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Your immune system is quite clever. It can sense when bacteria, viruses, or pathogens are invading, distinguish among them, and respond accordingly. But an overactive or improperly functioning immune system can lead to a variety of problems such as auto-immune diseases like lupus or diseases related to inflammation, such as hardening of the arteries (atherosclerosis). Nir Hacohen and his colleagues at the Ó³»­´«Ã½ and Massachusetts General Hospital want to find out more about the intricacies of how the immune system works and how it relates to these diseases. Nir is also collaborating with his wife Catherine Wu, an assistant professor of medicine at Harvard Medical School and associate physician in medical oncology at the Dana-Farber Cancer Institute, to build personalized cancer vaccines.

Nir answered five of our questions about his current investigations into immunology and inflammatory diseases and explained how studying the immune system is like taking apart a radio.

Q1: What are the types of questions that your lab is pursuing?

Nir: We pursue a few related biological questions: how does our immune systems sense pathogens, and how do the pathogen-sensing pathways play a role in infections, autoimmunity and cancer. We have recently started to ask how these pathogen-sensing pathways differ from one human to another and how these differences may affect health.

On the technological side, our main interest is to develop and use genetic perturbation methods for manipulating immune cells, especially RNA interference (RNAi) with our colleagues at the Ó³»­´«Ã½â€™s RNAi Consortium. We are equally excited about applying new methods for monitoring cellular states, such as protein mass spectrometry (with the Proteomics Platform) or Nanostring mRNA detection. Our goal is to use perturbation and measurement approaches to systematically analyze and reconstruct biological circuits.

Q2: How does our ability to fight off infections and diseases relate to autoimmune responses like lupus or inflammatory responses like asthma?

Nir: When you get an autoimmune disease or inflammatory response, something needs to start it up. There is increasing evidence that the infection-sensing pathways that we study are important in initiating or modulating numerous non-infectious diseases from atherosclerosis to neurodegenerative diseases. In fact, many human diseases are directly caused by mutations in pathogen sensors that inappropriately activate these pathways, without a pathogen necessarily being present. We hope that therapies that target pathogen-sensing pathways will end up being useful for treating diverse human diseases.

Q3: How do you go about figuring out the circuitry of the immune system?

Nir: Imagine taking apart your radio and trying to figure out how it works. You might remove each component of the circuit and see what happens. Some components may be important for continuous control of the volume, for tuning the station, for receiving the signal (e.g., remove the antenna and you just hear white noise), or maybe for amplifying the sound, etc. The problem is that in many cases, when you remove a single part, your radio will stop working completely and just listening to the sound will not give you any clue about what the removed part actually does. Therefore, you should be measuring the electrical current (and perhaps other properties of the radio) in each part of the complex circuit as you remove each part. This is essentially what we do in our lab, but in a biological context. We use the RNAi library to remove one gene at a time, and then we measure the activity of the cellular circuit at different points using gene microarrays, Nanostring, mass spectrometry or other tools. This allows us to understand the function of each part of the circuit and thus derive a better model of the larger circuit.

Q4: You’re a senior associate member of the Ó³»­´«Ã½ and an associate immunologist at MGH. How do these roles complement each other?

Nir: The Ó³»­´«Ã½ is where we take a systems biology approach to the biological questions, using all the equipment and technologies that we and others developed at the Ó³»­´«Ã½. The MGH is where we take more traditional approaches to immunology – focusing on mouse models of autoimmunity and infectious immunity – to test ideas that we derive from our systems approaches. In addition, we have access to patient samples through MGH, allowing us to apply our approaches to human disease.

Q5: What is it like working with your spouse? Can you tell us a little bit more about the project you are working on?

Nir: It is deeply satisfying to create something new together – analogous to raising children. This specific project is an exciting and creative activity that extends our partnership outside the home. We bring different skills and context to this project, complementing a genomics approach for identifying tumor antigens with a human immunology approach to develop a new cancer therapy in humans.