Research in Translation: Vedanta Biosciences [#1]
Identifying the key discoveries, technical advances, and creative ideas that make new medicines possible
Introduction
Vedanta Biosciences, the Cambridge, MA-based biotech company, is developing ‘defined consortia’ of bacteria to treat a range of medical conditions. What this means is that the company’s scientists identify a set of bacteria with health-promoting properties, crush them into powder, mix them together and package into pill form for patients to ingest. The company has several drug candidates that are pretty well along in the clinical trial process: VE303 to treat recurrent C. difficile infections (a condition for which there are already several successful FDA-approved drugs on the market), VE202 to treat inflammatory bowel disease, and VE707 to treat infections by other gram negative bacteria.
The goal of this series is to map out the long trail of basic scientific research that paved the way for therapeutic development. Each new edition will cover an influential paper (mostly papers noted as influential on the company’s own website) and identify the key discoveries, technical advances, and creative ideas that make new medicines possible. The target audience is aspiring research scientists (PhD students and intrepid undergraduates, young professors and industry professionals), who want to understand how research translates, and think about how their own research may translate as well.
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Jan 21, 2011 – Michael Barnes and Fiona Powrie – University of Oxford: The Gut's Clostridium Cocktail
At this point in time, nearly 15 years ago, the Human Microbiome Project (HMP) was well underway (its first phase ran from 2008-2013). The HMP and other large-scale population studies have established that microbiome composition (what specific bacteria and other microbes are present in someone’s gut) varies quite a lot between individuals. This variation is very pronounced across different regions of the world (e.g., developed vs. developing countries), due to differences in diet, lifestyle, and genetic background. But people living in the same place with similar lifestyles can have quite different microbiomes as well (and this composition can shift over time). The factors that influence microbiome composition are complex and not fully understood.
The scientific community believes (as many outside of academic circles now believe as well) that variation in the microbiome can influence health outcomes. This belief launched many companies, including Vedanta Biosciences, that have put their money on microbiome-based therapies.
The basic idea of these therapies is simple. You start by identifying two populations with different health outcomes that have detectable differences in their microbiome composition. One example – mentioned in the Barnes/Powrie article – is the finding that people in the developing world are less likely to suffer from allergic diseases than people in the developed world. Researchers think that this is due, at least in part, to differences in the microbiome, driven by the diet and lifestyle of the industrialized world. Along the same lines, you can compare people with a chronic condition like inflammatory bowel disease to people without the disease and see how their microbiomes are different - or look at a group of people treated with a specific drug and compare the microbiomes of those who respond favorably to those who do not.
In theory, once you identify a ‘non-healthy’ and a ‘healthy’ group that differ in their microbiome composition, you could supplement the microbiomes of the people in the ‘non-healthy’ group with whatever they are missing. However, just because there are differences in the microbiome between ‘healthy’ and ‘non-healthy’ individuals does not mean that these differences are causing poor health outcomes (they could instead be a downstream consequence of these poor health outcomes). To provide a rationale for modifying the microbiome of people with a clinical condition, you need to understand biological mechanism: What exactly are the microbes doing that is promoting good health? How are they interacting with the human body?
One major way in which the microbiome’s influence can be felt is through interactions between bacteria and the body’s immune cells. In the 2000s, studies had shown that the immune systems of germ-free mice (mice lacking a microbiome) are underdeveloped. This led to the idea, now well accepted, that the microbiome shapes and trains the immune system from an early age.
Barnes and Powrie shine a spotlight on T cells – a population of immune cells that plays a critical role in the adaptive immune response (which provides the capacity to remember past infections and respond effectively in the future). There are different sub-populations of T cells. Helper T cells (TH17) stimulate the inflammatory response and play tough defense against infectious pathogens. Regulatory T cells (Treg), in contrast, play a more calming role, turning down the intensity of the inflammatory response. Both are necessary. You need to mount a strong inflammatory response if you want to fight off an infection. But if the inflammatory response gets out of control it can lead to inflammatory disease.
This biological story of two T cell populations playing opposing roles presents a possible therapeutic strategy: develop therapies that put these two T cell populations in proper balance. Because the microbiome influences the size and activity of these T cell populations, you might be able to accomplish this goal by modifying the microbiome.
Barnes and Powrie provide support for this therapeutic strategy by describing existing studies that show how specific microbes influence these two types of T cells. All of these studies involved taking germ-free mice, selectively adding specific bacteria, and seeing what happens. Focusing on isolated agents (bacteria) in a simplified experimental model (germ free mice) is a common way that researchers try to decipher the role of individual actors in a complex system (the microbiome).
When a team of researchers from the Czech academy of sciences and Oxford (including Fiona Powrie) added a certain group of bacteria called segmented filamentous bacteria (SFB), the TH17 cell population swelled, and mice experienced worsened inflammation and arthritis (compared to germ free mice without added SFB). Other teams of researchers (at the California Institute of Technology, and the Institut national de la recherche agronomique in France) saw an opposing effect when they gave germ-free mice B. fragilis or F. prausnitzii (two common bacteria that are found in the healthy human gut microbiome). The Treg cells in these treated mice started producing more of a compound called IL-10, which helps calm the inflammatory response. Another set of scientists from the University of Tokyo found a similar positive effect when they administered a cocktail of different species (all belonging to a group of bacteria called the Clostridia) to germ-free mice. They saw enhanced Treg survival as well as reduced allergy and inflammation. The senior author of this group, Kenya Honda, is one of the co-founders of Vedanta Biosciences.
The translational potential here is clear – if this strategy of modifying the microbiome works so well in mice, perhaps you could also treat people with these cocktails of helpful bacteria. If the therapy was successful, it could influence an individual’s immune system so they are better able to fight off infections, or less likely to develop inflammatory diseases.
Though this has to be done carefully, as Barnes and Powrie note, because if you add the wrong bacterial species into the mix (like SFB), you can easily make things worse. This is trickier than it sounds, because even if know what these bad actors are and you keep them out of treatments, you may unintentionally provide bacteria that promote the growth of existing bacteria in the microbiome with undesirable effects (human patients are more complicated than germ free mice - they have an existing microbiome). Bacteria in the microbiome are well known to engage in cross-feeding: producing chemical products that serve as food sources for other bacteria.
There’s a reason why microbiome consortia therapies are just now emerging on the market – researchers had to start working out all the possible interactions between specific bacteria and immune cells (good and bad), and also study how bacteria in the microbiome influence each other’s growth and behavior. These biological frontiers are still being explored, and there is therefore a lot of room to improve on the microbiome drugs that have been developed so far.
Stay tuned for the next edition of this series…