From bioinformatics to biochemistry
Third-year graduate student Arish Shah worked in genetic sequencing before discovering a passion for developmental biology, striving to show that not all ribosomes are identical.
Besides the laptop, notebook, and usual laboratory paraphernalia, Arish Shah’s desk is adorned with mementos of the people and places from his life pre-MIT. He proudly displays a “don’t forget the rain” cross-stich reminding him of Seattle, a branded “Illumina intern” pin representing his time at the prominent biotech company, and a pair of mysterious, eccentric glasses that once belonged to an eminent biologist from his former research institute. Shah is currently a third-year graduate student specializing in biochemistry and developmental biology, although a few years ago he would have classified himself as a computer scientist, shying away from wet lab work.
Growing up in Silicon Valley, Shah had always assumed he would go into computer science. After all, that’s the career his brother had chosen. In 2007, he enrolled at the University of California, San Diego as a bioinformatics major, which, as he recalls, was heavy on the computer science and light on the biology.
“In the age of ‘Big Data,’ we rely heavily on algorithms to help process large amounts of data and find trends in our results,” he says. “Bioinformatics was this cool place at the intersection of biology and computer science — both things I really liked — so I went for it.”
Between his junior and senior years, Shah interned at Illumina, writing code that ran on the DNA sequencing machines to analyze biological samples. With the rise of modern “next-generation” sequencing technologies, he recalls the company was “hiring left and right.”
Following graduation, Illumina invited him back as a full-time bioinformatician, generating code that would allow their machines to analyze short RNAs. Although he generally enjoyed his work, after a year he started to feel like something was missing.
“At a certain point, I realized I wasn’t developing anything new,” he says, “I was just implementing things that other people had created.”
Soon after, Shah left the Golden State for the Emerald City, taking a job as a research technician at the Fred Hutchinson Cancer Research Center in Seattle. “They were looking for a computer scientist specializing in Illumina sequencing data analysis, and I was a bioinformatician looking to learn wet lab techniques,” he says, “It was a perfect fit.”
At the time, Cecilia Moens’ lab was using reverse genetic approaches to generate an array of mutations in the zebrafish genome, distributing these animals to researchers requesting specific modifications to specific genes. Shah arrived just as CRISPR, TALENs, and other genome editing technologies were replacing traditional genetic approaches. He ultimately developed a new CRISPR-based reverse genetic screen in developing zebrafish to create mutations quickly and efficiently at low cost, and then began a separate project investigating tumor cell motility and dissemination. He fondly recalls his days sitting in the dark at the microscope examining embryos and listening to podcasts.
“Designing an experiment, sifting through the data, and uncovering some previously unknown truth is incredibly gratifying,” he says. “It wasn’t until I joined a developmental biology lab that I realized you really need a core understanding of basic protein interactions and regulatory systems to develop new technologies and tools. I felt like I was beginning to contribute to humanity’s collective knowledge.”
Zebrafish are used in many labs to understand development. Crossing a male and a female fish on one evening will yield hundreds of embryos the next morning, and the progeny are initially see-through. This means that processes characteristic of all developing vertebrate embryos, like cell division and migration, are easy to track under a microscope.
After four years, Shah determined that — if he wanted to run a company or a lab of his own one day — he would need a PhD. He arrived at MIT in the fall of 2016, and began searching for a lab that would allow him to continue pursuing developmental research in zebrafish. He ultimately settled “somewhere between developmental biology and biochemistry,” selecting a new group headed by Assistant Professor Eliezer Calo (who started at MIT that same year). When he joined the Calo lab, Shah was one of just three lab members. Today, the team has grown to more than 10 people, including graduate students, postdocs, technicians, undergraduate researchers, and the occasional summer student.
Shah enjoyed the having the autonomy to design his own project and worked closely with Calo to set a research trajectory, which had him starting from scratch. While exciting, the downside was that there was nothing to build on — no preexisting data sets, databases, antibodies, or protocols. Although it wasn’t easy getting started, Shah now knows the intricate details of each and every one of his experiments, inside and out.
“Coming in, I had little to no background in biochemistry,” he says, “but I wanted to challenge myself by joining a lab that was working on a problem I’m interested in — developmental biology — using a new approach — biochemistry.”
Although Shah describes the Calo lab as being extremely multifaceted, the group rallies around the ribosome, the macromolecular machine that turns RNA into proteins. Specifically, the lab examines how ribosomes are built, how they’re used, and how they’re regulated.
According to Shah, scientists operated under the model that all ribosomes are identical. But in recent years it’s become increasingly apparent that not all ribosomes within the same organism, tissue, or cell are exactly the same. These machines are made of large ribosomal RNAs (rRNAs) in charge of carrying out protein synthesis, and are stabilized by binding a number of different ribosomal proteins. Zebrafish, Shah notes, contain two different kinds of ribosomes (let’s call them Ribosome A and Ribosome B) throughout their lifetimes, each comprised of different rRNAs.
“The obvious question is, Why would evolution result in two different rRNAs in the same animal?” Shah says. “Unless, of course, they have two different functions. And that’s what I’m trying to figure out.”
It appears that not every zebrafish cell contains both Ribosome A and Ribosome B at the same time. In fact, Ribosome B is only expressed during oogenesis as the egg is forming. At that point, Ribosome A — the more common of the two — is still turned off. However, as the animal continues to develop, Ribosome B is gradually replaced by Ribosome A.
“That’s what we’re really interested in,” Shah says, “because the functional difference between the two ribosomes is likely important for development. We just don’t know how; perhaps the ribosomes are translating different mRNAs.”
In 2018, Shah earned the Graduate Research Fellowship Award from the National Science Foundation and the Teresa Keng Graduate Teaching Prize from the Department of Biology. With several years of graduate school still remaining, he hasn’t yet decided whether he’d like to remain in academia long-term or return to industry.
“I just want to be really invested in the projects that I work on,” he says. “Academia is definitely set up such that I could do that, but if there’s an industry job that aligns with my scientific interests, I’d go that route too — as long as it’s curiosity-driven and discovery-based.”
To Shah, developmental biology epitomizes both those things. The job of the developmental biologist, he says, is to parse an elegant system that’s innately programmed for life. He points to his favorite quote from 20th century embryologist Viktor Hamburger: “Our real teacher has been and still is the embryo, who is, incidentally, the only teacher who is always right.”