The revolution will be multi-disciplinary
An image glows on the big screen: the colour of lavender, luminously backlit, populated with a precise grid of more than 100 slightly tapered blocks. As small objects flow from right to left, it becomes clear that the grid is a sort of maze of obstacles. The objects stretch and flow through the tight channels easily. But when they change shape, becoming more stiff, they get stuck in the channels and obstruct the flow.
Pioneering researcher Subra Suresh offers the brief video to illustrate the workings of sickle cell disease, a hereditary disorder that affects millions of people worldwide. The grid, he explains, is within a tiny microfluidics device with channels – just a few micrometres wide – to simulate blood vessels. Because of a defective gene in the haemoglobin, red blood cells that have discharged their oxygen into body tissues then transform into stiff sickles as they circulate back to the lungs.
In this state they can obstruct blood vessels, causing painful swelling and sometimes even strokes that are acute outcomes of the disease. The effect was clearly visible on the screen, cell by cell, as researchers reduced and increased the oxygen.
In a recent TWAS Medal Lecture, Suresh said the vivid image on the screen also reflects a revolution in medical research. By drawing from chemistry, biology, physics and a range of other fields, and with engineering to develop powerful new technologies, researchers are improving their knowledge of diseases such as sickle cell disorder, cancer and malaria. With new understanding comes the potential for new treatments.
"If you talk to most chemists," he said, "everything is usually chemistry. If you talk to many biologists, everything is typically centres around biology. If you talk to most geneticists, everything is probably based on genetics. What I am trying to show here is a combination of all of this. The intersection of engineering, sciences and medicine is very important."
Suresh also emphasised the importance of physics. It influences nanotechnology, biorheology and microfluidics. It helps researchers to understand the physical properties of blood cells and tissues at the molecular level. Taken together, these new tools give researchers insights that would have been impossible a decade ago, or even just a few years ago.
Suresh, a 2004 TWAS Fellow, has been at the forefront of the multi-disciplinary approach that is reshaping medical research, both as a researcher and as the leader of major research institutions. Today he is the president of Nanyang Technological University in Singapore. He served as president of Carnegie Mellon University in Pittsburgh, Pennsylvania (USA) from 2013-2017; he directed the U.S. National Science Foundation from 2010-2013; and earlier was the dean of engineering at the Massachusetts Institute of Technology (MIT). This path began in 1977, when he earned his bachelor of technology degree at the Indian Institute of Technology in Madras.
The pioneering work of Subra Suresh is featured in a new issue of the TWAS Newsletter.
Suresh is globally influential for his pioneering work on the mechanical properties of engineered and biological materials and for establishing connections between cell mechanics and human diseases. He has authored over 240 research articles and three books, and has 25 patent applications.
He delivered the TWAS Lecture on 28 November 2018 in Trieste, Italy, at the Academy's General Meeting. The 50-minute talk eloquently surveyed the landscape of contemporary medical research, moving with easy fluency from medicine to engineering and physics, and from the workings of the human spleen to malaria and cancer.
Three revolutions in science
Through much of his talk, Suresh focused on the importance of understanding cell properties, and how disease changes the physical properties of the cells.
For example, consider red blood cells: They are disc shaped, almost like a lozenge, about eight micrometres wide. (By comparison, a human hair is about 50 to 100 micrometres.) Suresh compared the cell to a little sack that's full of liquid haemoglobin.
During a life span of about 120 days, a red blood cell circulates millions of times through the body. In the lungs, it picks up oxygen. It carries the oxygen through the body, discharging it into the tissues. It must be able to squeeze through the narrowest vessels of the brain – about two to three micrometres in diameter. Then it returns to the lungs for an oxygen recharge.
"That means it has to stretch by more than 100% each time it navigates through one of these small blood vessels," Suresh explained. During its life span, "it has to stretch and go back to its shape many, many times.... The elasticity and the viscoelasticity of the red blood cell has to be at optimum levels, otherwise the cell will not be able to carry out its biological function.
"And if it loses its ability to stretch and go back, and if the cell cannot easily move through small blood vessels, for whatever reason, we will get a disease."
In Suresh's view, three revolutions now underway are dramatically improving researchers' ability to understand and visualise the physical properties of cells.
- Physics: Researchers are learning how cells are affected by various physical properties – acoustic, magnetic and electrical properties, for example. This helps to create new tools for analysis. Tools developed in the last ten to 15 years – including "optical tweezers" or "laser trapping" – enable researchers to capture single DNA molecules and to poke, prod and stretch the molecules with incredible precision to understand their characteristics. These advances have direct bearing on the future of diagnostics and testing drugs for therapy.
- Computation: Increasingly, research requires both experimentation and computer-driven simulation. As computers have developed "phenomenal" power in the past ten years, he added, "we can ask a lot of questions that cannot be answered either through computations alone or through experiments alone."
- Genetics and genomics: Technologies that allow for precise genetic manipulation create opportunities in the laboratory for understanding diseases in new ways.
With parallel advances in fields like nanotechnology and materials science, these revolutions are having an impact across the fields of medical research.
"Nature wants to work in a very precise way," Suresh said. "And these kinds of tools at the intersection of engineering and physics help our understanding."
Malaria and cancer: case studies
The physical characteristics of cells, new technologies, and the latest research – Suresh wove these strands together in case studies that showed the advances and potential advances in research on disease.
Malaria: Plasmodium falciparum is the parasite linked to 50% of malaria cases worldwide – and 99.7% in Africa. The UN's World Health Organization reports[link: https://www.who.int/malaria/media/world-malaria-report-2018/en/] that it is also the most lethal, linked to the majority of 435,000 malaria deaths worldwide in 2017.
After a person is bitten by a mosquito that carries the parasite, it gestates in the body for seven to ten days. Then the parasites (merozoites) emerge from the host's liver into the bloodstream, where they enter the red blood cells.
Soon the cell begins to stiffen. Typically within 24 to 48 hours, the cell becomes so sticky that it adheres to the inside of the blood vessel. Then it ruptures, releasing more parasites into the bloodstream, to infect other red blood cells. "The body tries to fight it by raising the body temperature – that's manifested as fever," Suresh said. "So there is a direct connection between physical properties and clinical symptoms in malaria."
Research by Suresh and his colleagues used optical tweezers to assess the stiffness of the infected blood cells. They found that the factor of stiffening was far greater than previously believed.
"When the dosage of an anti-malaria drug is given without fully knowing the mechanisms of how blood flows and the extent of red blood cell stiffening," he said, treating the disease is bound to be inexact. But an improved understanding of the cells' stiffness "can shape clinical decisions, such as the use of medications, to improve blood flow."
Cancer: Typically, cancer is diagnosed through various biomarkers – tissue samples, for example. Today, researchers are exploring whether cancer can be detected much earlier by identifying cancer cells circulating in the bloodstream, in emerging fields that include such terms as liquid biopsy and precision medicine. But, says Suresh, there's a basic problem:
"Can you take a few drops of blood...and find out if there are any circulating tumour cells? Can you isolate that one rare cancer cell out of hundreds of thousands of healthy cells? Essentially it's finding a needle in a haystack."
Current technology, such as filters or centrifugal separation, can change the properties of the blood cells, and that can cloud results. In recent years, Suresh and an international team of colleagues have begun to study whether sound waves can be used to separate cells of different sizes or different physical properties.
After some preliminary experiments, Suresh said, researchers took blood samples from three women who had been diagnosed with breast cancer.
"We did a blind test, with some other patients who did not have cancer," he explained. "Can we detect who has cancer, who does not, or whose cancer is in remission and who's is not? From the blood samples, we could detect one cancer cell among as many as 10,000 (healthy) cells."
The method needs to be refined for clinical use. Still, the potential value is clear.
"The goal is not to replace any existing method," he said. "But if we could have one more diagnostic tool, if we can diagnose someone's cancer a little bit earlier, then how many lives could we save? That's the spirit of this work."
Edward W. Lempinen