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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 Na-tional Laboratory. But I f rst 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. T is experience convinced me to become a me-chanical engineer so I could design and cre-ate 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. Af er graduation, I channeled my interest in aeronautics and astronautics toward work as an engineer in the Aircraf Engines Division of General Electric’s Technical Leadership Program while earning a master’s degree in mechani-cal 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 bio-medical engineering research. I chose the Harvard–Massachussetts Institute of Tech-nology Division of Health Sciences and Technology (HST) because it provided a mix of clinical and engineering education. I completed my doctoral research in the lab-oratory of Elazer Edelman, studying how diabetes af ects endothelial cell storage and transport of f broblast growth factor–2. T e HST curriculum included clinical training; through that program, I completed the f rst year of the medical school curriculum at

Harvard University and a 3-month subin-ternship 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 sys-tem; nanoparticle drug delivery; and devices to measure cell me-chanics. In the spring of 2012, Drexel granted me tenure.

INSIGHT TRANSLATIONAt this point in my academic career, I am thinking carefully about whether and how to move my research to-ward translation to the clinic. T e medical education and clinical introduction I received during my graduate work allowed me, with-out pursuing a medical degree, to learn about disease biology, interact with patients and physi-cians, and observe f rst hand how therapeutic decisions are made in the clinic. T is experi-ence taught me that bio-medical engineers must understand patho-physiology if they hope to contribute to the development of clinically useful therapies. Perhaps more importantly, interacting with actual patients crystallized for me the clini-cal relevance and human impact of my re-search. 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 collabo-

rations that will enhance my research, pro-ductivity, and contributions to the improve-ment of human health.

In this Commentary, I interview Garret FitzGerald, M.D., chair of the Department of Pharmacology and director of the Insti-tute for Translational Medicine & T erapeu-tics (ITMAT) at the University of Pennsylva-nia. My goals for the interview were to gain advice about (i) how to establish comple-mentary collaborations with investigators in the biomedical sciences; (ii) how to choose a research focus for my impending sabbati-cal; and (iii) the role a bioengineer can play in leading a large biomedical research and development team.

EXPANDING EXPERTISEQ. Alisa: As a PI who has trained in engi-neering 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

T R A I N I N G

“What Great Creation”Alisa M. Clyne1* and Garret A. FitzGerald2

*Corresponding author. E-mail: asm67@drexel.edu

1Mechanical Engineering and Mechanics, College of Engineering, Drexel University, Philadelphia, PA 19104, USA. 2Institute for Translational Medicine and Thera-peutics, Translational Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

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

Fig. 1. An engineer looks at physiology. o

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C O M M E N TA R Y “ ”sabbatical twice. In 1987, I went to Genen-tech to learn about molecular biology. I wasn’t going to become a molecular biolo-gist, but rather, to gain some understanding of the language, scope, opportunity, power of the tools, and the dif culty and limita-tions of trying to deploy that information.

T en in 2002, I did the same thing with informatics. I went to Oxford for 6 months, then to both Scripps and Genomics Insti-tute 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 ex-periences—on a per-month basis of invest-ment—probably had a greater yield in terms of their inf uence 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 under-standing of disease complexity and how to judge whether potential collaborators are as ef ective as clinical or translational research-ers. 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-of of the sabbatical invest-ment 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? T ey 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 bioinformat-ics? I’d say no, but do I need to go on sabbatical again to amplify my experiences and thus in-f uence my own research? Yes. I’m planning, in the next year or so, to move my research in the direction of systems biology—a shif that is happening in the entire pharmacology de-partment 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 specif c 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 stand-point, 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. T e reason for this is fear of f ying. 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 aca-demia, actually. It’s an opportunity for re-freshment 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. T e f rst 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 environ-ment?

Once you’ve identif ed your broad in-terests, the next question is: Where and with whom can I fulf ll my specif c career goals? T ere are laboratories like mine, in which we work in zebraf sh, in cells, and (very expensively) in rodents. But, we also do mechanistic research in human subjects. Although our group has scientists doing very dif erent kinds of research with very dif erent technologies, our lab meetings are collective so that everybody, hopefully, sees the big picture into which what they’re try-ing to do f ts. 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 clini-cal relevance, even if they wish not to pursue it, of what they’re doing and the complex-ity 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 pre-cision that you can never hope to obtain in the clinical domain—so that they can har-vest the advantage of that precision to en-hance 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 im-

portant unmet medical needs that can be ad-dressed by engineering approaches? Is it by at-tempting to translate the fundamental research questions you’ve been pursuing, or by working on unmet needs identif ed by industry scien-tists 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 motiva-tors, and one’s most satisfying path begins with a drive that arises from deep within to address a challenge that has attracted your attention. T at 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 sci-entists 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) re-search in the United States. Of en 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 ef ec-tively clinically signif cant discoveries, we need individual investigator–initiated “blue skies” research that of en yields translational opportunities in completely unpredictable ways. Without that independent investiga-tor–initiated fundamental science, there is no knowledge to translate.

BADGE OF COURAGEQ. Alisa: One of the next steps, for me, is to move into NIH-funded work. With my engi-neering background, how do I convince NIH grant reviewers that I am capable of conduct-ing translational biomedical research?

A. Garret: T e 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 f nd common ground. T e 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 f ank.

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C O M M E N TA R Y “ ”Q. Alisa: How do I best showcase my

knowledge and skills to meet and engage col-laborators at this transitional stage?

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

T ere’s a twin track one can pursue to engage collaborators. T e f rst track we’ve al-ready discussed: apply for funding as part of an RFA with a focus that f ts in with your re-search. T e second—and probably the more important track—is to look around your lo-cal environment and ask, “Who are the scien-tists I take seriously?” T en once you’ve made sure they are aware of your work, you can ask them whether they are interested in collabo-ration or whether they know of people you should meet with a view to potentially har-vesting 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 ex-pertise in the breadth of opportunity af-forded 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. T e 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 so-phistication that helps ref ne both the ques-tion and ultimately the tools that are devel-oped 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. T e breadth of the opportunity is enormous.

T e 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 pre-cisely 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: T e most obvious areas are tissue engineering, nanomedicine, and drug delivery. To harvest the potential of these f elds 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 lo-cal concentrations of the molecule, while at the same time performing engineering magic to ref ne the delivery system.

PARTNERING FOR THE CURESQ. Alisa: Do you think the process of translat-ing academic science requires partnership with industry?

A. Garret: I think translation can occur in a thousand dif erent ways. Obviously, in-dustry 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 fundamen-tal discovery to phase 3 trials to marketing of drugs. What we’re witnessing at the mo-ment 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 dif erent ways depending on the nature of the challenge. In academia, investments in human capital and infrastructure—ref ected in initiatives such as the NIH’s Clinical and Translational Science Awards, for exam-ple—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 re-searchers 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 mecha-

nisms 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 in-crease the likelihood that some either will transit the space or form partnerships that enable translation. I think it’s very impor-tant 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 transla-tion of their discoveries.

Q. Alisa: Do you think that a situation will arise in which industry engages academia to carry out specif c 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 fund-ing agencies, such as the Wellcome Trust. Generally speaking, the interests and behav-ior of funders have a big impact on the be-havior 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. T ere has been a drif in the direction of more and more RFA-type of research—where the funder says “T is is what you should do” or “Here’s a tar-geted research opportunity”—at the expense of unrestricted R01-type research. I can un-derstand the reasons for this, but I think it’s a fundamentally dangerous shif in emphasis.

T e other disturbing worldwide trend since the economic crisis is an increasing symbiosis between industry and government funders that includes scientif cally unquali-f ed 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 scientif c process delivers and shif the investment in science away from basic research toward what they see as likely to de-liver near-term impact.

An exemplar of this tendency is the coun-try that I come from; Ireland ef ected such a shif in resources for science af er a prioriti-zation exercise that was conducted mainly by people from industry and government, with only minor representation from Irish scientists and virtually none from outside. T is movement was coupled with a change

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C O M M E N TA R Y “ ”in leadership of Science Foundation Ireland (the Irish analog to NIH), which resulted in an assessment of funding priority that is con-strained by the prioritization-exercise guide-lines. (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 im-pact. So who decides what is impactful? T e initial plan is for it to be people from indus-try. But an idea that has been f oated is that crowdsourcing of public opinion should also inf uence research prioritization. I think this is completely harebrained and dangerous to the scientif c enterprise. So while I applaud increasing interactions with industry, I think we have to be a little cautious about this ero-sion of a commitment to basic science and preservation of the autonomy of the indepen-dent investigator.

RESEARCH REWARDSQ. 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. T ey go out and become engineers.

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

Q. Alisa: Right. So you published an ar-ticle in Science Translational Medicine (1) about creating a new discipline of transla-tional 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 intellectu-ally seductive experience. T e di% cult chal-lenge for most of our brethren who will go down that route is to tell them why they should care about another sort of intellec-tual endeavor.

In medicine, if you are well trained, usu-ally 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. T e odds are that as

you get older clinical practice will become increasingly routine. A great thing about sci-ence is that you don’t know what you’re go-ing to be doing next week. At the beginning of their careers, young physicians, perhaps more than other budding scientists, f nd 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 pro-fessional 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. C. Skarke, G. A. FitzGerald, Training translators for smart

drug discovery. Sci. Transl. Med. 2, 26cm12 (2010).

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

Citation: A. M. Clyne, G. A. FitzGerald, “What great creation.” Sci. Transl. Med. 4, 154cm10 (2012).

10.1126/scitranslmed.3004480

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