The melding of multiple scientific disciplines has again proven a powerful force for discovery, with a team of Singapore doctors and engineers debunking a major assumption in cancer research that has persisted for about half a century.
Scientists have long thought that tumour-like cell clusters circulating in the bloodstreams of cancer patients are cancerous, but the Singapore team has shown, with samples from 80 colorectal cancer patients, that they are not.
One of the lead researchers, Dr Tan Min-Han of the Institute of Bioengineering and Nanotechnology (IBN), said that after the paper came out in the journal Science Translational Medicine in June, many researchers in the field, whose assumptions had just been overturned, responded with "oh dear" and "oh my gosh".
But he added: "Science is always self-correcting, so this is the basis for moving forward."
The team that made this breakthrough was made up of researchers from the Agency for Science, Technology and Research, the National University of Singapore, and several hospitals and healthcare institutes in Singapore, and included Dr Koh Poh Koon, Minister of State for National Development and Trade and Industry.
We have very good collaboration with the hospitals and we can have access to samples - we are very grateful. And we know what kind of things they are worrying about.
IBN EXECUTIVE DIRECTOR, PROFESSOR JACKIE YIN, on being able to access samples from 80 colorectal cancer patients for research.
To make the discovery, they had to develop new scientific tools.
One of them was a "microdevice", a system of syringes and a pump that draws the blood sample through a tiny custom-made sieve.
The sieve is a silicon wafer punched with microscopic holes which let blood cells through but retained the cell clusters the researchers were interested in.
IBN executive director Jackie Ying, who spearheaded its design, said the microdevice reduced the time needed to isolate the cell clusters from hours to "a matter of minutes", produced a purer extract, and kept more cells alive.
Professor Ying added that samples could arrive at IBN at any time of the day from patients being treated in hospitals, and quick processing was crucial to keep the cells viable for study.
After isolating the cell clusters, the researchers had to develop another tool to read the genetic information in the cells to determine whether they were cancerous and where exactly they came from.
This meant not only reading a cell's DNA to determine whether it was cancerous, but also reading the RNA to ascertain the type of body tissue the cell belonged to.
RNA "translates" part of a cell's DNA to fulfill biological functions specific to a given type of tissue.
To accomplish this, the lead author, Dr Igor Cima, designed a set of chemical reagents that could simultaneously read the DNA and RNA from a single sample.
Dr Tan said existing methods could not read one type of sequence without destroying the other, making it difficult to be sure that the DNA and RNA came from the same cell.
When they compared the DNA and RNA sequences with genetic databases, the scientists discovered that the cell clusters floating around in the bloodstream actually originated from the non-cancerous blood vessels surrounding the tumour rather than from the tumour itself.
Drawing an analogy between cancer and an army, Dr Tan said: "These (cell clusters) aren't the front-line troops you thought they were, but perhaps they are still logistics and medical platoons supporting any army... That still gives information about how the army functions."
Dr Wong Seng Weng, medical director of The Cancer Centre, an independent clinic under the Singapore Medical Group, noted that the impact of the erroneous assumptions in the past on actual cancer diagnosis and treatment is limited.
"Diagnosis and treatment of cancer is not based on circulating tumour cells. There is still much controversy over the accuracy and utility of circulating tumour cells in the day-to-day management of cancer patients."
Meanwhile, the approach taken in the study shows promise for wider applications in the health sciences.
IBN has refined the microdevice into an automated "third-generation" version supported by software, and is looking for interested companies to commercialise it.
Devices like this could extract and analyse other potentially useful markers in blood and bodily fluids to help diagnose diseases, said Prof Ying.
Such markers include exosomes, small vesicles released from cells into body fluids like blood and urine that could serve as indicators of health and disease.
Prof Ying said: "We have very good collaboration with the hospitals and we can have access to samples - we are very grateful. And we know what kind of things they are worrying about."