This blog was written by JC Gutierrez-Ramos, CEO of Synlogic, as part of the From The Trenches feature of LifeSciVC.
Despite being central to life on earth, we know little about how microbes interact with each other, their hosts and their environment. Although DNA sequencing has enabled a new view on diversity and ubiquity of bacteria, we have just gotten a “glimpse” about microbial functions and community dynamics. Almost every habitat and organism hosts its own diverse constellation of microorganisms – its microbiome- its knowledge could transform our understanding of the world and propel innovations in health, agriculture, energy and the environment
Microorganisms have dominated, populated and shaped our planet for 3.5 billion years. Plants and multicellular animals (metazoans) first emerged between 700 and 800 million years ago, while modern humans have existed for approximately 250,000 years. Microbiomes shape their environments in a proportion that sometimes is difficult for us to grasp. For example, microbiome in the ocean produce half of the oxygen we breathe, and through photosynthesis, remove roughly the same proportion of carbon dioxide from the atmosphere. They also remove up to 90% of the methane from world’s oceans. The role of marine bacteria in re-mineralization (organic to inorganic) and in the deposition of carbon in the ocean relates directly to their fundamental role at the base of the food chain. Microbiomes that are in the air we breathe and in the soil we walk on perform similar chief functions.
To deepen our knowledge and accelerate this field and potential benefits, the Whitehouse launched the National Microbiome Initiative last month. This initiative is intended to create scientific tools, discoveries and training techniques that could advance efforts to cure diseases such as Parkinson’s and Diabetes, clean up oil spills, help with global warming and increase crop yields among other major impacts for ourselves and our planet. This initiative involves more than a dozen federal agencies, top universities, large and small corporations, and major philanthropies.
I had the privilege of being invited to the White House on May 13th for the announcement of the launch of this national initiative. At the launch meeting, I was able to participate in one of three panels, which focused on the potential of research in this area and the fruits that we might see for generations to come. I naturally spoke about the promising and potentially transformative approach to medicine that I believe microbiome could and will bring, putting particular emphasis in the approach that our company, Synlogic, is leading. Synlogic is engineering commonly used probiotics to perform corrected/enhanced metabolic conversions that are somatic in origin and are pathologically altered in certain diseases.
During the meeting Mr. John P. Holdren, Director of the White House Office of Science and Technology (OSTP), made clear the enthusiasm and the commitment to this area: “This is about connecting the dots and looking for common insights about different fields.” I reflected that we, at Synlogic, can attest to the importance of that vision. We are focused on engineering metabolic conversions in probiotic bacteria with high fidelity and potency. Although the metabolic transformations we focus on are physiological in nature, the basic principles of design and building of the genetic circuits that encode for them are the same principles that have been developed for biofuel bacterial metabolic engineering over the last 10 years. Biofuel Metabolic Engineering’s early novelty was in the synthesis of molecular biology techniques and the tools of mathematical analysis, which then allowed rational selection of targets for genetic modification through measurements and control of metabolic fluxes. Now it is well established that the two cornerstones of metabolic engineering are pathway integration and the focus on metabolic flux as a fundamental determinant of bacterial physiology after a new metabolic pathway has been engineered. This knowledge and talent has allowed us to build very potent and efficient synthetic metabolic reactions that might be able to compensate for the physiological deficiencies in the patient host. However this is just the beginning, I can imagine the power of a common platform, tools and measurements for ALL metabolic engineers. This will catapult the field logarithmically forward.
While I was at the meeting, I felt like every sentence had very significant meaning for the future of microbiome based drugs and specifically for Synlogic. “The microbiome is the only organ that can be replaced without surgery,” said Jo Handelsman, Deputy Director of the OSTP and a major force behind this initiative. “Just by eating differently, taking drugs, exercising and other things, you can have fairly immediate effects on your microbiome and your health… if we only knew,” she elaborated. In fact, peer reviewed publications have demonstrated that hundreds of metabolites in our blood stream are “signals sent by our microbiome.” These “signals” have been correlated with health and disease states, and it has been demonstrated that there is a significant change in response to diet, exercise and pathological states. Unfortunately, we do not know the rules, but I am certain that the field will decipher them over the next years.
In our own company, we use the microbiome as an “organ” that we modify transiently to perform a specific somatic therapeutic operation. The microbiome of a 160lb human is approximately 2-3lbs, which is about the size of a cantaloupe melon (!), and definitely bigger than a human kidney. It contains millions of bacterial genes, as opposed to the 24,000 human genes we carry, and is a highly metabolic flux organ. Synlogic’s approach is to add one metabolic function to the many others it performs. The “trick” is that the specific metabolic function we add to the microbiome is “broken” in our own human body, and now our “bacterial organ” is able to perform it and compensate for the deficiency of the subject treated. Currently, our “subjects” are experimental animal models, and we effectively “cure” them, but we will test these treatments in human beings early next year.
As we approach our human studies, we are naturally focused first on safety and then on differentiated efficacy. We believe, and have preliminary safety data in several animal species, that short term treatments (weeks to months) are safe and very well tolerated. However, we would like to know the impact of our treatments in the natural GI bacterial dynamics long term (months to years). We have started to address these questions through several academic and industrial collaborations. It is relatively easy to get the data to achieve this goal, but determining how to interpret the data is a different issue. “We do not really have a definition of what a healthy microbiome is, and that is we need,” Jo Handelsman said in the White House meeting, and she was exactly right. When we start to think about how to interpret changes endogenous microbiome population dynamics, if we see any, we realize that baseline characteristic parameters have not been well defined. “How can that be?” I asked my team. I see many good quality manuscripts being published every week that describe human microbiome alterations in health and disease. Since a 2005 Microbiome workshop in Paris, at least 8 broad programs to study the human microbiome have been launched in the world. These initiatives have generated massive amounts of data, but they are not easily comparable. For example, many studies in the human microbiota use the 16s ribosomal RNA gene to identify species and other taxonomical characteristics. The specific primers used for the amplification of this gene can have a big effect on the sequence results and in fact, the estimation of microbiota species have varied two to three orders of magnitude in different studies. This is one of the reasons why human microbiome healthy baseline is difficult to establish and precisely why the National Microbiome Initiative has a major effort on standardization. Three of the four major areas of focus in the National Microbiome Initiative deal with standardization and data sharing: establishing guidelines and prioritization for experimentation, set standards for methods, and a framework for data analysis. The fourth area deals with data sharing and IP rights.
I believe, along with many others, that this initiative will be the cornerstone of key advances to our understanding of the microbiome’s role in many areas, and certainly in health and disease. It will enable coordination among various microbiome efforts on the way, bring the development of new tools and interdisciplinary methods for microbe studies, such as imaging and metabolome analysis, develop priorities for a common research agenda and will help to establish forums that could be platforms for interdisciplinary discussion and global exchange. Get ready for a fascinating new world of microbes inside us .
