Becoming One is to Tread a Long and Winding Road that is Less Travelled, But Most Fulfilling, Says Professor Chng Wee Joo in a Recent NUHS Grand Rounds Talk.
Very often the question is asked, “What is a clinician-scientist (CS)?” The definition is muddled. The National Medical Research Council will give you one definition; our own doctors will give you another. Is it embedded in the qualifications of the individual, type of research that he or she performs, or the practice that the individual is in? For example, Cancer Science Institute director Dan Tenen is medically qualified, he does a wide range of research (that is more basic and mechanistic) but is no longer a practicing clinician. I’m medically qualified, I do clinical translational research while also delving into the mechanistic basic components of this translational research, and I continue to practice clinically.
What is a true clinician-scientist then? I don’t think there is a single definition. The way I look at it is this: what is the mindset of the person doing the research? Must he be medically qualified, so that he has insight into the clinical problems and is able to then identify what matters most for the patient? Does he need to be a practicing clinician? It will help. But then again, if he is always thinking about how to improve gaps in clinical management, in improving understanding of disease biology so as to find solutions to help patients, I think that would suffice as well. And I think importantly, he or she should also be a very important and effective link between clinicians and basic scientists (BS).
The Journey Matters As Much As the Destination
Very often, collaboration between scientists and clinicians fails because they don’t understand each other. The CS should be well-versed in the scientific methods and thinking processes required and act as the link (between clinicians and basic scientists).
I don’t just focus on the translational end or clinical end of the research, because I know that a translational project may take many years to bear fruit. There are different phases to the work – from discovery to understanding of the mechanism, to identifying a treatment, to conducting clinical trials to get the treatment into the clinic eventually. In Singapore, we are often in a hurry. We want someone to come up with a KPI in three years. If that’s the situation, you’d pretty much be forcing everyone to do work only to fulfill this objective. I think that is a waste because there are many unique diseases of the Asian phenotype that we need people in our region, in Singapore, in NUS to research. It can be a clinician-scientist and of course it can be a basic scientist as well, but we need to not forget about the entire process (that goes into translating research discoveries into clinical application).
I didn’t have all these things in my mind when I started my journey. All journeys have a beginning and mine wasn’t really very promising. I decided in secondary school and in JC that I really wanted to do medicine. I guess, many people then wanted to do medicine. It was a very popular degree to go for. I wanted to help people get better and I was interested in science and chemistry and so this provided a good mix. So I applied as most Singaporeans do, to NUS Medicine. Most applicants don’t get into NUS – and I was one of those. It wasn’t a very promising start, but I always look at the silver lining and the light at the end of the tunnel. There’s always a positive twist to something that appears disappointing at the beginning.
I ended up going to Leeds University medical school in the UK. At that point the only thing I knew about Leeds was the Leeds Football Club. I didn’t know much about the medical school though I knew a few Singaporeans studying medicine there who had pretty good feedback on the school. It turns out that Leeds does have a very strong programme in haematology, a strong pathology department and the medical school made some early discoveries on surgical techniques and tools. And so, this became one of the first lessons that I learned – a CS must be able to take rejection as well as criticism in his/her stride, because you will face much hardship in your career. But it was at Leeds that the seeds were truly planted and I became interested in research and translational-type research. I realised going through medical school that many of the important advances in medicine and treatment were through key scientific discoveries. Some of it were quite amazing, e.g. the discovery of penicillin and some vaccines. I also realized that just learning what is in the textbooks will not make things better for the patient, because there are too many diseases that have poor treatment options and outcomes. We are just starting to understand and describe some of those.
Indeed, there is plenty of research still to be done. In my last year at medical school I joined the radiology department on an elective to do research. This led to my first publication, the year I graduated, looking at PSA. It was not by intent but I was doing a project on Cancer and the Gleason score in predicting the stage of newly diagnosed prostate cancer. The topic itself was not the main thing; it was the participation and getting my feet wet that I really liked. Some people will find the process very laborious and unexciting, but I find that the excitement is in finding out something – in the joy of discovery.
So I was developing an interest to do this kind of work. Then after graduation I went to another historic place, York, where I did two years on a general medicine rotation that was supposed to prepare me for the MRCP exam. It was during this period that I encountered haematology. I wrote a case report when I was there and the combination of lab-based enquiry with clinical care connected particularly with my personal interest in diagnostics and problem-solving. So this was where my interest initially started.
After I finished my training as a Senior House Officer in the UK, I had to decide whether to stay and train as a specialist. I was already married then and the wife said, “Enough time overseas, better get home” because she had parents who were growing older. I came back. I interviewed with Endocrinology first because that was the one job that was advertised in the BMJ and Endocrinology was one of my potential choices. But I really wanted to do haematology. SGH didn’t have a position at that time and the NUH was only starting its haematology traineeship and this wasn’t advertised. A friend in the Ministry of Health connected me with the Head of Haem-Onc at that time, Lim Hong Liang. Hong Liang took me in for an interview with Liu Te Chih, who took a chance on me. So I joined NUH Haematology.
During that time, I had a colleague who was also interested in doing research studies and writing up case reports, and we encouraged each other on. I think environment is really important. At that time, I wrote up a case series on using cyclosporine to treat patients with renal failure who developed pure red blood cell aplasia due to EPO treatment. This was very topical at that time. The paper still remains highly referenced because people do use cyclosporine to treat this condition. I learned from my seniors at that time – Dr Liu and Dr Tan – that we truly ought to be observant and look at the clinical problem of our patients to obtain ideas and clues on what are the important things that we need to do for them, in terms of understanding what may help them.
As a trainee in the wards, I published quite regularly – small time publications like case reports and small studies. I was getting grants from the NMRC to do some small-scale research, so I was already ramping up towards a CS career path. But there wasn’t a really clear career track for clinician-scientists in Singapore in the early 2000s. Most people ended up as clinicians. But as with most things in life, sometimes you will need to have a bit of luck and timing. At that time, Singapore needed more CSs and A*STAR was offering an international fellowship to overseas institutions for two years of funded research training.
The idea at that time was that they don’t want to give you time for you to get a PhD – 2 years only; not 3 years, not 4 years. Because they want you to have enough training but not too much time away, so that you can come back straightaway to do your research in Singapore.
So I was fortunate enough to get one of these and I went to the Mayo Clinic. Before I went, I actually had no idea how to do lab-based research, and that was the research that I wanted to do, because I realised that there were a lot of exciting things happening in the areas of genomics and genetics. This was the time when microarray technology and the genome project were emerging. I felt that it was an important frontier and I needed the skills for basic research to be effective at the Mayo Clinic, so I had to prepare in advance in order to hit the ground running.
I had understanding chiefs who allowed me to work at a research lab for three months. I am very thankful to Prof Ito and A/Prof Motomi Osato, one of the senior scientists in Prof Ito’s lab at that time. I spent 3 - 4 months with them learning how to use a pipette, how to do PCRs, cloning, cell cultures etc. Nothing came out of that experience in terms of publications but it was very much an eye-opener.
Once, I sat in on one of their lab meetings. I could not believe how tough it is to truly be a good scientist. The postdoc who was giving a presentation was literally being picked apart for over-stating the interpretation of the data and Prof in his usual quiet but stern manner pointed out to him that what he said was incorrect. The difference is subtle. To my untrained mind at that time, I thought, “Wow, you mean this is so important?” But I learned that in science, we have to be very precise, and this is one of the problems that many of our graduate students have. In their theses, they state all sorts of conclusions and claims which their data is not exactly saying.
I had an opportunity to go overseas at an early stage. Very often young doctors come up to me and tell me they want to do a PhD. I see it differently; I do agree that we want more MD-PhDs, but I believe we ought to be flexible and give advice based on what kind of research the person wants to do in the end. I am not convinced that it’s always worthwhile to take the time to do a PhD if your work doesn’t require that kind of training.
So it’s the end in mind that is important. Those aspiring to do research on databases, analyse data or publish don’t need a PhD. We have other opportunities such as the Master of Public Health (MCI) – shorter courses, more focused, targeted towards that area. I think if you do need to do work that is mechanistic and more scientific, understanding of basic mechanisms and in the lab, then the discipline of doing a PhD may be useful. But again, what does the PhD study entail? The components of it are also important.
So if you ask me, on hindsight, I did do a PhD. Did I find it useful? If I had not done it, would my three years (one year at the Mayo Clinic) be enough for me to be where I am today? I would say yes. The most important component of that PhD were the three years of research discipline in the lab under good supervision. If I had not submitted a thesis and got a PhD, I wouldn’t have acquired the skills I need for the work I do today.
Many international professors observe that our PhD programme doesn’t focus on research; it focuses on coursework and finishing modules and attaining the required Cumulative Academic Points (CAP). You don’t really have a lot of time doing research. So whether learning on the job is enough or you need the formal certification, what is the formal qualification/education required?
I did a PhD at that point. I thought, why waste the time? It’s always useful to have a paper qualification in Singapore.
I was lucky also to have the help of A/Prof Evelyn Koay, at that time the Director of the Molecular Diagnosis Center (MDC), who was willing to take me on as a student. I did a part-time PhD. I did my research at the Mayo Clinic first before coming back to do my 1-year of courses/modules here as an Associate Consultant, running clinics and attending classes, taking exams etc. A/Prof Koay was very helpful and taught me that for scientific writing, you have to be quite meticulous. I was quite careless, and she would hand back the thesis to me with her comments in red ink.
A Turn in the Road
My journey had many twists. I wanted to go to Rochester to do myeloma research. Myeloma is a clinical entity that intrigues me. It’s a very complex problem that has interesting diagnostic dilemmas. Patients present with all kinds of multifactorial problems. However, nobody in Singapore then was really into myeloma and this was an area of very active growth in terms of drug development. Through one of my seniors, I was connected to the Mayo Clinic and they accepted me. I was going to do genomics and myeloma with Prof Rafael Fonseca, who was emerging as a very important person in this field at that time.
I was expecting to go to Rochester and as I was preparing all my winter clothing, Rafael emailed me a month before my departure. “Sorry, we have a change in plans. I am now going to Arizona – Mayo Clinic still – because I’ve been asked to go there to head this new division of haematology and set up a genomics collaboration with a big genomics institute in Phoenix. Are you still coming?” I said yes, because I want to learn from him. I threw away all my winter clothes and bought shorts and t-shirts because I was now going to the sunny state where you see cactus and sand and mountains and there’s hardly anything else. This was one major twist, but it turned out to be a great place because they were recruiting all these top scientists in myeloma and building a new institute and I got to be right in the middle of it all.
The second twist was that I was supposed to go there and learn about mutations in genes that control cell division. In myeloma there is a lot of abnormal DNA or chromosomal segregation. So the idea is, the genes that control mitosis are abnormal so that the separation of the chromosomes become abnormal. Within six weeks of getting to Mayo in Arizona, we did screening of these mutations using many patient samples and they were all negative. So it was back to the drawing board; it was not a programme that would work. Rafael quickly concluded that we should not waste time on this, and to start on a project with this genomic institute to look at microarray and gene expression in myeloma. One thing that the Mayo Clinic has a lot of is patient samples. So I went and learned different techniques to do microarray.
I picked up different sets of techniques that were completely different from what I was initially intending to learn. They were very useful techniques to acquire and continue to help me throughout my research career, because these have become a core skill. Within the first year, I managed to complete one of these projects and submitted the manuscript to the journal, Blood. To a Singaporean haematologist, Blood is the ‘holy grail’, the top haematology journal we read for the latest advancements, what we should do for our patients and so on. At the Mayo Clinic, Blood is the basic – you must do enough quality work to submit to Blood first. I submitted my work and thought, fat chance this will get in. Funnily enough, they came back with only minor revisions in the first round. So I thought, “Research is not that difficult!” I was lucky enough to get my first paper in Blood. This was the only time that it was that easy!
My 2 - 3 years at Mayo were spent working really hard. I was alone; my wife and children were back home. So all I did was research every day and I also read a lot. I was picking up a lot of new things, like gene expression. This is one thing which I find many of our younger postdocs and graduate students do not do, with many preferring the shorter route – their source of reference is Google or Wikipedia.
In their presentations, some refer to Wikipedia and that is not a good thing. You really need to read and understand.
So sometimes when I tell them to work on a newer area of research, I ask if they’ve read the key papers in this area and what are the essays that investigators use to look at this pathway (for example) and they look at me, in expectation that I would provide the answer. No, you must go and read and find out and enquire and plan and come back to me with a plan which we will then discuss. So I think the willingness to put in the hard preparation work is often not there nowadays.
Another thing that is important is the choice of mentors. I went to the right place at the right time; I didn’t just get Rafael – I got Keith (Stewart) and Leif (Bergsagel). These are fantastic scientists. Leif was the one who cloned all the mutations that we know of today in myeloma. He taught me more about scientific thinking. Rafael turned out to be a very good administrator-scientist, while Keith is very translational, seeing the clinical potential of many things. He is the director driving the precision medicine initiative for the entire Mayo Clinic and will be visiting us sometime later this year. So I didn’t get just one, but three mentors.
Mentors are important and you need to choose them carefully. It is not always the case that great scientists, very famous people, are good mentors. Not all leaders in their field make the best mentors. Neither do all senior people fit the bill. Instead, some of the junior and upcoming scientists are the ones who are very invested in people. For example, Rafael taught me that research is like an investment portfolio. You shouldn’t place all your money on just one project. You should have your portfolio of low-risk, middle-risk and high-risk projects. The high-risk ones will get high impact publications but you are prepared to fail there because it’s not always easy. The middle ones are the ones you get into Blood and so on and they are a bit harder but nonetheless do-able. Then the easy ones are maybe your impact factor 5 types, with a near certainty of getting published. And you want to make sure that you always have this so that at any one time, you’re publishing something. So you don’t have gaps in your publication history. I thought that’s very sensible and that’s essentially what I have done and still do.
And what is mentorship? They also taught me that it’s not knowing everything under the sun, but knowing where to get the information. Mentors know how to facilitate things; they know how to guide you when you’re unsure of how to do certain things, and they don’t control exactly what you do. The micro-managing type of mentorship really doesn’t work. Good mentors allow you creativity, freedom, they give you broad strokes – this is what they think conceptually you should think about. They offer you career advice.
When I was asked to be director of the National University Cancer Institute, Singapore, I went back to my mentors and asked, “What do you think?” I didn’t just ask our own guys. I consulted my mentors because they’ve been through it, are directors of institutes and they know whether it’s possible to continue to manage their research portfolio and all these things. So my mentors have become friends, which I think is a relationship that is worthy to establish and think about. We don’t always have very good mentors available in Singapore because the pool is small, though it is growing. There is no better time than now to be a clinician-scientist, but you need to be aware of all these things and plan carefully.
What It Takes
Recently there was an NMRC Symposium and many like Goh Boon Cher, Khoo Chin Meng and Tai E Shyong shared their experiences as clinician-scientists. As I sat there listening, I thought, “This is quite amazing because all of them mentioned very similar things – the need to handle rejection well and possessing tenacity, amongst others – which highlights to me that there are some qualities that are innate to all good clinician-scientists. That brings me to this question that I ask myself: now that we have funding for clinician-scientists and we have a mandate that we need to train 80 by 2020; can we really do that? Can we turn someone into a clinician-scientist? They must be born with certain qualities. And I think that is an interesting conundrum. But I truly feel that you must have some passion and interest because it is a very harsh environment; a very tough journey; you take a longer time than your colleagues – you must really want it. If not then, even if we give you money to help you with the first few steps, you ain’t going to continue on the rest of the journey because the money may run out. It’s not going to always be there. You have to fight for the money eventually.
Culture and Environment
A culture of research is very important. I was lucky to be in a department where there are clear role models. Boon Cher and many of us had understanding Heads who recognised even at that time, the importance of academic excellence and research. And I was given protected time as a junior faculty member and encouraged to do what I wanted to do. For Heads who want to build up departments with more clinician-scientists, some flexibility is very important. And of course, funding is important, though this should not be an issue in Singapore now.
Recruit and Build the Pool of Clinician-Scientists
Overall in the world, there is a fear that this group of people is diminishing. In America and Canada, part of this is due to poor funding. One important way to develop more clinician-scientists is to recruit the right people from medical school. The way we structure our interviews of students seeking admission to medical school here – do we consider the elements that will make good CSs or are we just recruiting pure clinician types? This is important to consider because whoever you recruit will determine the kind of output you most likely will get.
Once I graduated, I had to shift my focus to how could I be successful when I came back to Singapore. I would no longer be in the cradle that is the Mayo Clinic, with all the resources that they have, and this is where planning and strategy is important. You need to play to your strengths. I asked myself these questions:
- What is your strength?
- What do you need?
- What is available?
- What is important?
I did that thinking and realised that I would be in trouble if I wanted to do my own research alone. I have about 30 new cases of myeloma in NUH per year.
They (Mayo Clinic) have a few hundred each year. There was no way I could compete with these guys. Even if I want to build up a bank or a prospective cohort, it will take some time. So I needed to look at other potentials. During my time at Mayo, I made trips back home, talked to people here and understood who the people doing research in haematology were and what they were interested in.
At that time we had a new pathologist, Ng Siok-Bian, who was interested in a rare type of lymphoma called NK/T cell lymphoma. She was collecting samples. I thought that this was useful for Singapore as it is common, a very deadly disease that we know nothing about and I have the skill (in microarray gene expression) with which I could interrogate this kind of disease. So I worked with Siok-Bian and within two to three years, we submitted a paper. The collaboration has continued and we have become one of the known centres in the world that is studying the biology of this disease. So, you need to be strategic; you need to know your needs, your strengths, who you can collaborate with, and start to form some collaborations. This is the part that will bridge my gap and build my research in myeloma, and it is something which will take time.
Build the Research
Those who are interested in doing translational type research should build their infrastructure. You need your clinical database – you need this to be linked into a cell bank. If you need to do genomics, a bioinformatics framework or some ability to analyse that data is required. For those who want to do drug testing, you need to build the model, i.e. in vitro and in vivo drug testing platform. Do you fulfil them all in one day? No. It takes time, but you need to start with the first two i.e. a clinical database and cell bank – they are the easiest and they are your ‘currency’, because they are the resources your basic scientist researcher will come to you for. And this is where you will get your initial collaboration.
Over the last few years since I built up those databases, we’ve had engagement from NUS, from industry, from A*STAR to academic institutes to run different drug screening programmes for them. It’s produced more than 60 since 2009, just using these resources that we have built up.
Build the Team
"If you only do what you can do, you will never be better than what you are."
I picked up this quote when I went to watch Kung Fu Panda with my kids. It shows that you can learn from everywhere. I think this is a very profound statement. What it says is that we shouldn’t limit ourselves to our own comfort zones.
This is how I view building my team:
Complementary expertise. It could be easy for a PI to employ only those who know less than the boss. In this way you will never be able to go beyond your own comfort zone and grow. In fact, if I know that the project requires a lot of protein-based knowledge that I don’t really have, I get a good postdoc in that area to come and I build this team.
Keep good people and allow them to blossom. Some of my team have been with me for more than 10 years, getting long service awards. Tae Hoon, who is my bio-informatician, was working with me when I was in Arizona. When I came back to Singapore, he asked if I had a job for him – he wanted to be nearer to his home in South Korea. He’s been working with me for more than 10 years. The understanding we have is highly valuable.
Build the Programme
Over time, we have pieced things together and have a clear idea of the research we want to do, the disease models that we want. It an integrative approach, not haphazard, not piecemeal. I know that if I want to make a real impact on patients’ lives, I also need to improve the clinical trials capability in haematology. I was in a department that already had a very nice group of clinical trial coordinators and setup, so I was fortunate to be able to tap into that. But it requires energy. Before I came back in 2008/9, there was very little haematology research activity and Boon Cher will tell you that. Since then, we have built our recruitment so that over a period of 6 - 7 years, we have five times the number of patients recruited.
Last year, we were involved in a trial where we were one of the top recruiters in the world as a single centre here at the NUH for a global study in a disease like myeloma and which resulted in senior authorship in a paper that resulted in the approval of a drug. Again, small size doesn’t mean you cannot succeed. With organization, some energy and effort, you can also make an impact in the global setting.
Build the Network
It’s also important to build your network because if you’re alone, in this day and age, it is very hard to do good and impactful research. Collaboration is key. Sometimes I hear others say that it’s hard to work with colleagues from other hospitals. Well, in haematology we have managed to set up a national consortium. Each party has ownership of different programmes that makes research very effective. Sometimes we also find it hard to collaborate with our friends in Hong Kong, Korea etc. – we view them as our competitors. But again, we have managed to set up an international consortium that has been very successful.
We need to contribute to our institutions at some point in our careers and there is no better way to do so, than to be in a position to change policy so that we help to make things better.
My plate is full these days and they keep me going, because if there is only one thing and that thing is not really working well, you will actually become very frustrated. But here sometimes I’m frustrated in some areas but in others, I’m getting joy. So overall, it keeps me going.
Maintain Work-Life Balance
The other important thing is family. Have some interests outside of work. Spend time with your family. My family gives me the energy to do what I do: I am blessed to have an understanding wife. And because I have to be away from home sometimes, I am also thankful for the support of my staff.
A Worthwhile Journey
Apart from some personal accolades, the important thing is to be a good CS, to make impact for our patients. Through the work, I have seen the survival rate of myeloma patients almost double since the time that I began working on myeloma.
We have managed to implement new models of care that actually help our patients, such as the outpatient transplant, which reduces the length of hospital stay for the patient. There is no increase in mortality or complications, but it saves the patient about 30% of the cost of the transplant. And it frees up hospital beds for other patients.
Through our clinical trials, we’ve also seen patients who have benefitted from access to new drugs. A patient of mine was dying of a disease that was at end-stage. He participated in a clinical trial, had another two years of good quality of life, saw his daughter graduate from Pharmacy studies and his older daughter get married. This is a meaningful outcome for patients.
I’ve managed to be involved with and form the Asian Myeloma Network. I have helped start clinical trials in Asia so that we can push the agenda for our Asian patients. This has helped to elevate our institution’s international standing and drive some initiatives through the international myeloma working group, while also writing consensus statements. All these came about because I was able to stand on the shoulders of many giants. They have helped, supported, encouraged and nurtured me over these many years of my journey. That’s why it’s important for me to make it happen for my younger colleagues as well. Mentoring medical undergraduate and graduate students and our other doctors in the department and creating an environment and a legacy that can last for generations is what I want to do. It’s important to ensure that we make it happen for others as well.