This year, the Duke-NUS faculty published a number of brain-related studies that have contributed meaningfully to health and science research. This includes several that can be translated into solutions and treatments for patients and the public.
Associate Professor David Silver, Deputy Director of the Cardiovascular and Metabolic Disorders Programme and Director of Graduate Studies at Duke-NUS, led two important studies on the brain published in 2015. He was senior co-author of two Nature Genetics papers that proved that certain special fats found in blood are essential for human brain growth and function, further substantiating his 2014 findings published in Nature.
The DHA mystery
Prior to his appointment in Duke-NUS in 2012, Dr Silver was with the Albert Einstein College of Medicine, where he made the notable discovery of how the body stores fat. At Duke-NUS, his research continues to focus on lipid biochemistry, physiology and cardiovascular disease, and the ‘DHA mystery’. He recalled asking himself: “Is DHA really important for the brain? How is it transported there? How is it absorbed by the brain – and how does it get past the blood brain barrier?”
Together with Dr Long Nguyen, who joined Dr Silver’s lab in late 2012 and is now an Assistant Professor at the National University of Singapore (NUS), they tested and proved the theory that DHA was absorbed into the brain via a transport protein called Mfsd2a – a revelation worthy of a Nature paper publication. The Duke-NUS-led team also discovered that DHA is transported in a chemical form, called lysophosphatidylcholine (LPC), and found that mice without the Mfsd2a transporter had smaller brains. This led them to postulate that DHA is essential for brain growth in mice and humans.
Proof in the pudding
Fast forward to 2015 – Dr Silver approached geneticist Professor Joseph Gleeson, who had been studying a lineage with brain mutations in Egypt and Libya. Dr Silver theorised that these families must have similar mutations to the ones his team had engineered while doing his DHA research.
Working together, the Duke-NUS and Rockefeller University teams found that the two families indeed had Mfsd2a mutations that meant reduced transport of LPCs to the brain. This resulted in severely reduced brain size (called microcephaly), leading to death in children between the ages of one and six years.
In a separate case, Professor Andrew Crosby from the University of Exeter got in touch with Dr Silver about a similar mutation in a family from North Pakistan. Together they found another type of mutation in the Mfsd2a gene that reduced the transport activity of LPCs, causing intellectual disabilities, impaired control of limbs and absent speech.
Both studies established a link between the transport of LPCs by Mfsd2a and human brain growth and function. They also marked the first time a genetic disease was related to LPC transport in humans.
On the horizon
Taking his work to the next level, Dr Silver is developing novel LPC-based technologies such as a blood-brain barrier drug delivery platform and clinical nutrition, but maintains that his heart remains in the laboratory. “I love having the opportunity to make fundamental discoveries that could be of clinical importance,” he said, and will continue to delve into basic questions about biology and disease.
Professor Silver, the mentor
Apart from his focus on research, Dr Silver is a strong believer in mentorship. Dr Nguyen remarked, “Dr Silver is the kind of mentor that truly mentors. He gives his students and mentees the chance to prove themselves, allows them to test their theories and also gets into the lab with them to do the work. For example, Dr Silver gave Debra Quek, a Duke-NUS MD/PhD student in his lab, the chance to perform key experiments and analyse data for the Nature Genetics study published with Dr Crosby’s team. She was named one of the first authors, a rare honour for a student.”