By Associate Professor Lim Kah Leong,

Head, Department of Physiology

Some two decades ago, I was in a large academic audience gathered at a neuroscience meeting in Boston waiting eagerly to hear the latest developments in the field. As anticipated, the talks lived up to our expectations. However, the one that had left the deepest impression were the opening remarks by a Huntington’s disease (HD) activist, who told the audience boldly, “Please remember that the funds you have received for your research is for the betterment of human health and not for the betterment of your individual careers”.


Simple yet profound words. Joining the activist on stage was a man in a wheelchair. He was in his early 30s and had HD, a devastating brain disorder that robs sufferers of their movement control and cognitive abilities. HD patients exhibit characteristic dance-like movements known as “chorea” (etymology for the word “choreography”). Imagine trying to get around activities of daily living (e.g. drinking a cup of water, buttoning our shirt) while our limbs are seized by uncontrollable dance-like motions and we would be able to appreciate what HD patients go through every day.


The man was a pharmacy graduate who was happily married prior to his disease onset. Sadly, his wife divorced him shortly afterwards. But what was more wrenching was the man’s revelation that his 8-year old child had started exhibiting signs of the disease. It was not surprising to his audience, as we know that HD is an inheritable brain disorder that will hit subsequent generations progressively earlier in a phenomenon known as “anticipation”.


Nonetheless, the words of the HD activist (who spoke after the HD patient’s testimony) must have resonated with the audience. It was certainly a powerful message and in a way, a cry for help to biomedical researchers to focus on finding ways to mitigate the disease rather than finding ways to elevate their own academic reputations.


Research for new knowledge, or a search for answers?

Fast forward to the present – in a recent speech at the Leaders of Science Forum, Mr. Chan Chun Sing, Minister for Trade and Industry, asked, “How do we define success for all of us in this hall?”. He then suggested an answer: “Many people will judge our success from many different dimensions. Some look at input, some look at output, but I hope you will look at outcomes1. Among the several outcome measures that Minister Chan has alluded to is the translation of scientific results into clinical and therapeutic solutions that would help to improve the quality of life of people. This is consistent with Singapore’s recent rapid and aggressive move into translational biomedical research.

 


But what is translational research? To different people, it may mean different things. Notwithstanding the ensuing debate on the meaning of translational research, I suspect that most if not all biomedical researchers would appreciate that the end point of translational research, at least within the realm of medicine, is the development of a promising new treatment that could be applied in the clinical setting. I also believe that many basic scientists working on human diseases have this end point in mind, notwithstanding that their research is generally regarded as more upstream and at times, esoteric.


To help bridge bench to bedside research, it is noteworthy that the Government had aimed to generate 160 clinician-scientists (CS) by 20152. By virtue of their clinical and research training, clinician-scientists are well positioned to formulate and address scientific questions in the laboratory that are of direct relevance to the problems that they have encountered in the clinic. However, this would require doctors to spend a significant amount of time and effort in the laboratory, while fulfilling their typically demanding clinical duties. This is particularly challenging for young clinicians, who also need to chalk up enough clinical experience to sit for their specialist examinations.


Yet this is the very group that we need to aggressively target to refresh and replenish the pool of clinician-scientists in Singapore. The willingness to get out of their comfort zones, whether spending substantial amounts of time in research would help in their career development and promotion, the bonus that they would earn at the end of the year – these are pragmatic considerations that will influence the decision of clinicians considering careers in research. The numbers are telling. By 2016, only two thirds of the projected number of clinician scientists to be recruited had been achieved3.


Translational research the be-all and end-all?

The push for translational research is a global phenomenon. In Singapore, the game has changed in a fast and furious manner in a mere few years that followed Research, Innovative and Enterprise (RIE) 2015. During this period, the biomedical scientific community has witnessed the transformation of the research landscape from a curiosity-driven one to an environment emphasising the need for “Return on Investments (ROI)”. Under the RIE2020 Human Biomedical Science framework, the Ministry of Health identified five research areas of national priority, namely Cancers, Cardiovascular diseases, Diabetes Mellitus and other Metabolic/endocrine disorders, Infectious diseases, and Neurological and Sense Disorders.


These areas were chosen based primarily on the impact of the disease on our healthcare system and the availability of a critical mass of locally-based scientific talent who have the potential to find meaningful solutions to these health challenges. A task force for each of these disease areas was established to help determine specific problem statements and to develop research roadmaps toward solving the problems identified.

Each panel comprised a multidisciplinary group of experts in different domains. I was a member of the Neurological and Sense Disorders Taskforce Panel that includes clinician-scientists, basic scientists, a health service expert and an engineer. I also chaired its subpanel on Age-related diseases and complications. All in all, it took us nearly a year of discussions that included several panel meetings and a couple of “townhall-like” sessions with the neuroscience community at large to come up with our recommendations to the HBMS EXCO. We have articulated to the committee our collective strategic research roadmap to tackle the major neurological and sense disorders that Singapore is facing, in view of the increasing numbers of ageing people here. These recommendations include pathways to translate research discoveries into healthcare solutions, innovative medicines or medical devices for value creation and capture. Likewise, the various other taskforces also took similar lengths of time over their deliberations and proposals. All the materials from various taskforces are available online and I often encourage my colleagues to read them to get a better understanding on what are the research areas of strategic priority to this country.

 

Whither basic science research?

It is well known that biomedical science research requires a long gestational period for results to be seen. It is also well known that pragmatism is an active gene in the DNA of Singapore. To drive translational research, we have seen in recent years that the National Medical Research Council (NMRC), a staple grant funding agency for academic biomedical researchers, has tweaked their criteria significantly to better support research that is more downstream. Meanwhile, extra-mural funding from the Biomedical Research Council (BMRC) that traditionally supports Basic Science Research had disappeared altogether (It is now consolidated with the NMRC to support translational research).

I still remember the shock and disbelief felt by the Basic Science Community on learning the news of the BMRC removing its extramural funding for researchers in public institutions. One visiting senior investigator from the UK had even suggested to me to hold a demonstration to rally for support for basic science research funding. He told me the efforts of the Science is Vital group in the UK, a grassroots campaigning organisation formed in 2010 by a group of concerned scientists and supporters to combat threats to the public R&D budget4.


I thought that it was a preposterous proposition and immediately laughed it off, telling him politely that this is not how things are done in Singapore. However, it is evident that Basic Science research is progressively being circumscribed by current funding criteria. Even universities, which theoretically should represent safe havens for esoteric research, are not spared. Whilst the academic leadership appreciates the importance of what I refer to as the “sanctity of knowledge” that universities must protect, a very senior member has advised me to be pragmatic, saying that “without money, you cannot do research”.


The twain must meet

So, in our quest for translational research and outcomes, is there room for basic research? I often say that Basic-Translational-Clinical Research is a continuum. Without basic research, I wonder whose research discoveries would we be translating. However, given its unpredictability and long gestational period, many would argue that public funds should be better spent on research that is more downstream and which could directly impact human health.


Interestingly, in a recent blog entitled “Basic Research: Building a Firm Foundation for Biomedicine”, National Institute of Health (NIH) Director Francis Collins highlighted that “In an analysis of more than 28 million papers in the PubMed.gov database, researchers found NIH contributed to published research that was associated with every single one of the 210 new drugs approved by the Food and Drug Administration from 2010 through 2016”5. He concluded by saying that “All in all, the findings show that the contribution of publicly supported basic science to the development of the most promising recent new therapeutic advances has been even greater than had been appreciated. As we look ahead to the future, the biomedical advances needed to protect and improve our health—and the health of generations to come—will continue to depend on a firm foundation of knowledge built on basic research5."


Indeed, basic science research represents the bedrock of Medicine. The recent advancement in CRISPR/Cas9 genome editing technology that holds tremendous promise for correcting genetic mutations in humans (think HD) would not have been possible without its initial and rather accidental discovery in microbes. It was certainly not a purposeful translational-type research that led to the discovery of this revolutionary genome editing method.


The same could be said of PCR, which is now routinely used in the clinic for diagnostic applications. In developing novel therapeutics for incurable diseases like HD, it is pertinent to first understand the disease mechanism before a therapeutic roadmap could be conceived. To allow the lay reader to appreciate this, consider what it takes to repair an analog watch that is broken, then think how the watch-smith so easily fixes that broken watch.


Ditto the car mechanic who repairs a vehicle. The mechanism is key to fixing anything that is broken, be it an inanimate machine or the human body. However, knowing how each molecular player works in the body and how they are all interwoven in a tapestry of pathogenic pathways during disease states could appear to be complicated, esoteric and irrelevant as they are seemingly so far removed from downstream clinical applications. This is where mindsets have to change. This is also where basic scientists need to make more effort to engage clinicians, as well as the powers that be and the public, to help them understand the nature and promise of Basic Science research.


To move translational research forward, it is first important to recognise that we need both the upstream (i.e. Basic) and downstream (i.e. Clinical) engines. Whilst CS are pivotal in this equation, they alone will not be able to solve the problem. To put it colloquially, it would take a whole “kampong” to find solutions to seemingly insolvable clinical problems. For a start, we need to develop a common vocabulary for the two communities to understand each other, as it is well known that Basic Scientists and Clinicians tend to speak different languages.


A meeting of minds and equals

We also need to develop equitable partnerships between the two groups in scientific collaborations. I am aware that there are scientists who view their clinical partners as “cash-cows” and clinicians who view their basic science collaborators as “workhorses”. Unless and until we treat each other as equals, little could be achieved. Obviously, finding time to shadow each other’s profession would be an excellent way to promote mutual respect, understanding and trust. It would also be good to weave into the medical curriculum, topics that emphasise the importance of basic science research in clinical practice so that medical students who would eventually populate our hospitals could gain an appreciation of this aspect of biomedical work at the beginning of their careers.


Finally, it is important for all of us to recognise that Singapore is a small country with limited resources. Collaboration, not competition, is therefore the way to go. Developing partnerships across different institutions is important to establishing national resources to deal with diseases that we urgently need to combat. This will help maximise research productivity and minimise duplication of efforts.


Nearly twenty years later, the words of the HD activist that I listened to in Boston still reverberate in my head. I often remind myself that there is no place for ego in the search for solutions to human health problems. Since then, my philosophy of doing science has been simple: “Winning prizes is motivational, understanding the science of life is fundamental, but improving human lives as a result is monumental.”