A Scientific Rendezvous with Prof. David Brayden, University College Dublin, Ireland

By Vishwas Rai and Bozena B. Michniak-Kohn

Dr. David Brayden is currently an associate professor of drug delivery at the School of Veterinary Medicine at University College Dublin (UCD) and is a fellow of the UCD Conway Institute of Biomolecular and Biomedical Research in Ireland. Dr. Brayden joined UCD as a lecturer in veterinary pharmacology 2001, was appointed a senior lecturer in 2005, and became an associate professor in 2006. In 2012, he was the first Irish scientist to be made a fellow of the Controlled Release Society. From 2007 to 2008, he also served as a director of research for the School of Agriculture, Food Science and Veterinary Medicine.

Dr. Brayden received his Ph.D. in pharmacology at the University of Cambridge, United Kingdom, in 1989 and was appointed to a postdoctoral research fellowship at Stanford University, U.S.A. In 1991, he joined the pharmacology laboratory of the Irish biotech company Elan Corporation in Dublin as a senior scientist, followed by a project manager position working on several joint-venture drug delivery research collaborations with U.S. biotech companies.

At the 2012 CRS Annual Meeting, David Brayden was inducted into the CRS College of Fellows. Left to right: Kazunori Kataoka, David Brayden, Theresa Allen, and Martyn Davies.

Dr. Brayden is the author of more than 200 research publications and patents. He serves on the editorial advisory boards of Drug Discovery Today, European Journal of Pharmaceutical Sciences, Advanced Drug Delivery Reviews, and the Journal of Veterinary Pharmacology and Therapeutics. In 2010, he became an associate editor of the new international journal Therapeutic Delivery. He was chairman of the UK–Ireland Chapter of the Controlled Release Society (2003–2006), cochair of the veterinary programs at the CRS Annual Meetings (2003–2006), and served on the CRS Board of Scientific Advisors (2006–2009) before being admitted to the CRS College of Fellows in 2012.

Dr. Brayden’s major research interests are in oral peptide delivery and specifically in novel formulations of calcitonin. During his tenure at UCD, Dr. Brayden has been a successful Science Foundation Ireland (SFI) principal investigator, completing his PI research grant on the topic of oral delivery of novel muco-adhesive polymeric peptide conjugates in 2009. His current lab group comprises four Ph.D. students, two postdocs, and one technician. Dr. Brayden’s research group has been awarded a number of prestigious honors, including the best research paper prize of the Journal of Veterinary Pharmacology and Therapeutics (2005) and the American Biographical Society Hippocratic Award for services to medicine (2012). 

Apart from maintaining an intensive teaching schedule, Dr. Brayden also serves as director of the Irish Drug Delivery Network Strategic Research Cluster, funded by SFI since 2008. This program links scientists and engineers in partnerships across academia and industry to address crucial research questions, foster the development of new and existing Irish-based technology companies, and grow partnerships with industry that could make an important contribution to Ireland—and its economy. In this role, he leads the cluster team of scientists across four academic centers: the UCD Conway Institute and the schools of pharmacy at Trinity College Dublin, Royal College of Surgeons in Ireland, and University College Cork.

Q         Initially, I would like to ask you some questions about your educational experiences in graduate school. Why did you decide to take another higher academic degree? What made you select the pharmacology program at University of Cambridge?

A         My opportunity at Cambridge arose through a mixture of luck, timing, and my CV being spotted by a potential supervisor. I was actually enrolled in my first year in a postgraduate M.Sc. pharmacology thesis programme at UCD when I saw an advertisement by the University of Cambridge that was sent to Irish universities. They were looking for applicants with first-class honours, so I applied as it had a fantastic reputation in science. In 1985, it was also expected that you would do your Ph.D. abroad, as Ireland was entering a deep economic depression at the time, and there was little research grant money available. Then, a few months later, Prof. Alan Cuthbert, a fellow of the Royal Society (FRS) and head of the Pharmacology Department at Cambridge, wrote to me and said he was interested in my CV, as I had relevant research experience in my M.Sc. project on cystic fibrosis (CF). He had separate grant money and, between us, we wrote a successful scholarship grant to the British Council. I then got into Peterhouse College at Cambridge in 1985 and stayed there for four years. I couldn’t believe that someone that well known would take that chance on me without ever even having met me! However, I was always going to do a Ph.D., as I enjoyed my undergraduate thesis work, and it was almost expected of that group of 12 honours students at UCD. But to answer your question, Cambridge selects you, not the other way around!

Q         What are your memories (good and bad) of your graduate experience? What was your thesis project, and how did you approach the hypotheses and solve some of the major challenges?

A         My project was to see if I could grow sweat glands in culture from CF patients and to see if the gene defect in chloride transport persisted, as this would allow in vitro assays to test novel drugs. I eventually learned how to pick out sweat glands from skin and to grow out epithelial cells on plastic and then onto filter supports for transport studies. This was long before you could buy Transwell® filters, and we used to make our own for 10% of the cost. For the first year, I messed up a lot and kept infecting precious cells, some of which came from patients undergoing heart-lung transplants. Alan Cuthbert was a great supervisor, though, and he had me doing other related side projects so I would get well trained and have thesis data coming through all the time. He didn’t really like me taking holidays at Christmas to go home, though, as one time when I returned to Cambridge, fungus was crawling out of my cultures, and he ignored me for about a month! Then, I cracked the cell culture piece and the project took off—I recall getting about a year’s worth of good data in two months, and I was in the lab in that period at all times of the day and night. The Cambridge pharmacology department and Alan Cuthbert’s lab were full of really clever people, and ideas came from all sides in that environment. I would be introduced to scientists who had molecules that could work in my epithelial transport system, and it was up to me to make the collaboration happen. My early papers from that time were in good journals, and one of Alan Cuthbert’s strongest points was that he taught his students how to formulate hypotheses, how to prove them, and then how to write properly. Cambridge was one of the happiest times in my life, and all the memories of college life were fantastic. At Peterhouse College, you would often be invited to meet the college’s Nobel Prize winners at formal dinners, all part of the experience.

Q         How was your transition from the United Kingdom to the United States? Did you notice any major differences between the U.S. and U.K. systems? How different was the environment at Stanford University to that at the University of Cambridge?

A         In the space of a week, I went from the formal atmosphere of a 500-year-old dark Cambridge college to the beautiful, bright “new” Stanford campus, where some people went to lectures in shorts and on skates. I took up a post as a postdoctoral researcher in Prof. Jeff Wine’s CF lab. As a graduate student at Cambridge, I was part of the college system and all its rules, whereas postdoctoral research at Stanford was all about papers and making breakthroughs. As an environment, again it was an amazing place full of brilliant people. I remember going to a seminar by Lubert Stryer, who had actually written one of the most famous biochemistry textbooks I studied as an undergraduate. Stanford was very exciting, with visits by presidents and writers to the campus on a daily basis.

Q         Would you recommend an experience in the U.S. academic system to young researchers from Europe? What advice would you give to such researchers about the transition?

A         I would. At Cambridge when the U.S. offer came, they told me to take it, as it is important to learn how science research is done in the United States. I suppose that, being from Ireland, my U.S. move was pretty typical of many of that generation, as the economics of Ireland were terrible in 1989 (unfortunately not unlike the current period), but doing a postdoc abroad is a pretty essential part of research training in any case. The question is whether you will return at some point. My aunt and uncle immigrated to California in the 1950s and remained there, but when you are in your mid-20s, you don’t really think of these things, as such decisions tend to look after themselves later. The transition was not difficult, and I quickly settled into Jeff Wine’s lab, which was very international and accommodating to visitors. I got married earlier in the year during my Ph.D., and having a partner share the experience made the move easier.

Q         Please tell us a little about your experience during your postdoctoral research. Was the postdoctoral research related in any way to your graduate research project? How did you manage the transition to being a postdoctoral fellow?

A         When I was writing up my Ph.D. in 1989, I wrote to Jeff Wine at Stanford as, similar to Alan Cuthbert, he was a top man in CF research, and his group were excellent at patch clamping, a technique to look at ion channels in single cells. I wanted to stay in CF research, as there was a lot of unfinished business around the ion channel defect once the gene was discovered in 1989. This was the time when many naively thought that gene therapy with an adenovirus vector would quickly cure CF. In the project, we wrote a quite decent paper about the mechanism of action of a blocker of a chloride exchanger for the American Journal of Physiology. One lab experience I remember clearly to this day was actually seeing the important chloride channel responsible for the CF defect popping away under a patch clamp from a cell on the oscilloscope. This was the channel that was eventually correctly assigned as CFTR, as there was a major dispute in the literature over the identification. At Stanford, as a fresh postdoc I was quite junior in a lab full of experienced scientists, but this meant I got great training. Also, Jeff Wine had very different qualities from Alan Cuthbert, so I learned from two of the best mentors and have the highest admiration for both as they had major influences on my career, and I have maintained contact with both ever since. Jeff’s own daughter has CF (she is still well today), so it was personal for him, and it motivated the laboratory in a positive way.

Q         You decided to move from academia to industry and then back to academia. Please tell us about your experiences with these two different worlds.

Members of the Brayden lab (from left: Dr. Leilani Santos from Melbourne, Australia; Dallin Hubbard, visiting Ph.D. candidate from University of Utah, U.S.A.; Dr. David Brayden; Sevenja Sladek, Ph.D. student from Germany; Dr. Martina Gogarty from Dublin, Ireland; and Tauseef Ahmad, Ph.D. candidate from Delhi, India). Additional members are Ed Walsh (Ph.D. candidate from Dublin), Tanira Aguirre (Ph.D. candidate from Brazil), and Fiona McCartney (Ph.D. candidate from Dublin).

A         In 1990 I went to a CF conference after the gene was cloned and the channel defect was discovered. It was obvious that the molecular biologists were then going to be the key players in CF, so I started thinking about how I could adapt my skills in intestinal epithelial ion transport into other areas. At Stanford, the top drug delivery company, Alza, was close to the campus, so I kept hearing about them and their research, and this set me thinking about leveraging my knowledge from ion transport to drug transport and that the models I had worked on could be adapted for oral drug delivery. Then, in 1991, Elan in Ireland advertised a one-year job in Dublin to set up their in vitro pharmacology lab, and I saw an opportunity to return and at least to be able to say that I gave it a shot before emigrating. Elan provided excellent training and facilities, and in the 10 years I actually spent with them, I was given a lot of responsibility in managing joint ventures with U.S. biotechs, again with excellent on-the-job training. They allowed me to build my own group and saw that publishing research would give the technologies a lot of credibility, but it also allowed me to maintain an international research profile. In many ways, I continued as an academic in Elan and had tremendous freedom, certainly in the first few years. The big difference from academia was that the research was all about meeting milestones and deliverables, and it was team-based but highly competitive within the company. In 2001, I was looking for a new challenge, and it emerged precisely from the relationships I had helped build between Elan and the academic community through joint supervision of Ph.D. students, having summer students in the lab, and lecturing at UCD. UCD rather surprisingly suggested that I should apply for a lectureship in veterinary pharmacology at UCD (even though I am not a vet!), and another phase began. Since 2001 I have run my own research lab working on oral drug delivery, teaching pharmacology to vets and scientists, writing grants and papers, and putting through Ph.D. students. Being an academic these days requires entrepreneurial skills, so the training I got in Elan has been of great benefit, as keeping the show on the road can be similar to running a small company. It certainly helped me when I was appointed director of the SFI Irish Drug Delivery Network Cluster, a public-private partnership, in 2007.

Q         You are also involved with companies as an independent consultant. Please share with us any important advice you may have.

A         I enjoy consultancy work, as it gives me access to cutting-edge science and scientists, and I learn as much from the client as the other way around. I would never do it as a day job, however, as the pressure to have clients would be immense and the income unreliable. My advice, if undertaking consultancy, is to be completely trustworthy in relation to confidentiality and declare even perceived conflicts of interest up front. As a consultant working with several companies, you are being placed in a very responsible and sensitive position, and you have to compartmentalise knowledge so as not to compromise any client’s know-how and strategy. It is also a given that you provide the service on time and to the highest quality and never promise more than you can deliver or consult in areas outside your competency. Reputations can be lost very quickly, and drug delivery research is a small world.

Q         Tell us some of the highlights of your current research areas.

A         We have just published a paper in JCR on how intra-articular injections of nanocomplexes of hyaluronic acid, chitosan, and salmon calcitonin resolved inflammation in a mouse model of inflammatory arthritis.1 This was the result of a three-year collaboration during which we showed that calcitonin down-regulated an inflammatory mediator, NR4A, and then we reproduced it in vivo by formulating it in a nanocomplex. It is one of the most technically difficult pieces of research I was ever involved in, as it required experts in NR4A, the KBxN mouse, and formulation of nanocomplexes, none of which was very familiar to me, so I had to generate the team and glue the pieces together. The importance of the work is primarily the demonstration that the mouse model can be used to screen nanomedicines for inflammatory arthritis. Current research is mainly through a large EU FP7 consortium (TRANS-INT) on oral nanomedicines with 19 partners, including Sanofi and Roche (www.trans-int.eu), where we are providing one of the oral nanoparticle formulations, are examining uptake in the intestine, and will be loading with selected peptide payloads. We are also working on a nutraceutical project funded by the Irish Department of Agriculture examining how we can make a milk-derived bioactive tripeptide nanoparticle that might lower blood pressure.

Q         Tell us which of your publications you are most proud of and why.

A         My very first paper during my Ph.D. still means a lot to me.2 I don’t know how important it was really, but I do remember what I had to go through to get it published and that every piece of data in it was mine. My supervisor would spend days making sure that every word in the paper was accurate, and I have always tried to do the same for my own Ph.D. student papers. It is rare to get that sense of ownership again as you move on in your career. At Elan, we wrote a paper on microparticle uptake by the intestine that has been cited 135 times.3 I don’t recall that it was particularly special at the time, and maybe many cited it to disagree with it! Other papers from that period that we thought were really important were rarely cited, so you never know! With Per Artursson’s group at Uppsala, we wrote a well-cited and controversial paper on the human M-like cell model.4 This model can be used to examine particle and pathogen uptake in vitro, and we still use it profitably in our current research. Of the more recent papers, our ADDR one on how sodium caprate was researched from cells to current clinical trials in oral formulations is one that provides a roadmap on how to take such a substance right through to potential market.5 Finally, for my vet colleagues, we got a best paper award from JVPT in 2005 for the discovery that the antiparasitic agent selamectin inhibited P-glycoprotein, and this had clinical relevance.6

Q         Please tell us about your teaching courses. What is the teaching focus area, and how do you apply effective teaching practices?

A         On my first day in UCD, an experienced colleague took me aside and told me that I shouldn’t be there if I was not interested in teaching, even though I was hired ostensibly to set up a research programme. I completely agree with this and cannot abide a tendency for some universities to hide away their top researchers from teaching duties. I teach undergraduate courses in pharmacology to vet students and courses in drug discovery and development to final-year science students. I also make a big effort in delivering specialist modules to UCD’s structured Ph.D. programme. In my first few years in UCD, I attended every course going on to see how to improve my teaching as, although I was a decent enough presenter, that is not the same as learning how to teach students. Staff are expected to develop online teaching portfolios encompassing philosophy and reflection and also to listen to feedback from external examiners and students. There is a focus now on online material, and the IT aspects of teaching are rapidly changing. In fact, I did my first narrated online lecture when I was chairman of the CRS Webinar committee, about two years before I did any for the university, so again, a good example of how CRS can benefit its volunteers in many ways.

Q         Do you have any advice for young scientists who face many challenges with shrinking finances for grants but also many new opportunities with globalization of research?

A         Strange times indeed with very little certainty on grant funding. A paradox for drug delivery scientists is that the focus of governments on applied translational research actually puts them in a far more fundable position than basic biomedical scientists. This may not be much consolation for grant writers operating in environments where less than 20% success is the norm, so we are all having to accept our share of rejection in grants and to look at referee comments as objectively as possible before getting back on the horse. I’m sure most of the CRS Newsletter’s academic readers are busy writing economic and impact statements for their recent research grant applications, so this is a new language and set of requirements for the modern grant writer. Still, drug delivery researchers should be able to adapt to the current trends better than most. They need to think laterally and to collaborate with top scientists from many disciplines to elevate the scientific impact of their applications. In addition, drug delivery researchers have the possibility of generating industry collaborations more easily than other disciplines, and these are also generating favour with funding agencies, who want to promote and provide support for these relationships. Young scientists trained in my own lab have done well in industry or as young lecturers and postdocs in all parts of the world. What they each have in common is the necessary fierce determination and ambition, allied to technical ability.

Q         Your current appointment is at a veterinary school. Tell us a little more about what the environment offers at such a school for those of us who have not had this experience.

A         The UCD vet school is the only one in Ireland and is over 100 years old. It produces 120–130 vets a year in its American and European Veterinary Medical Association accredited degree programme. The staff are a mix of clinicians and preclinical lecturers like me, and the school’s research ranges from the study of small and large animal diseases, zoonoses, and parasitology to more basic research in animal physiology. The school has a training hospital for students to treat companion animals and horses and a farm for large animal research in the country. The hospital has had unusual cases from the zoo (arriving by police escort), including a much-loved tiger. The vets get the same kind of training as medical doctors, and one of their boasts is that they can treat more than one species! It’s possible to get animal tissue for drug delivery work in addition to rodents, so it’s an interesting place to do research.

Q         Please tell us about your favorite activities and hobbies when you are not involved with research and your other duties.

A         I do a lot of hill walking with family and friends in County Wicklow, known as the garden of Ireland, which is 10 km from where we live. I read a lot and am in a book club that meets in one of Dublin’s oldest pubs. I played competitive amateur league tennis until this year, when my lower back told me to stop punishing it and to give it a break. I also play the violin and was trained to grade 8 standard in my teens, so the odd bit of practice keeps me sane, especially if one of my graduate students is driving me up the walls. Other than that, I am a keen sports fan, going to many Leinster and Ireland rugby games and going through the regular torture of watching Liverpool FC on television.

References

1. Ryan, SM, McMorrow, J, Umerska, A, Patel, HB, Kornerup, KN, Tajber, L, Murphy, EP, Perretti, M, Corrigan, OI, Brayden, DJ. An intra-articular salmon calcitonin-based nanocomplex reduces experimental inflammatory arthritis, J. Controlled Release 167: 120-129 (2013).

2. Brayden, DJ, Cuthbert, AW, Lee, CM. Human eccrine sweat gland epithelial cultures express ductal characteristics, J. Physiol. (London) 405: 657-675 (1988).

3. McClean, S, Prosser, E, Meehan, E, O’Malley, D, Clarke, N, Ramtoola, Z, Brayden, D. Binding and uptake of biodegradable poly-DL-lactide micro- and nanoparticles in intestinal epithelia, Eur. J. Pharm. Sci. 6: 153-163 (1998).

4. Gullberg, E, Leonard, M, Karlsson, J, Hopkins, AM, Brayden, D, Baird, AW, Artursson, P. Expression of specific markers and particle transport in a new human intestinal M-cell model, Biochem. Biophys. Res. Commun. 279: 809-813 (2000).

5. Maher, S, Leonard, TW, Jacobsen, J, Brayden, DJ. Safety and efficacy of sodium caprate in promoting oral drug absorption: From in vitro to the clinic, Adv. Drug Deliv. Rev. 61(15): 1427-1449 (2009).

6. Griffin, J, Fletcher, N, Clemence, R, Blanchflower, S, Brayden, DJ. Selamectin is a potent substrate and inhibitor of human and canine P-glycoprotein, J. Vet. Pharmacol. Ther. 28: 257-265 (2005).

 

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