Bedside to Bench: Asthma Patient turns Asthma Researcher

James Lee, Ph.D., is a biologist specializing in molecular development. He's a bench scientist by training who spent six years at the California Institute of Technology studying the reproductive strategies of sea urchins. Not quite medical science, but in those days, Cal Tech did very little medical research and Dr. Lee was seeking to build a sustainable research program that would straddle the line between bench and bedside research.

His search took him to Columbia University where he studied gene transference technology. Gene transference, or the science of transferring genes into mouse models, was new technology in those days and funding in this emerging area of science was more readily available as compared to the study of say, sea urchins. It also allowed Dr. Lee to stay in the lab. At Columbia, he worked alongside Frank Constantini, Ph.D., one of the first scientists to perfect the science of transferring genes into mice.

Born and raised on Long Island, Dr. Lee was first diagnosed with asthma when he was 13 years old. His asthma can be severe at times. He almost left graduate school after a serious bought with the disease. "I decided that if I didn't start working on the disease I was dealing with in my life, I might not live very long. I guess people like myself think we can solve the world's problems. I thought, 'Well OK, I'm going to solve asthma. I'm going to cure this thing.' As naive a statement that is, I started working on asthma, specifically on the predominant cells that infiltrate the lungs of asthmatics called eosinophils," he said.

Eosinophils are a rare white blood cell that can increase in numbers as a result of an allergic inflammation, such as asthma or parasitic infections. Instead of studying asthma itself, Dr. Lee delved deep into eosinophils. He tracked its role in asthma, lung disease, food allergies and cancer. That journey led to establishing one of science's most highly regarded eosinophil laboratories in the country with a track record in top science journals such as Science. Dr. Lee still has much work ahead of him – in particular, proving his mouse studies true in humans. He's shown a direct causative link between eosinophils and disease in mice, but he hasn't yet shown this is true in humans.

In 2007, Dr. Lee, an associate professor of biochemistry and molecular biology, was named Mayo Clinic's Distinguished Investigator from Arizona.

Q. You could have gone to just about any institution to build your research program, why Mayo Clinic?

A. As much training as I got at Cal Tech to understand basic research and at Columbia Presbyterian in the use and characterization of mouse models of human disease, I had no fundamental background or understanding of patients' diseases. So one of the things that attracted me to Mayo Clinic, particularly Mayo Clinic in Arizona, was the truly wonderful atmosphere of partnership between basic research scientists and clinical colleagues. When I interviewed here it was clear that I wasn't a second class citizen. It was clear that I was going to be a valued colleague. They were very much interested in my opinions and willing to teach me what I needed to know. It was clear from moment one that two plus two added up to a lot more than four because of that attitude.

Q. Your success here seems to speak a lot to the importance of interdisciplinary research.

A. I've been able to take all of the training and expertise I had and with the help of clinical colleagues here, not only have we established absolutely novel models of various human diseases – particularly respiratory diseases, such as asthma – but we did this by starting from scratch. With the help of my Mayo colleagues, we've skyrocketed and have become one of the prominent, if not the most prominent labs studying human diseases using mouse models. Particularly those diseases surrounding allergies and those diseases involving the role or potential role of the white blood cell known as an eosinophil. It's been a wonderful ride. A ride that is not possible without my clinical colleagues.

Q. Colleagues have described you as an extraordinary scientist – eccentric, but extraordinary. Would you agree?

A. I'm a wacky scientist. I don't shy away from it. I don't often wear the blue blazer. I'm not what you'd consider a 'normal' Mayo clinical colleague, but I'm Mayo through and through. I'm more of the out-of-the-box thinker, which I find is the only way for me to get ahead. To Mayo's credit, it's okay. They understand that and work with it. I'm allowed to think out-of-the-box. And in many ways, prosper from those interactions.

Q. Earlier in your career, when you were thinking outside the box, did you run into any resistance from the establishment?

A. In terms of the ideas I put forth to explain human disease?

Q. Right.

A. All of the time. But that's not unique to me or unique to research. That's true everywhere. Nobody likes change. Everybody's got lots of investments into disease and into their view of disease. When you come along with a new idea that challenges old dogma, feathers get ruffled. And that's okay. Every time my ideas get challenged, my feathers get ruffled too. You've got to suck that up. You just basically got to go "Okay. Bring it on. Show me what you've got. Let's see if I'm right. If I'm right, I'm right. If I'm wrong, then eventually I'm going to have to change my tune. As I tell the kids in my lab, the data, the data, the data, regardless of my viewpoint.

Q. What's the best way to overcome resistance? Is it publications or are there other approaches?

A. Obviously you've got to get peer review. You've got to get publications. But you've got to be relentless. You've got to believe that you're right. Now, at the same time you've got to recognize you could be wrong and roll with the punches, but you've got to believe in your ideas. If you just let other people talk you into being wrong, you're wrong. I must admit, being relentless is a big part of this sometimes. Just push it, push it, push it. Again, with the understanding that, 'OK, if I have to accept the fact that I'm wrong in this area, fine.' I would argue to you that I've learned and made greater strides in situations where I was wrong and had to think this through and come up with an idea that was better than my original idea.

It's hard to admit when you've been wrong, but I've profited from this. I've profited from being wrong by being right even better. My ego would probably prefer that I get it right the first time. Unfortunately, like baseball, if I get three out of ten, I'm doing good – I'm going to the Hall of Fame. That's the life of basic research. Three out of ten and you're in the running for Nobel. Two out of ten and you're a bum from Toledo.

Q. You've tracked eosinophils into asthma, lung disease, food allergies and cancer. What's next?

A. Our next target is transplant biology. Eosinophils were recognized as one of the first cells known to be recruited by organs undergoing transplant rejection. And so in a lab meeting it occurred to us, we understand the eosinophils analogy very well; we understand the role of eosinophils in gut diseases and in cancer – so, can we use those tools and insights to try and understand if eosinophils have a role in transplant rejection?

We have changed or have begun a process of changing the medical school paradigm that has been around for five decades that says eosinophils are the prominent cell type recruited to the lungs of asthmatics. They are recruited in an attempt to deal with a perceived threat, but they mediate tissue damage.

Well, that paradigm did not fit with our mouse models of what the eosinophils were doing. We ran into a gigantic roadblock, but nonetheless, as I told you, we have to be persistent. And if we believe what we believe, and the data is the data, then we just couldn't give up. Again, with Mayo's support, we were able to pound away at this issue. We can now show, at least in our mouse models, that not only are eosinophils associated with asthma, but in these mice we can show that eosinophils are a causative link to disease and the pathologies that occur in the lungs of asthmatic patients – at least in mice.

Q. How will your research affect patients?

A. Right now we're trying to translate back up to people. In order to be clinically relevant we need to understand clinical phenomena, which means we need to understand what's going on in patients. We've successfully used our mouse models to show that eosinophils are likely to play a significant role in asthma. Now, we need to translate that data from bench to bedside to see, if indeed, these fundamental mechanisms are also working in people. If they are, we translate that into therapeutic modalities.

Q. Inhaled cortical steroids are very effective in treating the underlying inflammation associated with asthma, so is there really a need for new treatments?

A. They're very effective, but they're immunosuppressive in nature. When used in high doses they have undesirable secondary effects such as bone loss and increases in glaucoma. The immunosuppressive character of these drugs open you up to more bacterial and viral infections. So if one could envision targeting only the eosinophils, leaving the rest of the immune system intact, something that inhaled cortical steroids do not do, we could see an improvement in treatments.

But first we must determine if there is a causative role for eosinophils in asthma and other diseases such as food allergies. Also, do the eosinophil activities modulate or onset at tumor growth? These are all open-ended questions. We have data to suggest that eosinophils are indeed playing some kind of role, but the exact nature of that role in patients remains to be resolved.

Q. What has been your greatest accomplishment in research to date?

A. Our generation of an eosinophiless mouse was the greatest accomplishment this lab has ever done. Ten years ago my colleague and wife, Nancy Lee, suggested that we ought to try and create a genetically engineered mouse with no eosinophils, but had every other white blood cell unaffected. I remember shaking my head like, "Are you crazy? How are we going to do that?" And in that mother-like, stern fashion of hers, she wagged her finger and says, "I come up with these ideas. They're good ideas. You make them work!" In 2004, we created our mouse, which we call Phil.

Using that mouse, we were able to unambiguously show that the eosinophils played a causative role in the development of disease symptoms associated with asthma. This work was published in the journal Science describing the creation and characterization of Phil, the eosinophiless mouse.

It was fun. It really was. I can't describe the excitement that we had of counting the days down until the journal came out. And then the absolute pandemonium that we had, the little lab in little Mayo Clinic Scottsdale, outcompeted the world and published in the journal Science. It was even surprising for us - it was like "Wow!"

It was a landmark discovery. For the first time we had a means by which to unambiguously make statements as to what eosinophils can and cannot do.

Q. What does having received the Distinguished Investigator status mean to you?

A. I'm humbled, but this is really a reflection of the work of folks who work for me. Obviously, I play a role, but they work obsessively and they really believe in what they do. I point them in the right direction, counsel them, keep them from getting too depressed when things don't work and keep them calm and collected when their successes overwhelm us all.

I'm an extraordinarily lucky individual to be able to find a place like Mayo Clinic and be part of a bigger team. As a basic researcher my world was centered around the Nobel laureates at Cal Tech – clinical phenomena was far away. In those days, joys came from completing experiments. Well, now that pales in comparison to hearing the reactions of patients we've helped. It's an amazing feeling.