Dr. Patrick: Well, you mentioned something earlier about the combination of perhaps even probiotics with bacteriophage or combination of antibiotics with bacteriophage. Can you explain to people what bacteriophages are?

Dr. Elinav: Absolutely. So bacteriophages are intriguing viruses that in contrast to the viruses that we all, you know, will suffer from these days are viruses that do not infect humans, and they do not infect any mammals or any eukaryotic cells. These are viruses that only infect bacteria and only attack bacteria. And these viruses are exceedingly common in nature. You can find many, many types of these viruses in our environment. And in fact, these viruses are the big enemies of the bacteria that surround us. So there's kind of an arms race between bacteria and these bacteriophages which attack bacteria, with the phages trying to kill bacteria and the bacteria developing a means of defending themselves against these viruses. It's an intriguing arms race which led to some groundbreaking discoveries such as CRISPR, which is, you know, one of these defense mechanisms which has been now massively exploited by science in order to genome edit, for example, genes of interest. This is what occurs in nature.

What we and others are thinking about in utilizing phages is that, you know, we have a huge unmet need in the microbiome field. Imagine that you find a member...a microbe, a bacteria in the microbiome which contributes to disease, contributes to IBD, contributes to cancer. What do you do? How do you get rid of these bacteria without harming the entire microbial surrounding that is so important for our health? Antibiotics are very limited manner of doing this. Antibiotics are non-specific. They have big adverse effects. They result in the emergence of resistant strains. So you cannot use antibiotics forever for your entire life. And many of the disease-causing bacteria in the microbiome are antibiotic-resistant. So what do you do? We have really an unmet need in having no means of taking out a microbe from the microbiome when we want to eliminate its bad effect.

And so we thought that phages could represent an attractive means of attacking a bacteria without impacting the entire microbiome because phages are very specific in their targets. A given phage would only attack a certain family of bacteria that has receptors which the phage recognizes. Now, I told you before that bacteria as part of this arms race have developed very strong defense mechanisms against phages. So if you give just one phage, it is very likely that the bacteria it would attack would generate defense mechanisms that would make it resistant against this phage, and so your therapy would not be successful.

So what we are doing, we are generating cocktails of phages that are targeting the same bacteria through different receptors or different mechanisms, and together these phages are killing the bacteria without allowing it to develop this antiphage defense system. And if this is successful and we're now in the midst of clinical trials, we would be able to really take a needle out of the haystack by targeting a single bacteria or a single type of bacteria without killing the entire microbiome and causing a substantial collateral damage.

Dr. Patrick: I wasn't aware that the bacteria were developing these defense mechanisms kind of you can think about it, you know, as similar to like antibiotic resistance in a way, I guess. What are your thoughts about then perhaps a future where we have this targeted type of treatment where in addition to maybe your bacteriophage cocktail that's targeting maybe, you know, one or perhaps two of the pathogenic type of bacteria and then combining them with a commensal type of bacteria in terms of, you know, allowing these precision probiotics in a way, perhaps, I don't know, maybe there's another name for it, but where you're actually allowing the types of bacteria that we know are commensal that maybe perhaps these people are not...are lacking and this is a way to actually get them to be colonized?

Dr. Elinav: Absolutely. I totally agree with what you suggest. And I think, you know, at the very young microbiome field, we're at the stage of understanding more and more of these interactions and the roles of different bugs and their communication systems, and also are increasingly busy in generating these new treatment options that hopefully would be put on the clinical shelf in years to come. But I am totally with you with the prospect that these new interventions would be combined with each other in contributing to what we call personalized or precision medicine. In other words, I would speculate that exactly as this suggests, a phage cocktail that would eradicate a family of bacteria from the microbiome would be successfully combined with a probiotic or maybe a precision or next-generation probiotic which would have the ability to colonize in a given person and would replace the niche now freed from this disease contributing microbe. So a combination between probiotics and phages between dietary interventions that would enable better probiotic activity and so on and so forth are what I anticipate for our future.

Dr. Patrick: What do you think the potential timeline would be on this, you know, ultimately replacing some of our current ways of like antibiotic treatment, for example, which is a very blunt sort of...you know, it uses a very blunt mechanism? As you mentioned, it wipes out everything, good and bad bacteria.

Dr. Elinav: Yeah. I mean, when we criticize antibiotics, we need to be very careful. You know, antibiotic interventions have amazingly transformed human lives, human health, human medicine. You know, they increased I think close to 30 years of life span within a century and at least partially took care of what is considered to be our number one, two, and three cause of mortality for millions of years. However, as we discussed previously, antibiotics are also associated with many prices that we pay, and we're just beginning to appreciate what they do to our microbiome. I don't think that the current medical interventions would be replaced, but I am very hopeful that we would be able to implement them with new precision data-driven approaches that would enable to increase the efficacy of these treatments and to be combined with them. As to the timelines...you know, there is quite a hype or overhype with the very young microbiome field, and partially, it's justifiable because, you know, in a matter of a decade and a half, we've discovered that our human body in addition to the 20 something thousand genes that are encoded in our human cells also contained 3 million and more bacterial genes that we didn't appreciate and we didn't know anything about. So this is for sure at least in my view a revolution, but we're only at the beginning of understanding this new world.

Remember that, you know, it took decades for cardiology to get to a point where, you know, catheterization and all the fancy interventions that are saving lives today have been matured and developed for clinical use. We're only talking about a very infant field, lots of research, lots of advances, but also lots of challenges. I don't want to give a time estimate, but I'm hopeful that within the next decade, we will start to see some interventions maturing in a data-driven way into the clinical shelf.

Dr. Patrick: That would be great. What role do you think or what role does the so-called virum play in human health? And do you think that science may yet find that viruses modulate health like in unexpected ways?

Dr. Elinav: Absolutely. And I think one of...the only reason we're so much into bacteria in the microbiome especially in the gut microbiome is because we have the tools, and we're a little bit lazy in kind of searching "under the lamp" and going where it's comfortable. But the more we probe into the virome and the fungome and the parasitome, we find that there are whole kingdoms within our microbiome which are understudied and underappreciated, but nonetheless, I think that they have potential huge impacts on how the human body behaves in health and on the risk of developing disease and even on other kingdoms within the microbiome. So there is huge amount of exciting research to be conducted in decoding these roles of these other kingdoms, and, you know, the future will tell us.