by biogeo at 10:13 AM on June 22, 2016 [2 favorites]

On postview, I was correct, and naturally did so better than I could.
posted by biogeo at 10:16 AM on June 22, 2016

For genetically engineering gut microbes with advantageous traits to be a thing we will need to use bacteria that can compete with the wolves in our guts that we already have, which means undomesticated cultures

Not necessarily; if you take the probiotic at every meal, for instance, it doesn't have to outcompete anything in your gut, it just has to hang around long enough to accomplish some function on its way through. And a finite half-life is kind of a win-win for drug makers and regulators alike. (We don't really understand the rules governing which strains/species will stick around in what environments yet, though, so even figuring out what's going to persist at all is kind of a difficult thing to figure out.)

no one has yet to demonstrate that they have a culture of anything that will actually positively affect the health of either healthy or sick volunteers when given live that doesn't also have the exact same effect when given dead ... The most plausible theoretical model for why this is the case posit that probiotic cultures, live and dead, serve as especially effective food for feeding the cultures you already have.

I think an even more compelling explanation may be immunomodulation. Those cultures don't provide a lot of calories or even resistant starch relative to dietary sources. They do, however, provide specific molecules known to be involved in immune signaling (e.g. lipopolysaccharide, peptidoglycans, anything else acting on Toll-like receptors) and heat-killed microbes have been shown to have effects on immune signaling comparable to live microbes. Influencing microbial cell adhesion might be another factor.
posted by en forme de poire at 12:35 PM on June 22, 2016 [4 favorites]