Research

Interested in Microbiome Research at Harvard Chan?

If you’re a current student, fellow, or faculty at the Harvard Chan School who would like to initiate a new microbiome-related research project, please feel free to get in touch. If you provide a brief description of your microbiome research interests, the HCMPH steering committee is happy to facilitate letters of support, inter-departmental collaboration, advice or advising for students and fellows, and Center membership.

 

Population Health Research

Population health researchers at the Harvard Chan School leverage epidemiologic techniques to understand how the human microbiome interacts with our bodies to identify populations at risk of a myriad of diseases.

Researchers benefit from access to Harvard’s cohort studies such as the Health Professionals Follow-up Study and Nurses’ Health Studypowerful resources with biennial participant data collected from more than 200,000 individuals over the last 30+ years, including measures of lifestyle, behavior, and characterization of over 60 diseases. Collectively, these studies comprise more than 3.5 million biospecimens, providing a unique resource to examine microbiome links to lifestyle, metabolism, genetics, and disease.

In 2016, the Harvard Chan School was awarded $5 million from the Massachusetts Life Sciences Center to collect microbiome samples from tens of thousands of healthy individuals and patients in order to develop the BIOM-Mass resource. This provides the world’s most comprehensive population-based biobank to study human microbiome interactions across a wide range of conditions. This effort builds on Harvard’s longitudinal cohort studies and will allow researchers to link already collected genetic, biomarker, lifestyle, environmental, and health factors to the microbiome.

In one study using rich longitudinal data, researchers assessed the microbial ecology of the gut microbiome and its metabolic activities as a baseline “parts list” of microbes and chemicals linked to these prospective cohort data. This included DNA and RNA sequencing of the gut microbiomes of 308 participants in the Health Professionals Follow-Up Study. Individuals provided four stool samples: one pair collected 24-72 h apart and a second pair ~6 months later. The microbes carried by each individual were relatively stable over time, while other measures of microbial molecular activity and active biochemistry changed more rapidly. The results showed the relative personalization of each individual’s microbial composition, while repeated or short-term measures better capture dynamic features such as newly-generated chemicals that may play a role in triggering or sustaining disease. This work thus helps to identify a wide range of new microbial organisms and pathways potentially targetable to treat or prevent health conditions.

 

Quantitative Data Analysis

Advancements in technology and big data science are enabling scientists to harness an unprecedented volume and variety of data in many fields. For the microbiome, data scientists at the Harvard Chan School are developing novel computational methods to investigate the roles of microbial community function in health. This work involves bioinformatic algorithm development to relate the microbes present in an environment to their biomolecular activities using high-throughput technologies to generate metagenomic, metatranscriptomic, proteomic, or metabolomic data.

Portions of the Human Microbiome Project, for example, were led at the Chan School, leading to the first catalog of microbiome structure and biochemical function across the human body. This includes the largest population to date for which deep microbial sequencing was carried out not only in the gut, but for oral, skin, and urogenital microbes, identifying the unique chemical and molecular signaling activities carried out by microbes in each of these environments. The study showed the surprisingly persistent effects of early life experiences such as breastfeeding, which can influence microbes in the gut for decades afterward. It also identified human genetic variants that influence our microbial interactions, and which microbes change in response to dietary exposures as opposed to remaining stable and unique over time.

These studies require the development of new computational tools with which to precisely identify microbial changes, molecules, and strains linked to health. Bioinformatic models of microbiology and molecular biology typically inform our understanding of mechanism – exactly which bugs or molecules are carrying out specific biological processes – but there’s still a surprising amount to be learned about the human microbiome. Most microbial DNA and other biochemistry represents “dark matter” that we can see, but don’t yet understand. This leaves an exciting scientific gap to bridge between the microbial details we now have the technological tools to measure and understanding how they can be used to predict or mitigate disease risk.

 

Laboratory Science and Basic Discovery

Thus, although there are upwards of two pounds of bacteria in your gut right now, we don’t know yet exactly what they’re doing there. We know that they’re helping to digest food, keep your immune system in good shape, and probably fight off metabolic disorders like diabetes and obesity – but we don’t know how the human microbiome functions to promote health and disease.

Basic scientists at the Harvard Chan School conduct research to identify specific species, pathways, molecules, and metabolites of interest within the microbiota. Using a variety of approaches encompassing genetic, metabolomic, proteomic, and biochemical platforms applied to populations ranging from large cohort studies to small biomarker-driven clinical trials, researchers seek to identify specific pathways and mechanistic bases by which the microbiome influences health and disease states.

It turns out, for example, that your gut “tastes” some types of parasites: cells very similar to those found on your tongue for chemical sensing are used to detect microbes as well. The colon, which houses most of our microbes, includes an essential barrier between us and our microbiota. Parasites can also be members of this gut microbiota, but they are typically sensed by our immune system and removed (unlike “normal,” beneficial microbes). Harvard Chan scientists have shown that tuft cells, a type of taste-chemosensory cell, accumulate during parasite infection. They are the primary source of parasite-induced immune responses, which can then help to clear potential infections, a process particularly relevant for global health in areas with greater risk of environmental parasite exposure.

Researchers thus move facilely between large human data sets and in vivo and in vitro model systems with the goals of determining basic biologic mechanism and realizing these findings for precision medicine. The Center’s overall mission includes the advancement of epidemiologic investigation for the translation of microbiome discoveries into effective clinical interventions.

 

Clinical Applications

The Harvard Chan School’s ability to be translational in the microbiome research space enables knowledge gleaned from the benches of laboratory science to be leveraged in clinical practice (and vice versa) so that new microbiome therapies can be developed and tested with increased rigor, effectiveness, and efficiency.

Diagnostics/Early Detection: Harnessing the microbiome to detect diseases, such as pancreatic cancer, that are currently often diagnosed only after reaching advanced stages. This includes studies of microbes in easily accessible environments, such as saliva, where changes may be early indicators of disease development.

Therapeutics/Chemoprevention: Advancing preventative interventions and chemoprevention approaches by identifying factors associated with disease risk (e.g. in colorectal cancer) that can be targeted with therapeutics.

Precision Medicine: Delivering medical treatments and live cell approaches tailored to an individual’s microbiome and personal health characteristics. Treatments such as fecal microbiota transplants, for example, are effective in certain conditions (but not others) and must be tailored to each individual and disease.