Patrick J. Casey
Senior vice-dean of research, Duke-NUS Graduate Medical School, Singapore
James B. Duke Professor of Pharmacology & Cancer Biology, Duke University, US
AsianScientist (Aug. 12, 2015) – When Singapore launched the biomedical sciences initiative in 2000, the need for clinician-scientists who could bridge the gap between bench and bedside was immediately felt. In response, the National University of Singapore (NUS) sought out an international partner to launch Singapore’s second medical school, one that would take in graduates rather than undergraduates and focus on training them to conduct urgently needed clinical research.
Duke University, a research powerhouse, fit the bill. Thus the Duke-NUS Graduate Medical School (Duke-NUS) was born, with both parties signing a memorandum of understanding in 2003. Although the mission of Duke-NUS was clear, it was not immediately obvious how exactly the challenges of developing a brand new university should be tackled, and there remained the question of who would be the most suitable person for the job.
Patrick Casey, a cancer biology expert and the James B. Duke Professor of Pharmacology & Cancer Biology at Duke, rose to the occasion. Involved right from the beginning, the present senior vice-dean of research at Duke-NUS saw the potential in the fledgling medical school, and moved both his family and his laboratory over to Singapore in 2005.
Ten years on, Duke-NUS has established itself as a leading research institution, with its researchers publishing in brand-name journals and winning fellowships, grants and awards. Recently, Duke-NUS researchers were also involved in developing ETC-159, the first made-in-Singapore cancer drug.
As this month’s interviewee for Asia’s Scientific Trailblazers, Professor Casey shares with us the latest findings from his ongoing research, what it takes to build a medical school from scratch and where medical education in Singapore is headed.
As a G protein researcher, what has been your most exciting research finding to date?
For me personally, it was discovering 25 years ago that Ras proteins and other G proteins are modified by lipids in a process called ‘prenylation’ and that lipid modification was required for the function of the proteins.
That gives us a new handle on trying to control their activity if we could target the enzymes. One of our major contributions to the field was to identify the enzymes that attach these lipids. We have embarked on programs to find inhibitors to these enzymes for development as novel therapeutic agents.
What role do G proteins play in the development of cancer?
There are two major classes of G proteins: small G proteins (the Ras family in particular) and big G proteins (heterotrimeric G proteins, the ones that couple information from G protein couple receptors, GCPRs). They participate in two very different types of biology.
Ras proteins are strongly implicated in cancer. In fact, the first human oncogene that was identified by Robert Weinberg 35 years ago was the Ras protein. They are hyper-activated in probably half of all human cancers, so targeting that family of G proteins is the major undertaking in cancer research.
The Ras proteins themselves have been difficult to target, although we have new approaches that we’re testing–mostly the targeting of the downstream of factors, the molecules downstream that relay the signals, the kinases in particular. A number of those compounds are in clinical development and have already been approved for anti-cancer agents.
The Ras family is particularly prevalent in pancreatic, leukemia, lung, bone, bladder cancer–those I would say are the major sites. The Ras proteins are activated by receptor tyrosine kinases (RTKs) and chief among them is the epidermal growth factor receptor (EGFR), which is amplified in many cancers, particularly in breast cancer.
Many of the new agents in breast cancer target the Ras pathway by targeting the EGFR. Tyrosine kinase inhibitors–a major class of anti-cancer drugs–work in many cancers at least in part through impacting the Ras pathway.
What are some of the clinical applications of your research?
The first enzyme that we identified, farnesyltransferase (FTase), was a major development in the 1990s. Many drug companies developed compounds, did medical trials and thousands of patients were treated with FTase inhibitors.
Unfortunately, the response rates were very low, partly because there’s another enzyme called geranylgeranyltransferase (GGTase-1) that can step in and restore function when FTase is inhibited. So we have another program developing GGTase-1 inhibitors, thinking that maybe if you put the two together, we might get better responses.
But most of our attention is currently on the enzymes that set the Ras proteins up for another modification: methylation. Isoprenylcysteine carboxyl methyltransferase (ICMT) is the single enzyme that modifies all of the different prenylated proteins. We have spent the last ten years focusing our attention on the methylation step and we have developed agents to inhibit it.
My wife (Mei Wang) is a clinician scientist here and we work together on this program. A lot of it is her program in trying to understand the role of ICMT in tumorigenesis and tumor progression. Over the last five years, she has published a number of papers showing that if we block this step, we can see an impact on cancer cells, both in culture and in animal models.
There are many opportunities for leadership and research in the US, what made you take up your role in Singapore?
Both my wife and I were looking for ways to grow our research and to do something different and special. The opportunity to come here and start this medical school was quite an exciting opportunity because we were in the ground flood.
My wife had been doing more clinical medicine and wanted to do move it more into research and this provided an opportunity for her because she could have a research laboratory in this new school and also the funding situation here for clinician scientists is very good.
For myself, I was looking for something in research leadership and it really provided me with the opportunity to build up enterprise. I was very keen to test out some models about how to build a research enterprise that focused on translational medicine and this seemed to be an ideal opportunity for that. The leadership position was exciting to me because there was good funding to build the enterprise, the medical school and its research components.
What was your biggest challenge in building up the medical school?
The biggest challenge was trying to ensure that we were meeting the needs and expectations of all of the stakeholders. There were multiple stakeholders–the Ministry of Health, Ministry of Education, A*STAR, National University of Singapore, Duke University and SingHealth. Every one of these entities was excited about the possibilities and what this school could do but they all had different ideas of what it should be.
So it was really about balancing all of these expectations and staying on course to bring this new type of medical education to Singapore and build a new type of research institute here. Those were the challenges but there was great commitment on the part of all parties to be this successful and this really helped us to get through that period.
Was it difficult to adapt the US/Duke style of education and research to Singaporean students?
It was not as big an issue as we thought when we came over. By the time we arrived here in 2005, the transformation was already well underway. NUS had really transitioned from being a regional educational institution to being an international research-driven institution. The Nanyang Technological University had established biological sciences and a strong research emphasis, particularly for post-graduation education.
We get reminded occasionally that developing relationships and building consensus is important in Asia. You spend a little more time on doing than in the US but it’s not that much different.
In your opinion, what is the most important determinant of success in a medical school?
I’d say first and foremost, you have to train good doctors. The quality of the doctors and that you are producing a cadre of doctors who not only practice medicine but improve the practice of medicine.
But when we think of specialized [institutions] like Duke-NUS, our entry-graduate entry model would be more mature students coming in through the door–the average age of a first year student of ours is 24 years-old. So they’re several years older, a little more mature.
In addition to practicing medicine, we teach them how do research and train them in leadership because we expect that our graduates are going to be out there improving the practice of medicine in many different ways–through research, leadership, clinical trials, etc.
But foremost, they have to be a good doctor!
You’ve been in Singapore for about a decade, where do you see the Duke-NUS Graduate Medical School heading in the next decade?
What I see is our first graduates are going to impact the practice of medicine in Singapore. Our first class is now in its fourth year of residency, so they’re within about a year of completing their post-graduate education. They’re going to start populating the echelons of public medicine and beyond in Singapore. You can start seeing an impact of our graduations on the health system and in healthcare delivery.
From the school’s standpoint, there is a greater alignment and integration with our major health system partner, SingHealth, such that it really is seamless between Duke-NUS and SingHealth. There’s going to be a complete continuum, research-wise and in clinical, between the medical school and health system, so that it looks as much like an academic medical center as would the Duke University in the US is.
We expect our graduates to be life-long learners and continue in advancing whatever aspect of medicine they choose for their career paths.
What impact do you foresee Duke-NUS graduates making?
First and foremost, of course, would be those who have become clinician scientists. They train in medicine and in research and at the end of their ten years, they would be faculty in the medical school or clinician scientists in the health system. They would spend as much time doing research as they do seeing patients, or more time doing research. So they’re trying to advance through research.
And then there’s another cadre that is primarily delivering medical care but is still engaged actively in research and leadership aspects. Their research is particularly on clinical trials and clinical research development.
And then I’m quite sure we’ll have a small cadre–like we see in the US–that train in medicine, maybe spend some time in the public system delivering healthcare but will transition to the private sector. They will become the medical directors of biotech companies and assume leadership roles in aspects of medicine and medical research, be it in the public or private sectors.
If you look 20 years from now, you’ll see several of our graduates occupying key roles in the ministries or in the public service organizations, e.g. Health Sciences Authority, Ministry of Health.
When Duke-NUS opened, it changed the landscape of medical education in Singapore. How do you see that landscape changing now that there are three medical schools?
There is a great need for medical professionals in Singapore. Even with three medical schools, you’re just going to barely be keeping up with the needs of the country.
There is a bit of dynamic tension and competitiveness between the schools, but I’ve been impressed with how much collaboration there is across institutions in Singapore and I expect that to continue. By having more than one school, people feel that they continually need to refresh and energize their approaches, making sure that they don’t get too [stagnant]. Medicine is always advancing, research is always changing, medical schools have to continually change and advance what they do as well.
Singapore’s medical scene is quite young in comparison with other countries. How do you think Singapore and Asia stand against the rest of the world?
Singapore stands very well in Asia and with the world right now. Certainly, it’s one of the top in Asia. Of course there’s Hong Kong, Korea–they’re doing pretty well as well but for the size of the country, I think Singapore is punching above its weight right now.
The big question of course moving forward is about the great investment that the government has made in the biomedical sector–will it continue and will it be able to continue to support the type of research that has brought Singapore to where it is?
We clearly need to be able to show some tangible returns on that investment in the next decade, in terms of improving the health of Singaporeans and improving the delivery of medicine, its impact as well as economic development, in terms of spin-offs, biotech companies and technology that has been developed and commercialized.
Are there any areas that you feel that are in need of development or strengthening?
I think most areas are developed very well here. We’re a little concerned that there’s going to be too much of an emphasis on applied and directly commercializable research. That is OK, if you’re going to look at a couple of areas and say here’s something we feel that we have a competitive advantage in. But we need to make sure that we don’t lose sight of the fact that it’s the firm foundation in the basic science that made it all possible.
If you don’t maintain that firm foundation, the layers you put on top of it–commercially-oriented research–aren’t sustainable, because the base has to remain solid. We need to ensure that there’s adequate funding for translationally-oriented basic scientists. That can really advance the state of knowledge in their field.
Where do you see yourself in the next ten years, will you still be in Singapore or Asia?
I think so! Initially, we thought we’d come here for two or three years to help get the school off the ground and then go back to Duke, my wife and I. And every couple of years we think about it but when we think about what we would do back in the US, it doesn’t seem as exciting as what we’re doing here, so I think I am going to stick it out till retirement now–we’ll see!
No promises on that one; you never know what the future is going to bring, but we have no plans to move. For both of us, we very much like what we’re doing and we’re doing things we really like to do and that matter.
This article is from a monthly series called Asia’s Scientific Trailblazers. Click here to read other articles in the series.
Copyright: Asian Scientist Magazine; Photo: Duke-NUS Graduate Medical School.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.