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Sunday, March 29, 2009

SINGAPORE has invested substantially in the biomedical sciences, hoping that it will provide significant growth to its economy.

The scale and vision are breathtaking, and the scientific world is taking notice and talking about our bold initiatives.


On closer inspection, most of the investments have been in basic research.

International panels of advisers have recommended that the logical progression is to match these investments with the complementary development of translational and clinical research, leveraging on the high standard of medicine in Singapore.

The research spectrum

IN TRUTH, biomedical research is a continuum and the separation of basic (at the lab bench), translational and clinical (in the hospital) research is somewhat artificial.

Permit me to illustrate from my clinical practice from the trenches.

I am quite frequently referred patients with recurrent colorectal, appendix, ovarian and stomach cancers for re-operation. Such patients generally do not make it past one year.


But in one group of patients that we had re-operated on, together with chemotherapy perfusion of the abdomen, 70 per cent of them survived at least a year, and half made it past three years.

They were part of a clinical trial to develop better ways of treating them.

In an early stage, Phase 1 trial, new chemotherapy drugs, chemicals which target specific cancerous cells, and various combinations of treatments were tried on the patients, primarily to assess toxicity and side effects.

In a Phase 2 trial, promising therapies were then used to assess tumour response; whether such treatments prolong survival rates and improve quality of life.

These were then compared with known results of the current standard of care. In a Phase 3 trial, we compared the new treatment (surgery and chemotherapy perfusion) with the standard of care - palliative chemotherapy - which does not cure but slows the progression of the cancer and prolongs life.

In general, Phase 1 trials require the least number of participants. For Phase 3 trials, the numbers required go up to hundreds or thousands of patients.

Is it necessary to do Phase 3 trials which are logistical nightmares and require sometimes up to five years to complete? If such treatments could save lives, why not make do with phase two results as the basis of practice in medicine?

The reason is this: Many treatments done at different times will give significant differences in results. Other treatments shown to be promising in Phase 1 and Phase 2 studies have been shown in Phase 3 studies to actually be inferior.

True improvements to patient care can be borne out only when they work on large numbers of patients participating in later-stage trials.

In our laboratory at the National Cancer Centre Singapore (NCCS), we have, with the patients' consent, collected their tumours and immediately implanted them into the abdomens of mice.

The idea is that the rodents will be the experimental models for the diseases, showing how the tumours progress and react to drugs.

We have been particularly successful as the tumours grow as they would in human patients. We then use various drug combinations in these mice to work out the most successful combination.

This is an example of translational research - the process of taking scientific discoveries and using them to help patients.

Basic research questions to ask in intra-abdominal tumours or metastases are: Why and how do tumour cells get implanted in the abdominal lining? Is it by a simple shedding of tumour cells when the tumours penetrate the walls of an organ or is there a selective process where certain cells with specific biological characteristics favour the abdominal lining rather than, say, travelling in the blood and attaching to the liver or lungs?

As a rule of thumb, those doing basic research have much less need for patient materials or contact, and they study fundamental biological processes. In translational research, investigators study disease entities in animals, or handle tissue and other biospecimens without having direct contact with the patients.

It is generally only in clinical research that the investigator - a doctor - gets to shake his patient's hand.

The doctor's role in research

IT IS apparent that for good and successful clinical and translational research, labs and hospitals must be close to each other.

Dr Donald Tan, director of Singapore Eye Research Institute (Seri), recently showed that for a fraction of the funding of venerable institutions such as Johns Hopkins in the United States or the Melbourne Eye and Ear Institute in Australia, Seri is as productive, if not more so. Because the eye centre here treats so many people, this quality care provides tremendous opportunities for excelling in clinical and translational research.

As we delve deeper, it gets more complex.

Doctors involved daily in wrestling with problems of their patients come up with the relevant questions to ask. They often have insight not available to bench researchers working in isolation.

They also have the necessary clinical investigative skills to conduct trials. Perhaps because of continually dealing with uncertainty in the hospital, they are better able to cope with human experimental conditions (such as non-compliance) than bench scientists.

Most of all, clinicians have the trust of their patients whom they hope to recruit for their projects.

When things go wrong, as they sometimes do, doctors are also often able to salvage the situation. Nobel laureate Sydney Brenner said at a recent Humphrey Oei Distinguished Lecture at NCCS that modern biomedical research should move away from 'bench to bedside', to 'bedside to bench'.

What he means is that experienced, astute, well-trained clinicians should take a bigger role, in partnership with their fellow scientists, to address the major issues in medicine and biology.

Easier said than done.

All developed countries are grappling with the issue of getting more doctors to undertake research.

Indeed, the cadre of physician-scientists is shrinking as young doctors are forced to choose between performing research or practising medicine, but not both because of the time commitment required.

There are several other problems peculiar to Singapore.

Major medical schools in developed countries have a nexus of teaching hospitals clustered around medical schools. The academic departments and faculty lead in these teaching hospitals.

Harvard University has Brigham and Women's, Massachusetts General, Beth Israel and New England Deaconess hospitals, for example. London University has four colleges of medicine, each with their respective clusters of teaching hospitals.

At the National University of Singapore, there are virtually no academic departments or faculty members in any of the teaching hospitals other than the National University Hospital.

How is research to be conducted in these teaching hospitals and national centres without university support and faculty leadership?

What career structures are available for the academically inclined clinicians? The remuneration of a doctor is based on the volume of patients he sees.

This is compounded by the paucity of laboratory space on the hospital campuses which generally have few, if any, labs dedicated for research.

In addition, well-trained clinicians in Singapore have a strong 'default mode' - they can move to the lucrative private sector.

Unfortunately, we have seen many of our best and brightest do so.

Many of our doctors are sent to world-class medical institutions for further training.

Nearly all have returned with glowing reports from their host institutions, and many recount attempts by these institutions in recruiting them as faculty, as they excel in research.

An NCCS doctor recently did research training at the Van Andel Research Institute in the US, and in one year won two consecutive awards at the prestigious American Society of Clinical Oncology annual meetings.

Yet when we measure many of these doctors' productivity after they return, there is often a shocking reduction.

The discordance would suggest that it is a systems issue, rather than a shortage of talent.

In the West, with the academic model well-institutionalised, clinician-scientists are already a rare breed because of the time and effort needed to undertake such work.

In Singapore, the situation is made worse by heavy clinical loads, inconsistent reward systems and limited faculty support or laboratory facilities.

What of Singapore's biomedical initiatives?

Can we afford to be sanguine, relying on the millions we have invested and the foreign talent we have attracted?

Critical to the equation is systems re-engineering; and this calls for a shake-up of how hospitals and institutes are co-located, and the treatment of doctor-scientists here.

We need a diversity of robust medical institutions where doctors can have parallel careers in academic centres.

If clinical and translational research is deemed so important, we can expect to be a lot more successful in persuading them to embark on that long and often tortuous career path.

But first, they must see substantial increases in research funding for their work, and have access to laboratories where they can be mentored and then allowed to experiment and think freely - a mixture of rigorous training and nurturing of creativity.

The doctors and clinician-scientists must also be given time to simply think.

With this in place, I am confident they will rise to the occasion. Doctors, in my experience, do not so much believe what is said, but rather act on what they see is being done.

Excitement and high expectations are, however, a double-edged sword.

If we do not succeed, we will end up with a large pool of disenchanted but highly trained doctors and clinician-scientists.

There will be no shortage of countries and reputable institutions willing to snap them up.

Therein lies the paradox of our biomedical initiatives. We can't afford to fail.

The writer is director of the National Cancer Centre Singapore, vice-dean of Clinical & Faculty Affairs at the Duke-NUS Graduate Medical School and assistant CEO of Singapore Health Services.

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