masthead2017v2.jpg 

April 11 - 13, 2017

Boston, MA USA

Translating the Microbiome From the Bench to Bedside: Challenges and Opportunities in Developing bioTherapeutics and Diagnostics

The Official Blog of the Annual Translational Microbiome Conference

The official blog of the Annual Translational Microbiome Conference provides readers with information, insight and analysis regarding the microbiome.

Key Innovations in Microbiome Therapeutics: Translating the Science into the Clinic

These microbiome insights brought to you by Dana Barberio, Principal at Edge BioScience Communications and Arrowhead Publishers and Conferences.

These are glamourous times for the microbiome space. The microbiome has captured the heart of the media, and this red hot scientific area has spawned intense attention from researchers, courtship by investors and a myriad of unique business opportunities and partnerships among companies ranging in size from small start-ups to global pharmaceutical companies. Multiple companies with therapeutics in clinical trials are jockeying for position in a heated race to market, many with their lead candidate targeting Clostridium difficile (C. diff), and with a wide variety of other applications in the queue. Key players in both the scientific and business side of the microbiome space will be gathered together at Arrowhead Publishers’ 3rd Annual Translational Microbiome Conference, taking place in Boston, Massachusetts April 11th-13th 2017. Let’s capture an eagle eye view of that conference by looking at recent advances in the microbiome space, and some of the key topics represented at the conference.


Scientists are rapidly discovering the microbiome’s sophisticated and widespread network of interactions that affect human metabolism, neurology, the immune system and skin. The microbiome plays a role in radically different areas of health, such as nutrition, early childhood, hygiene, infectious disease and chronic health conditions. There is evidence that dysbiosis in the gut is a factor in an astounding array of conditions and diseases: inflammatory bowel disease (IBD), atopy, asthma, cancer, obesity, Type 2 Diabetes, fatty liver disease, and neurological disorders.

Hot Areas of Scientific Research
While investors, companies and the media are currently having a love affair with the microbiome (I decline to call it ‘hype’), arguably the science has yet to live up to the expectations. But the scientific foundation is gradually being constructed and is forthcoming with many recent studies. A January 2017 small scale clinical study of Autism Spectrum Disorder provided evidence of improved ASD symptoms resulting from Microbiota Transfer Therapy. A Dec 2016 Caltech study in a mouse model of Parkinson’s disease established that gut bacteria not only contribute to the disease, but apparently play a causal role. There are future market opportunities for treatment of anxiety, depression, and autism that may evolve from an understanding of the science behind gut-brain interactions. Emeran Meyer, MD and professor at UCLA, discusses these topics in his book “The Mind-Gut Connection: How the Hidden Conversation Within Our Bodies Impacts Our Mood, Our Choices, and Our Overall Health.”


IBD has been linked for decades with dysbiosis in the gut microbiome, and more recently scientists have been gaining a deeper understanding. Laying a foundation for defining the mechanisms for this was a March 2014 study by Dirk Gevers of Janssen Human Microbiome Institute with a multi-cohort study comprehensively defining the microbiome diversity landscape of Crohn’s Disease and identification of potential biomarkers. A February 2017 study provided evidence that IBD can be distinguished as two subtypes with distinct microbial signatures, as Crohn’s Disease and Ulcerative Colitis. These microbiome signatures are critical in the development of therapeutic targets.


Another hot area is in the immunotherapy space: predicting patient response and modulating gut bacteria to optimize treatment. Research at MD Anderson Cancer Center in February of 2017 implicated gut bacteria in melanoma patients’ response to PD1 checkpoint inhibitor immunotherapy. Patients that responded to the immunotherapy had a greater diversity of gut bacteria and larger numbers of a specific bacteria than those who did not respond.


With a partnership that will translate microbiome research in immunotherapy into the commercial space, Bristol Myers-Squibb and Enterome entered into an immuno-oncology focused partnership in November of 2016 for the discovery and development of microbiome-derived drug targets and biomarkers to be used in cancer therapeutics and companion diagnostics.


We’ll hear more about these topics at the conference.

Areas with Great Market Potential
From a January 2017 review article by University of Chicago’s Jack Gilbert (conference keynote speaker) and Thomas Kuntz, a hot area in need of more research is in drug response and interaction, as there are already more than 60 drugs known to interact with the microbiome. Enhancement of personalized treatment in a clinical setting will involve a deeper understanding of bacteria’s role in drug metabolism and host variation to drug response, in particular as it corresponds to an individual’s microbiome (and host ‘omes’). For example, a March 2014 study found genes in the gut bacteria Eggerthella lenta that can be used as predictive microbial biomarkers for inactivation of the cardiac drug digoxin, with potential application in studying drug pharmacokinetics and clinical interventions.


Another area with large market potential according to Gilbert and Kuntz is in addressing alternatives to the widespread overuse of broad-spectrum antibiotics and the resulting health-endangering spread of bacterial resistance. One alternative involves targeting specific bacterial pathogens or enzymes with precision antibiotics and therapies. Multiple companies are focused in this area, including Eligo BioscienceSecond GenomeAvidBioticsC3J Therapeutics, and EpiBiome, all of whom have platforms which selectively kill off harmful bacteria while protecting commensal bacteria.


Of course, precision prebiotics and probiotics are another hot focus area, which may involve a systems biology/bioinformatics approach such as used by Seres TherapeuticsEvelo BioSciencesMetabiomics and others.

Empowering Deep Level Understanding with Big Data
If you consider the complexity of genomic and environmental factors such as lifestyle, diet, toxins, polypharmacy, metabolomics, and the gut microbiome, it’s clear that we need some high level bioinformatics to interpret the enormous amount of data for translation into the clinic.
Microbiome-based precision medicine will stem from a deep level understanding of the mechanisms involved in the complexities of host-microbiome interactions. The ultimate level of analysis may come through a systems biology paradigm, which uses mathematical/computational models to analyze large datasets and simulate system behavior with network-based analyses of the interactions between different types of ‘omics’ data (such as genomics, transcriptomics, proteomics and metabolomics), providing novel insight into complex biological systems, new biomarkers and enhanced drug discovery and development. For example, a March 2017 article proposes an ‘omics’-based precision medicine approach for elucidating genomic and metabolic interactions in the microbiome-gut-liver axis. These Big Data practices are expected to transform clinical practice.


Jack Gilbert, one of the keynote speakers at the conference, has a brand-new startup, Gusto, which produces formulations of probiotics. They use a computational modeling platform, GUST+, which predicts bacterial interactions and their effect on the immune system and human health by compiling data from human studies and running thousands of simulations.


One technical hurdle faced in the microbiome therapeutics space is in securing precise taxonomic assignments for bacteria based on sequence alignments, which is a computational challenge for both 16S and shotgun libraries, due to the short Next Gen Sequencing read lengths. This creates an obstacle for identification of reliable clinical biomarkers and hinders follow-up experiments. James White of Resphera BioSciences, at the conference, will discuss a novel approach for high-resolution microbiome profiling of 16S sequence data, which provides accurate species-level characterization.

Databases and Specimen Collection
In the case of Fecal Microbiota Transplantation, the rapid entry into clinical practice preceded the science. The FMT National Registry, a public-private collaboration, was established as a database of clinical and patient-reported outcomes intended to establish the short- and long-term safety and efficacy of FMT.
Another organization, The BioCollective, provides a resource for obtaining human fecal specimens paired with data for use in microbiome research and development, eliminating the need for researchers to recruit individuals for studies.

Frontrunners in Clinical Trials
As leaders in the field rapidly uncover the mechanisms driving the microbiome’s role in disease, the foundation is being established for capitalizing on the science in order to decrease disease and improve health. Farthest along in clinical trials is Rebiotix, with a drug candidate, RBX2660, for recurrent Clostridium difficile in Phase 3 trials. Their Microbiota Restoration Therapy (MRT) platform, which targets other diseases as well, delivers a broad spectrum of live microbes into a patient’s intestinal tract for rehabilitation of the microbiome.


At the conference, we will hear first-hand from a few of the companies in the trenches of clinical trials - Rebiotix, Seres Therapeutics and Vedanta Biosciences - on regulatory considerations, customer expectations, messaging implications, and other critical factors involved in developing and launching microbiome therapeutics.


Partnerships and Regulation
While the scientific and technical resources are critical, we will also hear about the equally critical business side - the role of partnerships as well as regulatory and patent issues.

Since probiotics have widespread acceptance by clinicians and the general population, microbiome therapeutics is at an enviable jumping off point for some microbiome companies. However, the FDA is of course involved in prescription products. The criteria for FDA approval involve defining bacterial colonization, what effect colonization has and how fast it occurs, and the pharmacokinetics/ pharmacodynamics, among other factors. This is for live bacteria. The addition of genetic manipulation adds another level of complexity in gaining approval.


Big Pharma has taken a huge interest in the microbiome space, with numerous partnerships. Among those leading the way was a partnership in 2014 between Second Genome and Pfizer, in which the two companies engaged in a large observational study with the goal of gaining a better understanding of the connection between obesity, metabolic disorders and the microbiome. Three major pharma investment funds have invested in Second Genome. Second Genome is partnering with Monsanto in applying big data science, bioinformatics and machine learning to drive discovery of microbiome-based solutions that can help farmers better manage on-farm challenges.


In 2015, Janssen and Vedanta Biosciences struck a deal involving Vedanta’s out-license of its most advanced clinical candidate VE202: a mix of bacteria from the Clostridia subspecies that are a potential treatment for several IBD disorders: Crohn’s disease and ulcerative colitis.


Most recently, in November of 2016, the aforementioned Bristol Meyers-Squibb and Enterome established an immuno-oncology focused partnership.


Join us to hear more on all of these topics and the many exciting opportunities and challenges in the microbiome space at Arrowhead Publishers’ 3rd Annual Translational Microbiome Conference. We will see you there!

 

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The Mike Rowe of the Microbiome Space

By Martha Carlin, Chief Executive Revolutionary, The BioCollective

In every industry there are dirty jobs that must be done to fuel the business.  Business Insider recently published “Small World: 20+ Startups Targeting the Microbiome” a review of just some of the exciting new microbiome ventures that are primarily focused in four key areas - diagnostics, genomics, dietary supplements, and intestinal health/disease targeted therapies.[1] These ventures use convenient and available samples for their initial R&D obtained from relationships with universities, hospitals and friends and family. When a promising discovery is made from that initial research, it may be necessary to test it on a larger and more representative population and this is where the The BioCollective comes in. 

Everybody poops.[2] But nobody wants to have to “deal with it.” One of the biggest barriers to accelerating microbiome research is getting a sample from everyone doing their duty! (or dooty depending on the age of your audience!) So we approached the problem from the Pooper’s perspective. We created a kit that is easy to use in the comfort of your home, ick-free and even a little bit fun. There is no scooping, probing, dipping or mixing needed. There are no messy plastic “hats,” bowls or containers to be disposed of. The process is seamless with nothing left behind, so to speak. Our BioCollector patent-pending design collects the entire sample, keeping it viable and ready to leverage into any number of research pipelines. Once the live sample reaches our lab, it is divided into smaller portions and cryopreserved enabling many types of research on the same sample. One sample can generate data from phage to fungi and culture. We are much more than DNA! 

Subject recruitment and sample collection is one of the top five cost drivers in research, but when we do the “dirty job” of providing samples to support microbiome research we can save thousands of dollars from the process. The BioCollective has made pooping a fun and profitable way to participate in microbiome research. We use engaging and innovative ways to get people of all ages and walks of life to become members of The BioCollective with the goal of building a microbiome resource full of samples that are actually representative of the US population. We go beyond the narrow and limited population of WEIRD (white, educated, industrialized, rich and democrat)!

In exchange for providing a sample to aid in research members receive a share of revenue from sample sales and feedback on where their sample is being used. We also provide the member with options for learning what’s in their gut from a basic 16S analysis to whole genome sequencing.  For the super curious, we can provide specialty analysis such as metabolomics, 18S and transcriptomics through our sequencing partners.  

Learn more about what we do and how you can become an active participant in the field of microbiome research at Arrowhead’s 3rd Annual Translational Microbiome Conference, being held April 12-13, 2017 in Boston, MA.

 

[1] https://www.cbinsights.com/blog/microbiome-startups-market-map-company-list/

[2] This is fact, and for an excellent read on this subject, may we suggest “Everyone Poops,” by Taro Gomi, https://www.amazon.com/Everyone-Turtleback-School-Library-Binding/dp/0613685725

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Tailoring Microbiome Interventions: The Intersection of Precision Medicine and the Microbiome

By Carrie Brodmerkel, Senior Director, Systems Pharmacology & Biomarkers, Janssen R&D

The microbiome gets a lot of press these days, from leading scientific journals such as Science publishing a special issue “Microbiota at Work” in April, 1 to articles about fecal microbiome transplants in major newspapers like the Washington Post.2 Many articles tout the need for a healthy gut microbiome and that the diversity of the gut microbiome is what maintains not just gut health but overall health. But for all of the hype, what do we really know about what a healthy microbiome looks like? What do we really know about the impact of the microbiome on health and disease? Is there a universal definition of a healthy microbiome or is it more likely that the each person has his or her own unique healthy gut microbiome?

A study published in 2015 in Science Advances studied the fecal, oral and skin microbiome of an Amerindian tribe, the Yanomami, who were completely isolated from the Western world.3 The researchers found that the Yanomami had the highest levels of human microbial diversity ever reported. They also don’t suffer from Western diseases like cardiovascular and metabolic disease or autoimmune and inflammatory diseases. Does this infer that gut microbial diversity equates to better health and less disease? That has not yet been proven and it may be that the microbiome in this tribe works in conjunction with a far different lifestyle and lack of chemical and pharmaceutical impacts and interventions to support a lack of disease. Still it drives the question of whether personalized cocktails of microbes will be needed to achieve optimal gut health for a given individual or group of individuals with similar microbiomes?

This collision of microbiome research and the precision medicine space, and the potential need for patient selection and personalization of microbiome therapies, will play out as microbial based therapeutics begin to hit the clinic. Evidence supporting this need already exists from fecal microbial transplant studies in C. difficile and inflammatory bowel disease where the response rates in an unselected population of patients leaves opportunity for improvement. Efforts to understand the functional effects of the microbes that inhabit the human gut and determining which promote health and which promote disease will be essential in unraveling the microbial communities necessary to promote health at the population or cohort level.

Hear more about Janssen’s efforts to define patient stratification strategies and personalized medicine in the age of microbial-based therapeutics at Arrowhead’s 3rd Annual Translational Microbiome Conference, being held April 12-13, 2017 in Boston, MA. For more information, visit: http://www.microbiomeconference.com

1 Science Magazine April 2016 http://science.sciencemag.org/content/352/6285

2 https://www.washingtonpost.com/news/speaking-of-science/wp/2016/04/28/scientists-think-theyve-found-the-secret-to-better-poop-transplants/?utm_term=.91f00d298c91

3 http://advances.sciencemag.org/content/1/3/e1500183.

Interestingly, despite their isolation and no known exposure to antibiotics, it was found that the tribe harbored bacteria that carried functional antibiotic resistance genes, including those that confer resistance to synthetic antibiotics and are syntenic with mobilization elements.

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Interview with Mollie Roth: Executive Director of The Microbiome Coalition (TMBC)

 

Interview with Mollie Roth, JD

Executive Director of The Microbiome Coalition (TMBC)

 

What is The Microbiome Coalition and what’s its goal?

The Microbiome Coalition (TMBC) represents a variety of commercial entities working toward commercial success in the microbiome field, united by their desire to promote greater public understanding of the role of the microbiome in human health and wellness, and the desire to advance appropriate regulation, needed investment and required infrastructure.

Recognizing that a shift in how microbiome based medicine and research is implemented will not happen simply because a body of scientific evidence suggests it should, TMBC has identified key goals to support and advance the industry, including: Education, Regulatory Engagement and Standards. You can learn more about what we are doing on all three fronts at http://www.themicrobiomecoalition.com/

 

How did TMBC come to be formed? 

Although I started my career as a litigator for the pharmaceutical industry, I have always had an affinity for making business run better. I spent 10 years working with a precision medicine consulting company helping pharma drug development teams understand how to co-develop and launch companion diagnostics.

In early 2013, I started working as a consultant in the microbiome space and became interested not only in the vast body of research that was happening across multiple industries – pharmaceutical, diagnostic, consumer products and nutrition – but in the challenges for companies to become a commercial success. Many of the hurdles and challenges this industry faces mirror exactly the experience in the precision medicine field – an unclear regulatory path, unclear business models, a lack of standards, differing reference databases among others.

It was my opinion, based on my experience in the precision medicine field, that a coalition of companies in this space could better address and overcome these challenges than any one company could. Thankfully the founding companies agreed with me and TMBC was born.

 

You said one of TMBC's goals pertains to standards, is there a problem with standards in the microbiome space?

In scientific research, standards allow for and ensure quality in research and the generation of quality evidence that can be compared across researchers and companies. Absent uniform standards, the quality of scientific research can be uneven and lacking in credibility, making it difficult to make confident, concrete assertions or predictions regarding evidence for improving practice or consumer outcomes.

For example, in the precision medicine space, we saw the lack of standards cause issues when it became apparent that there were no standardized practices for how samples being used to generate clinical data for diagnostic tests were handled. There are a number of groups already hard at work on two distinct standards issues in the microbiome space – how samples are handled and sequenced as well as how the vast volume of information generated in this space is processed. 

TMBC will serve as a clearinghouse for these activities already underway and will bring these disparate groups to the table to ensure they are engaging with each other so the industry ends up with a set of conformed standards, rather than numerous sets of non-interoperable standards.

 

What companies formed TMBC?

The founding companies are a visionary set of innovators who quickly understood the need for a coalition of companies working toward commercial success in the microbiome space and have provided seed support and substantial resources to get the coalition off the ground. They include AOBiome, Whole Biome, CosmosID, Abbott Nutrition, The Mayo Clinic, Diversigen and Second Genome.

 

How important are collaborations in the microbiome space?

 As incredibly important as they are in any area of new scientific research!

There are literally hundreds of small startup companies making incredibly exciting discoveries with regard to the microbiome, but without the resources or global reach to complete their research or get products approved and launched. Collaborations with larger companies, carefully crafted to ensure a win-win, are not only vital but imperative to move this space forward.

Further, now that we are a few years into the “age of the microbiome” we are starting to see a convergence between microbiome therapies and precision medicine, as companies consider how patients might need to be stratified based on their microbiome to determine who best to treat. The business models of how pharma and diagnostic companies can best collaborate and work together will continue to be vitally important as these two spaces continue to merge.

 

Is membership in TMBC open and to whom?

Membership in TMBC is open and we welcome any company, association or individual with an interest in advancing the commercial viability of microbiome based therapies, diagnostics, consumer or nutrition products to address and improve human health and wellness. You can learn more about membership options at http://www.themicrobiomecoalition.com/become-a-member/

 

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The Medium is the Message

I write this, the inaugural blog post for Arrowhead’s 3rd Annual Translational Microbiome Conference, as I listen to election result returns and find cheer in the gains that my current home state of Arizona has made in voting in a minimum wage increase and in voting out an antiquated (literally and figuratively) sheriff. But this election has far greater implications for us all in the scientific community.

It is clear that science is having a hard time gaining a foothold these days. The good news is that the Pew Research Center found that 79% of 2,000 people polled think science has “made life easier for most people” and 71% believe that investment in science pays off. The bad news is that as soon as a scientific question becomes politicized, it seems no amount of evidence can sway people’s minds. For example, over 50% of the people surveyed believe that GMO foods are generally unsafe whereas 88% of scientists polled think they are generally safe.1 My very unscientific personal poll in asking friends and colleagues about GMO foods quickly reveals that the question of GMO food is almost universally confused with the issue of Monsanto and GM wheat. The fact that we believe in the value of science does not necessarily reflect an understanding of its nuances.

How and why certain scientific issues – GMO foods, vaccines, climate change among others – become politicized is beyond the limits of this post but is driven in some large part by how the media reports on scientific research.2 And I think we in the microbiome community need to be aware of the potential dangers of microbiome-based research becoming tainted by a whiff of spoiled milk.

Spoiled milk, what am I on about?

Earlier this year health officials at the CDC announced they had discovered a pathogenic connection between raw milk from a Pennsylvania dairy and two illnesses in 2014 — one in California and the other in Florida. If you are not aware, the raw milk community is a vociferous and outspoken one, and the backlash was quick. When the CDC stated that the samples were “closely related genetically” and that the raw milk was the “likely source” of the illnesses, opponents were fast to pounce and ask why the CDC could not say they were 100% certain. 100% certainty is an unattainable goal in science, as we know, but that does not mean the general public will understand that.

So when that same public goes from demanding 100% certainty that a specific bacteria in raw milk caused some illness, how are they likely going to react to the idea of “poop in a pill” or fecal microbiome transplants? Again, my utterly unscientific poll of my Facebook cohort, and their reactions to my posts on this subject, suggest “not very well” is the answer. And how the media ultimately portrays this research will have a substantial impact on how it is received, and where it brushes up against hot button topics – like access to raw milk – it is likely to become a hot button issue itself.

The role of the media, and how they report on the microbiome and their role in the messages the public receives, will be explored by moderator Colleen Cutcliffe, co-founder and CEO of Whole Biome, in her panel “The Media and the Microbiome” at Arrowhead’s 3rd Annual Translational Microbiome Conference, being held April 12-13, 2017 in Boston, MA USA.

We invite you to join us and help guide the conversation.

1 http://www.pewinternet.org/2015/01/29/public-and-scientists-views-on-science-and-society/

2 Although I will recommend the very compelling albeit slanted read, Science Left Behind: Feel-Good Fallacies and the Rise of the Anti-Scientific Left by Alex B. Berezow, a microbiologist, and Hank Campbell.

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