CommentaryTraining

“What Great Creation”

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Science Translational Medicine  03 Oct 2012:
Vol. 4, Issue 154, pp. 154cm10
DOI: 10.1126/scitranslmed.3004480

Abstract

In this case study, an early-career mechanical engineer interviews an established translational bioscientist about mechanisms for merging engineering and biomedicine to pursue clinically informed research questions.

Case. I am Alisa Morss Clyne, an associate professor of mechanical engineering and principal investigator (PI) of the Vascular Kinetics Laboratory at Drexel University. I grew up in Illinois, where my parents worked as scientists at the Argonne National Laboratory. But I first fell in love with designing and constructing creations while working with my dad in his woodshop. One summer, I attended an engineering program at the University of Illinois. This experience convinced me to become a mechanical engineer so I could design and create new entities.

I graduated from Stanford University with a degree in mechanical engineering. Stanford’s program had innovative and inspiring professors and an emphasis on creativity and design. After graduation, I channeled my interest in aeronautics and astronautics toward work as an engineer in the Aircraft Engines Division of General Electric’s Technical Leadership Program while earning a master’s degree in mechanical engineering.

As part of the master’s program, I was inspired by a lecture on the biomechanics of the cardiovascular system and decided to return to graduate school to engage in biomedical engineering research. I chose the Harvard–Massachussetts Institute of Technology Division of Health Sciences and Technology (HST) because it provided a mix of clinical and engineering education. I completed my doctoral research in the laboratory of Elazer Edelman, studying how diabetes affects endothelial cell storage and transport of fibroblast growth factor–2. The HST curriculum included clinical training; through that program, I completed the first year of the medical school curriculum at Harvard University and a 3-month subinternship on the hospital clinical wards.

In late 2006, I began my independent career as an assistant professor at Drexel University. My lab works on deciphering how physical forces and biochemical changes interact in diseases of the cardiovascular system; nanoparticle drug delivery; and devices to measure cell mechanics. In the spring of 2012, Drexel granted me tenure.

An engineer looks at physiology.

CREDIT: C. BICKEL/SCIENCE TRANSLATIONAL MEDICINE

INSIGHT TRANSLATION

At this point in my academic career, I am thinking carefully about whether and how to move my research toward translation to the clinic. The medical education and clinical introduction I received during my graduate work allowed me, without pursuing a medical degree, to learn about disease biology, interact with patients and physicians, and observe first hand how therapeutic decisions are made in the clinic. This experience taught me that biomedical engineers must understand pathophysiology if they hope to contribute to the development of clinically useful therapies. Perhaps more importantly, interacting with actual patients crystallized for me the clinical relevance and human impact of my research. In the next few years, I will have the opportunity to take a sabbatical, and I want to use the time to learn new skills, explore in vivo disease models, and develop collaborations that will enhance my research, productivity, and contributions to the improvement of human health.

In this Commentary, I interview Garret FitzGerald, M.D., chair of the Department of Pharmacology and director of the Institute for Translational Medicine & Therapeutics (ITMAT) at the University of Pennsylvania. My goals for the interview were to gain advice about (i) how to establish complementary collaborations with investigators in the biomedical sciences; (ii) how to choose a research focus for my impending sabbatical; and (iii) the role a bioengineer can play in leading a large biomedical research and development team.

EXPANDING EXPERTISE

Q. Alisa: As a PI who has trained in engineering sciences, what are some mechanisms for enhancing my knowledge about human pathophysiology, broadening my repertoire of technical expertise, and staying up to date with the latest challenges in cardiovascular disease when I don’t spend time in the clinic?

A. Garret: I’d look at that through the prism of my own experience. I’ve gone on sabbatical twice. In 1987, I went to Genentech to learn about molecular biology. I wasn’t going to become a molecular biologist, but rather, to gain some understanding of the language, scope, opportunity, power of the tools, and the difficulty and limitations of trying to deploy that information.

Then in 2002, I did the same thing with informatics. I went to Oxford for 6 months, then to both Scripps and Genomics Institute of the Novartis Research Foundation, which are side by side, for 6 months. And again, not in my wildest dreams did I want to become a bioinformatics expert. But I did want to understand the language they spoke, the reasons why I should care about informatics, and how it might be relevant to my own laboratory. I’d say both of those experiences—on a per-month basis of investment—probably had a greater yield in terms of their influence on my research program and the way that I run my lab than any other similar period of time during my career.

So I think that’s what you’ve been through. You’ve gone through something that hasn’t made you a Doctor of Medicine (M.D.), but has shown you why you should care about biomedicine and has given you an understanding of disease complexity and how to judge whether potential collaborators are as effective as clinical or translational researchers. One of the things I wanted to accomplish was not just how to build bioinformatics into my own environment, but also how to know who’s good and who’s not. Obviously, I couldn’t assess these scientists on my own, but another spin-off of the sabbatical investment was that I met friends and collaborators who are devoutly invested in the business and who I could then turn to and say, “What do you think of this person? They look pretty good to me.”

I think you’re in the same situation. So, do I need to go back every 5 years and spend a year doing something similar in bioinformatics? I’d say no, but do I need to go on sabbatical again to amplify my experiences and thus influence my own research? Yes. I’m planning, in the next year or so, to move my research in the direction of systems biology—a shift that is happening in the entire pharmacology department at [the University of Pennsylvania]. So, do you need to be a clinical clerk again? No. But what you might do is take time to refresh, now in a more specific fashion, your understanding of biomedical research in the clinical environment.

Q. Alisa: Having just received tenure, I have a sabbatical coming up in the next few years. I can gain more depth in clinical and translational research, but there ’s also basic biomedical research—I’ve never done RNA interference or knockout mouse models. For someone who wants to do translational research from the more basic science standpoint, which experience do you think has more value?

A. Garret: I’ve read somewhere that, of the people entitled to take a sabbatical, only 10% do. The reason for this is fear of flying. Scientists think their world will fall apart if they leave it for a while.

I’m a huge advocate of scientists taking advantage of this wonderful opportunity. I think it’s one of the reasons to be in academia, actually. It’s an opportunity for refreshment and refocus in the personal and professional domains of your life. So when you’re thinking about your sabbatical, there are two important questions to ask. The first is a high-level one: In what general research area does my interest lie? Am I interested in working in a cardiovascular environment? Am I interested in targeted drug delivery that’s applied in a cardiovascular environment?

Once you’ve identified your broad interests, the next question is: Where and with whom can I fulfill my specific career goals? There are laboratories like mine, in which we work in zebrafish, in cells, and (very expensively) in rodents. But, we also do mechanistic research in human subjects. Although our group has scientists doing very different kinds of research with very different technologies, our lab meetings are collective so that everybody, hopefully, sees the big picture into which what they’re trying to do fits. And in our environment, that big picture actually spans the translational divide. What you’re looking for is that type of environment applied to an engineering application in the clinical domain.

I think the real challenge in this business is for basic scientists to appreciate the clinical relevance, even if they wish not to pursue it, of what they’re doing and the complexity of addressing questions in humans. On the other hand, it’s crucial to educate people from a clinical background as to the beauty, rigor, and precision of basic science—a precision that you can never hope to obtain in the clinical domain—so that they can harvest the advantage of that precision to enhance the sophistication of the questions that one can ask in the clinic.

Q. Alisa: In the melding of biology and engineering, how does one best identify important unmet medical needs that can be addressed by engineering approaches? Is it by attempting to translate the fundamental research questions you’ve been pursuing, or by working on unmet needs identified by industry scientists or clinicians?

A. Garret: I’m a great believer in the line from Shakespeare, “To thine own self be true.” People are their own best motivators, and one’s most satisfying path begins with a drive that arises from deep within to address a challenge that has attracted your attention. That challenge may be one that prompts you immediately to stretch for clinical information or experience, or it may be a fundamental one that you hope may be ultimately projected by you or by other scientists into clinical realization. But the last thing I think one should succumb to is to let the perceived priorities of others dictate one’s science.

In one way, a metaphor for motivation-driven science is the fantastic success of U.S. National Institutes of Health (NIH) R01-funded (investigator-initiated) research in the United States. Often within our own community, researchers articulate the tension between R01-funded science and translational science. But I have both R01 and translational grants, and I don’t see any tension. If we are to translate effectively clinically significant discoveries, we need individual investigator–initiated “blue skies” research that often yields translational opportunities in completely unpredictable ways. Without that independent investigator–initiated fundamental science, there is no knowledge to translate.

BADGE OF COURAGE

Q. Alisa: One of the next steps, for me, is to move into NIH-funded work. With my engineering background, how do I convince NIH grant reviewers that I am capable of conducting translational biomedical research?

A. Garret: The ideal approach for you in terms of entry into the NIH environment is through a program grant, which depends on interdisciplinary integration. Given your expertise, I’d be surprised if you can’t find common ground. The bar to entry is a bit lower than an unsolicited RO1 if you’re part of a program grant application, particularly if it’s in response to a request for applications (RFA). But even if you’re writing a grant on your own, you can address the perception of your inexperience in the biomedical realm by having collaborators who support and defend you on that flank.

Q. Alisa: How do I best showcase my knowledge and skills to meet and engage collaborators at this transitional stage?

A. Garret: If you have independent funding, a strong training record, and publications, potential collaborators will take you seriously. It’s all about conveying what you bring to the table in terms of scientific expertise. In a sense, it’s your badge of courage.

There’s a twin track one can pursue to engage collaborators. The first track we’ve already discussed: apply for funding as part of an RFA with a focus that fits in with your research. The second—and probably the more important track—is to look around your local environment and ask, “Who are the scientists I take seriously?” Then once you’ve made sure they are aware of your work, you can ask them whether they are interested in collaboration or whether they know of people you should meet with a view to potentially harvesting that collaborative opportunity. You’ve joined ITMAT, which has 1700 or 1800 members. One way to investigate researchers’ interests is to search the ITMAT database.

Q. Alisa: How do you think engineers can have the greatest impact in translational medicine?

A. Garret: I don’t pretend to have expertise in the breadth of opportunity afforded by interactions with engineers, but in a general sense, I think what engineers bring to the party is that they’re actually used to making something. The test of their accomplishment is whether it works. In fact, people like me are not used to making things. In that sense, engineers have more advanced experience of the translational process than those of us who are biologists or physicians. What these other groups bring to the engineers is a biological sophistication that helps refine both the question and ultimately the tools that are developed to address the question. You can see it across a whole range of possibilities: stem cell biology, localized delivery or activation of therapeutics, and mechanical approaches to tissue and organ repair. The breadth of the opportunity is enormous.

The challenge is that we have linguistic and cultural hurdles to overcome, but many of the great discoveries in medicine have come from people willing to undertake precisely those types of challenges. We see it now with computational biology, which is beginning to change the face of biomedical research in a fundamental way. I don’t for a moment think that this can’t be overcome, and investments in translational medicine are rearranging the incentives to foster the overcoming of this hurdle.

Q. Alisa: What are some characteristics of an academic research project that is ready to move from the basic to the translational realm?

A. Garret: The most obvious areas are tissue engineering, nanomedicine, and drug delivery. To harvest the potential of these fields requires an understanding, on the part of all scientists, of precisely what they are trying to achieve together and why that could be important as well as coincident developments on both the biomedical and engineering sides that then progressively intrude. You can make all sorts of nano-widgets that won’t be translated unless you take into account the special requirements of the molecule you’re trying to deliver. So, for example, you may need to model the local concentrations of the molecule, while at the same time performing engineering magic to refine the delivery system.

PARTNERING FOR THE CURES

Q. Alisa: Do you think the process of translating academic science requires partnership with industry?

A. Garret: I think translation can occur in a thousand different ways. Obviously, industry does some things much better than we do in academia. Perhaps we do some things better than they do. I think we’re at an interesting stage in the drug discovery and development arena. Traditionally we’ve had large vertically integrated companies that do everything in house—from fundamental discovery to phase 3 trials to marketing of drugs. What we’re witnessing at the moment is the disintegration of these vertically integrated companies and a move to a more modular approach to drug discovery and development; modules will be drawn from biotechnology companies, academia, and the pharmaceutical industry and assembled in different ways depending on the nature of the challenge. In academia, investments in human capital and infrastructure—reflected in initiatives such as the NIH’s Clinical and Translational Science Awards, for example—are really designed to enable academia to play in that space.

So for instance, back in 2004 when we established ITMAT, we articulated only two objectives: (i) to increase the number of researchers who can do their science in what we call the translational space, which was between proof-of-concept in model systems and elucidation of drug-response mechanisms and variability in phase 2 trials, and (ii) to identify and reduce the barriers that confront these researchers. What we weren’t saying is that we’re supporting researchers in the translational space in order to increase the likelihood that some either will transit the space or form partnerships that enable translation. I think it’s very important not to dictate to scientists what kinds of research they should pursue, particularly in the academic environment, because such an approach will be unsuccessful. Rather, institutions should enable their scientists to do—extremely well—what they choose to do and, if appropriate, lower the barriers for forming partnerships that facilitate translation of their discoveries.

Q. Alisa: Do you think that a situation will arise in which industry engages academia to carry out specific kinds of research projects?

A. Garret: With the advent of National Center for Advancing Translational Sciences and recognition of their value, academia-industry partnerships are poised to be a focus of NIH as they have become for other funding agencies, such as the Wellcome Trust. Generally speaking, the interests and behavior of funders have a big impact on the behavior of those who are funded. But I have two concerns. One is that I think the reason to be in academia is the freedom of choice that it confers on its scientists. There has been a drift in the direction of more and more RFA-type of research—where the funder says “This is what you should do” or “Here’s a targeted research opportunity”—at the expense of unrestricted R01-type research. I can understand the reasons for this, but I think it’s a fundamentally dangerous shift in emphasis.

The other disturbing worldwide trend since the economic crisis is an increasing symbiosis between industry and government funders that includes scientifically unqualified politicians who legitimately say “We’re investing in biomedical science. Where’s the yield?” Such politicians and some people in industry then demand a much faster yield than the scientific process delivers and shift the investment in science away from basic research toward what they see as likely to deliver near-term impact.

An exemplar of this tendency is the country that I come from; Ireland effected such a shift in resources for science after a prioritization exercise that was conducted mainly by people from industry and government, with only minor representation from Irish scientists and virtually none from outside. This movement was coupled with a change in leadership of Science Foundation Ireland (the Irish analog to NIH), which resulted in an assessment of funding priority that is constrained by the prioritization-exercise guidelines. (It has been said, for example that Higgs would never now be funded by SFI.) Funding decisions will then be made on the basis of the track record of and research proposed by the investigator but also the perceived impact. So who decides what is impactful? The initial plan is for it to be people from industry. But an idea that has been floated is that crowdsourcing of public opinion should also influence research prioritization. I think this is completely harebrained and dangerous to the scientific enterprise. So while I applaud increasing interactions with industry, I think we have to be a little cautious about this erosion of a commitment to basic science and preservation of the autonomy of the independent investigator.

RESEARCH REWARDS

Q. Alisa: As an engineering professor, I spend a lot of time teaching. Most of the people I teach don’t go into research or academia. They go out and become engineers.

A. Garret: You can say the same thing in a medical school.

Q. Alisa: Right. So you published an article in Science Translational Medicine (1) about creating a new discipline of translational medicine. How can we teach students who are not planning to do research how to operate in and appreciate the translational environment?

A. Garret: I think it’s a challenge. I know as a physician that the chance to speak to people, discern what their problems are, treat them, and make them feel better is an unbelievably rewarding and intellectually seductive experience. The difficult challenge for most of our brethren who will go down that route is to tell them why they should care about another sort of intellectual endeavor.

In medicine, if you are well trained, usually by the time you’re 35 you’ll have seen one of at least most of the types of cases you’ll see in your life. The odds are that as you get older clinical practice will become increasingly routine. A great thing about science is that you don’t know what you’re going to be doing next week. At the beginning of their careers, young physicians, perhaps more than other budding scientists, find this knowledge threatening. But as you get older, the most rewarding thing about research is the clash of the new, the unexpected, which keeps you intellectually stimulated. So even for people who are primarily practitioners, research can add a dimension to their professional lives that they will appreciate more and more as they get older. It’s the reason you went back to school to get your Ph. D.

References and Notes

  1. Acknowledgments: The title is from “All’s Well That Ends Well” by William Shakespeare.
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