Meet the Expert

Learn what Dr. Vercelli, a scientist at the forefront of complex lung diseases, has to say about the field and her work!

Dr. Donata Vercelli is a Regents Professor at The University of Arizona, as well as Director of the Arizona Center for the Biology of Complex Diseases, and Associate Director for the Asthma and Airway Disease Research Center. Dr. Vercelli’s group research the complex interactions between genetics, epigenetics and the environment that control the susceptibility to complex lung diseases, such as allergy and asthma. Dr. Vercelli was kind enough to share her thoughts and experiences working in this field.

 

Interview:

Q: What was your research training background and how did you start your research career?

I am an MD who always knew that research was the ultimate goal of my career. In Italy at the time, you couldn’t get a PhD. I wanted to get the most rigorous biological education, and that was through medicine. I also thought having a connection between basic biological research and human health was important, and that’s what took me to where I am today.

 

Q: Once you had your MD, how long did it take you to start your own lab or start working more the bench?

I started working at the bench when I was in medical school because that’s what I knew I wanted to do but I also knew that I wanted to swim with the best. I got my degree, I then went through 2 rounds of specialty degrees; so I am specialized in hematology and immunology.

I wanted to really go and take my chances, so I went to Harvard. I was there for almost 10 years in the division of immunology at Boston Children’s Hospital, and that was all bench work. That’s where I decided, that even though I was in a division that had patients, the day wasn’t long enough to fit in both and so my work was all at the bench. I started studying the regulation of allergic mechanisms at a very basic level, in humans at the time, and that’s where I started following the trajectory I am still in; trying to understand how allergy and asthma come about.

I was becoming a little envious of my colleagues, who were working with mice, one bench removed, because I saw that their experiments could be designed and manipulated in a way that you couldn’t do in humans. So I ultimately decided that I wanted to switch from a purely human type of research to a mixed one which was predominantly mouse-based and that’s what I did when I moved to Arizona.

Q: That seems to have been a fairly straight track; you didn’t start out in a completely independent field within hematology or immunology and then find your way to airway defense? You’ve always been within this research domain?

I am an intellectually omnivorous person, not only in medicine but in general. I always knew that there would be many things that would interest me, and by no means I am trying to say that the mechanisms of allergic inflammation are the only things that would interest me, in fact, quite the opposite. It was mostly what I could do at the highest level under the circumstances. When I started working at the bench, at the university in Florence, there was one lab that was already internationally established. I knew that there I could get the training I needed and wanted, at the level of quality I wanted. There I got the credentials to join one of the best laboratories in the field, in one of the best universities in the world. For me it was both a choice of field and being able to pursue that field at the level I wanted.

What I found extraordinarily fascinating was how incredibly specific and selective the mechanisms of IgE regulation and allergy were. It was going after processes that were so subtly and precisely regulated that I found interesting to study.

Q: What does the general landscape of your research field looks like, and where do you fit within it?

There are probably dozens of laboratories in the world that study asthma, allergic asthma, and allergic inflammation and its various iterations. Our angle is, I think, quite special in that we are interested not primarily in the induction of the disease but in the protection against it. Again, this is based on my preference for working largely with mouse models but getting my queues from humans and what human populations studies are teaching us.

I have always been in love with the data and the studies done, initially in Europe and then by us with our European colleagues here in the States, about the ability of certain environments, particularly farm environments, to confer protection against allergy and asthma. These are real-life experiments that have shown over and over again, with an amazing reproducibility, how powerful these environmental influences are in conferring protection against asthma and allergies. Now we begin to understand that this protection is linked to exposure to microbes and their products. The targets now are microbes in the environment and how they influence the microbes that we ourselves carry in ways that confer protection.

Most recently, our niche in the field of research on asthma-protective mechanisms has been expanding to include standardized bacterial lysates. These lysates can be administered through the airway, as if you were to inhale farm dust, and they seem to have strong protective effects.

Q: Is it fait to say that your lab is translationally focused?

Yes, I think so. I think this is important to work on human health-related issues, not just practically, because we are NIH-supported, but also because it is extraordinarily insightful to investigate models that tells us how our species co-evolved with the environment in ways that help our health.

I’m the type of scientist who doesn’t follow techniques, I follow problems and I import approaches, techniques, technologies into what we do based on the questions we’re asking. Once you start doing that, your trajectory becomes amazing. I’m a question driven scientist, which means I’m always out of my comfort zone because I always have new things to learn – but that’s why I am happy to get up in the morning and go to work.

 

Q: How long have you been a SCIREQ equipment user? Which equipment do you use?

We started “flexiVenting” years ago for a very critical reason. As an MD interested in basic mechanisms of asthma within a translational framework, I always heard clinicians lament the fact that mouse models are informative only up to a point. I had to agree with them if I looked at the way many mouse studies are designed. Most of these models essentially explore inflammation but only in terms of immunity. Yet, there is a structural “lung” component to asthma which can’t be ignored.

There was already an old flexiVent Legacy machine at our Center, owned by a colleague of ours. We started using it and eventually we got our own FX, which we like a lot. In fact the mouse work for one of our seminal papers, the one in the New England Journal of Medicine in 2016, relied on this machine.

 

Q: Could you talk a little bit about the insights that you’ve been able to get from the system that you wouldn’t have been able to otherwise?

In our experiments we always ask to what extent the purely inflammatory aspects of allergic inflammation processes that we induce or prevent (e.g., cell infiltration of the lungs, histological changes, cytokine production, etc.) relate to lung function.

Using the flexiVent, we can explore whether a process is occurring in the larger conducting airways, as opposed to the more peripheral smaller airways. This is very important because we need to know where in the lung these processes are occurring. Moreover, lung function and inflammation don’t always go together, and it is fascinating to see when they do or they don’t.

 

Q: What kind of mouse models are you currently working with?

We started using the work-horse model of allergic asthma, the OVA model in BALB/c and B6 mice (to be able to use knockouts). In the last couple of years, though, we are using more and more models in which we do not administer any adjuvant or anything systemically. We used HDM initially, but it was a little annoying because of inter-batch variability. Now, we prefer to use Alternaria alternata. The epidemiologic data linking Alternaria exposure to asthma in humans are overwhelming, and Alternaria can be given intranasally without adjuvant. These models can involve intense inflammation and can be chronic or more acute.

We also have another area of interest related to the microbiome, where we use both SPF and germ-free mice. Here we have learnt that the conditions in which mice (germ free mice but most importantly, SPF controls) are kept are very important. We have been through quite a few permutations to make sure we were using mice on the same genetic background and now we can compare these mice with confidence. Interestingly, we had to move our SPFs to a dirty facility because we discovered that the facility at our institute is so clean that our SPF mice were more similar to germ free than they are to SPFs. This makes a difference in their airway resistance profiles, a difference that is not subtle. 

 

Q: What are some of the things that bring you the most satisfaction from your research?

Understanding things that puzzle me. That’s what gets me out of bed in the morning. I always tell my people that the experiments that interest me the most are the ones that fail because that means there is something we don’t understand and we have to find out. Experiments that work are great, because you publish them and it means you got it , but you don’t learn much from them: you simply confirm something you already knew because you designed the experiment that way. 

 

Q: What advice you have for someone that wanted to start in your research field?

I will quote to you Noam Chomsky, a great friend of ours who is, I think, one of the greatest intellectuals of our time. Noam often talks about the willingness to be puzzled. I think that our science, our discipline, is so mature, that it is time for us to embrace complexity.  I am a little concerned when I see that a lot of people, especially younger students, like to use very complex computational tools to simplify and oversimplify their findings. I think they should do the opposite: they should go after complexity. Because the moment you start doing that is when things begin to become interesting, and links and interactions begin to appear.  If you can take two identical mice, put them in two different rooms and realize how profoundly that influences the way those mice behave, you understand that there is nothing simple in what’s going on.  So, I am all for embracing complexity and not shying away from it. This is what I tell my students.

 

Q: What is next for your lab and for your research?

Our line of investigation that focusses on protection granted by the natural environment is definitely something we want to develop further. We have a very large program project that was funded by NIAID to understand why if you are a Hispanic living in Tucson your probability to have asthma is 4-5 fold higher than if you are a Hispanic living immediately across the border, 60 kilometers away in Nogales, Mexico. 

At this point we feel that we have the intellectual framework to ask these questions We have fantastic collaborators who are leaders in the microbiome field and we have the tools to see what is in the environment, what is in the subjects, in their guts, in their lungs, what is the microbiome before birth, at birth, what the mother transmits to them etc.. I think we can now move along this trajectory from the prenatal period, which I think is essential, and we want to model this in mice. We are going to go after microbes and their metabolites. I think we can really get a good shot at understanding this model, and because it’s a human-based model, its biological significance is extremely high. I think we have the tools to bring together immunology, epigenetics, microbiome, all of the pieces. That’s our goal, for the next few years at least.

Thank you Dr. Vercelli for taking the time to do this interview!
 
Dr. Vercelli recent publications:

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