Three Questions w/ Ajit Singh

In 1953, James Watson and Francis Crick studied remarkable X-ray images made by Rosalind Franklin—and then put their minds together to unpack what Watson called “the secret of life.” Their study “A Structure for Deoxyribose Nucleic Acid,” published in the journal Nature, revealed the geometry of DNA. In the decades since, scientists have discovered many of the details of how DNA works and how genes are turned on and off in both healthy and diseased cells. UVM post doctoral scientist Ajit Singh continues the search. He studies in the laboratory of Professor Karen Glass, a researcher in the UVM Larner College of Medicine’s Pharmacology department and the UVM Cancer Center—part of a team investigating the signals that regulate genes and how alterations in these pathways are involved in cancer and other diseases.

Rhonda Lynn, in UVM's Graduate College, connected with Singh to learn more about his story and his work.

You study DNA and the intricacies of how it works. Where did this interest begin?

AJIT: As an undergraduate, I did some research in human genetics to determine how common features are inherited in humans. I was surprised to see that, although I look physically very similar to my brother, we have many distinct inherited characteristics from our parents and grandparents, such as tongue rolling, straight/curly hair, and so on. This piqued my interest in learning how the information encoded in DNA is controlled.

You grew up in India and are now at the University of Vermont to extend your exploration of DNA. Tell us about that journey.

AJIT: I was born in Uttar Pradesh, a state in India. My father served in the Indian army as a medical officer. He often moved jobs, so I attended seven different schools throughout my studies. Each new home, new place, and the search for new friends made it a typical childhood adventure. This childhood experience has helped me adapt to new environments more quickly. After completing my high school studies, I moved to the southern part of India to attend Bangalore University.

After college, I joined Dileep Vasudevan's team at the Institute of Life Sciences in Bhubaneswar, India, to investigate the riddle of how DNA is packed into cells— eukaryotic cells with a nucleus, which includes all animals, plants, fungi, and many unicellular organisms. I worked in his lab on the structure and function of what are called “histone chaperones” and discovered their role in DNA packaging.

To deepen my understanding of this part of biology, after I finished my Ph.D., I moved to Karen Glass’s lab at the University of Vermont. My research aims to discover how chemical changes in these histone proteins help manage DNA packing and make DNA accessible for translation of the information in its unique sequence. To understand this, I use various cutting-edge structural biology techniques in her lab, such as X-ray crystallography, nuclear magnetic resonance, and cryo-electron microscopy.

Can you tell us more about your research and its wider goals?

AJIT: Many organisms, including humans, plants, and parasites, have their DNA condensed into chromosomes. Each chromosome is, basically, a bundle of linear DNA looped into a complex called the nucleosome, which is composed of histone proteins and DNA. A wide range of biochemical reactions alter how histones interact with DNA—and control how DNA is compressed into chromosomes. I’m interested in a portion of proteins called “bromodomains.” Proteins that have these domains interact with the nucleosome and are often involved in regulating DNA processes, such as replication and repair.

In Dr. Glass’s laboratory, my research focuses on bromodomain-containing proteins in a parasite, Plasmodium falciparum—the main cause of malaria around the world. According to a WHO estimate, there were 409,000 global malaria fatalities in 2019, with children under five being most impacted. There is a pressing need to define the molecular pathways that lead to disease from P. falciparum—due to this parasite's alarming growth in drug resistance in recent years. It's interesting that this parasite’s genome encodes eight bromodomain-containing proteins and that at least one of them is crucial for the development of malaria. My recent publication on the crystal structure of one of these proteins —called PfBDP1—will aid in the development of drugs to fight malaria.

When you're not in the lab, what do you enjoy doing in Burlington?

AJIT: I like to bike, hike, play cricket and tennis, watch American and Indian movies, spend time in nature, and cook. Over the past year that I've been living in Burlington, I've discovered that it is endowed with a wealth of natural beauty, such as the snowfall in the winter. It seems like someone is showering a flower on me. I tried skiing for the first time this winter! The autumn maple tree leaf color shift is really stunning too. UVM has a really welcoming and supportive atmosphere.