Prashanth Suravajhala, a biologist and bioinformatician, stared down the Brucella and human genomes and wondered whether the vast swaths of non-coding regions and pseudogenes might in fact encode “novel synthetic molecules.” These hypothetical proteins (HPs) could be unique to the individual organism and could interact with known proteins encoded by the genome. Thus, if real, the stretches of DNA that include what Suravajhala considered “known unknowns” could have significant implications for health, disease, and development. With this black box in mind, Suravajhala and his colleagues took an in silico approach to investigate HPs and determine whether they could be synthetically expressed. Said Suravajhala in a recent conversation, “as a part of my PhD, I gained an interest in identifying the ‘known unknown’ or KU regions in the genome.” The hypothetical nature of proteins putatively encoded by these sequences appealed to him, leading his PhD lab to develop a database of all human HPs. In 2007, he released the HYPO database (http://www.bioclues.org/hypo), describing the project in the accompanying publication:
Genes with unknown function are called orphan genes while their transcripts and peptides are called hypothetical proteins. There are many genes and their associated proteins that remain uncharacterized in the human genome. A database of human hypothetical proteins with ascribed functions could be helpful for biologists to search for potential proteins of interest.”
As he has continued trying to figure out whether supposed non-coding regions of the genome do in fact produce proteins, Suravajhala sketched out an idea that ultimately won the PLOS Synthetic Biology T-shirt design contest, an idea that groups of HPs may interact in novel and unique ways.
“We were working on something we called the interactome of hypothetical proteins across the human genome. What we realized is that at times you have the entire genomic repertoire of a human cell clustered to such an extent that all proteins in a specific organelle look like they’re overlapped when we make a heat map or protein-protein interaction map of that particular organelle.”
In contrast, of course, proteins separated by a membrane (for example, that of the mitochondria) rarely interact. Suravajhala suggests that this sequestration could let HPs within an organelle could cluster and form “flotillas” of interacting molecules. Obviously, significant work is still required to move these proteins and interactions from the realm of putative to biologically relevant, but the in silico modeling has begun to pay off with the annotation of 18 HPs in Brucella.
As he thought about how flotillas of HPs could lead to novel molecular interactions, Suravajhala created the design shown here where stretches of known protein-coding regions are interspersed with known unknowns (yellow), which could be tested through cloning and subsequent synthetic expression to look at potential products. When brought together in an organelle (represented by the abstract “hand”), this interacting set of proteins produces putative biological events (represented by the black and orange strand).
Suravajhala hopes that his work and abstract design will encourage synthetic biologists to think about unique ways to visualize their research. “I would like for the community to think about how synthetic DNA can influence their projects. I hope synthetic biologists will conceptualize and visualize genomes through images, giving them a creative means to use the genetic variation in genomes to create synthetic molecules.”
Outside of his research, Suravajhala is associated with Bioinformatics.org, based in Boston, MA. He also runs an organization he founded in 2005 called Bioclues. He says that Bioclues (which stands for BIOinformatics CLUb for Experimenting Scientists) is a non-profit virtual organization designed to provide a mentoring portal for young scientists.
“Currently serving over 3400 members from nearly 30 countries, we aim to bring together Indian bioinformaticians, foster a strong working mentor–mentee relationship, provide access to bioinformatics resources, and organize conferences and workshops. Additionally, we work to provide valuable information about research, training, education, employment and current events and news from bioinformatics, genomics, and related fields. Bioclues is an affiliate of ISCB. We work primarily in four areas, specifically, Mentoring, Outreach, Research and Entrepreneurship. So far we have had over 10 publications with over 15 conference proceedings, and organized 10 virtual conferences and workshops in collaboration with Bioinformatics.Org.”
After his PhD work, Suravajhala gained additional research experience through short-term post-doctoral projects. More recently, he has accepted a position as Bioinformatics Manager in the Department of Quantitative Systems Biology at Copenhagen University, starting January 19 of 2015. In this position, he plans on continuing his work on HPs and known unknown regions of the genome, shifting from eukaryotic cells to focus more on bacteria such as Brucella. His hope is that using bioinformatics and synthetic expression of putative bacterial proteins will lead to deeper insight into the etiology and progression of infectious disease.