Harvard University - Department of Molecular & Cellular Biology

SRIRAM SRIKANT AND ANN RAN RECEIVE DEPARTMENT HONORS

by Cathryn Delude

October 4th, 2013

Two MCB graduate students, Sriram Srikant (G3, Rachelle Gaudet and Andrew Murray labs) and Fei Ann Ran (G7, Feng Zhang lab at the Broad Institute) were honored for outstanding research achievements at the department’s annual Woods Hole retreat in September 2013.

(l to r) Rich Losick, Sriram Srikant, and Catherine Dulac

Sriram Srikant received the Peralta Prize, which is awarded annually to an MCB graduate student entering the third year of study. The prize is named for the late MCB Professor Ernest Peralta and recognizes the most outstanding dissertation proposal submitted by a second-year graduate student. Srikant said, “This award is truly special to me in that it acknowledges the contributions of members of the Gaudet and Murray Labs, the current G3s (my classmates), and everyone in the department in conversations that have kept me thinking constantly and make day-to-day work great fun! I am very grateful to my PIs, Dr. Rachelle Gaudet and Dr. Andrew Murray for their mentorship, suggestions and the intellectual freedom they give me in my PhD; and my committee Dr. Harrison, Dr. Kahne, and Dr. Denic for their time and thoughtful suggestions in taking my ideas forward.”

Ann Ran (l) and Matthew Meselson

Ann Ran received the department’s Meselson Prize, which is awarded to an MCB graduate student or team for “the most beautiful experiment of the year.” Ran said, “I’m really excited to have the opportunity to share our work. I'm very lucky to have many great collaborators and mentors who made this work possible, so I'm quite thankful for that.” The prize was first given in 2008 to commemorate the 50th anniversary of the groundbreaking 1958 experiment by MCB Professor Matthew Meselson and Franklin Stahl – at the time a Caltech grad student and post-doc, respectively. Their experiment proved that DNA replication occurs when each strand copies itself to produce two identical daughter strands. The Meselson-Stahl work has been called ‘the most beautiful experiment in biology.”

About the Prize Recipients

Sriram Srikant: Peralta Prize
Dissertation Proposal:

Dissecting the mechanism of Ste6, an ABC transporter involved in S. cerevisiae mating.

“I will ask how molecular machines achieve substrate selectivity that can be tuned over evolutionary time. ATP-binding cassette (ABC) transporters are a ubiquitous class of proteins that contain remarkably conserved ATPase domains yet transport very diverse substrates. ABC transporters make pathogens and cancer cells resistant to multiple drugs. I will study the substrate selectivity and transport mechanism of Ste6, the ABC transporter that exports the farnesylated mating pheromone, a-factor, in S. cerevisiae, the budding yeast. The combination of pheromone and transporter is evolutionarily ancient: lipid-modified pheromones and Ste6-like transporters are present in the mating systems of fungi that diverged over 500 million years ago. I will use mating assays in S. cerevisiae to study the ability of this phylogenetic set of ‘mutants’ to complement Ste6 deficiency in a-factor export. This survey, along with studies of the export of a comprehensive a-factor mutant library, will help us identify features of pheromone and transporter that control transport. For biochemistry, I will reconstitute the transport of a-factor across artificial membranes using purified Ste6. This isolated system allows the use of substrate and nucleotide analogues to trap intermediates in transport and test predictions of mechanistic models. The complimentary approaches of in vivo assays in yeast and in vitro biochemistry and structural studies will allow me to understand the mechanism, physiology and evolution of these important and ubiquitous transporters.”

Nomination
In their joint nomination of Srikant’s proposal, Professors Murray, Gaudet and Daniel Kahne wrote: “He encapsulated his original ideas in a clear, concise proposal and defended them with intelligence and vigor. He demonstrated a mastery of both approaches – biochemistry and genetics – and the different kinds of experiments that these approaches enabled. He had an interesting perspective on the prioritization of the approaches, favoring the genetic approach as more feasible to obtain information about Ste6 substrate specificity. This was an interesting discussion with three biochemists as examiners. He must be pretty good since he convinced us he was right!” Elsewhere, they referred to him as “brilliant, fearless, creative, outgoing, helpful, and a stellar experimentalist,” and also humble and charming.


Ann Ran: 2013 Meselson Prize
Beautiful Experiment

Ann Ran carried out her “most beautiful experiment” in the laboratory of Feng Zhang at MIT and the Broad Institute. “We adapted a microbial immune system called CRISPR for gene editing applications in mammalian cells, and showed that this system is very easy to customize and implement for diverse applications,” she explained. “I hope that being able to change the DNA of organisms in such an easy and precise way will significantly enable learning how genetic variations contribute to normal biology and disease, and beyond this, creating possibilities for engineering synthetic pathways.”

Nomination
In nominating Ran for the Meselson Prize, Professor Zhang praised “her passion for science, motivation, and insightfulness in experimental planning and design. She has already emerged as an intellectual leader in CRISPR-based genome manipulation technologies as well as made significant contributions that have catalyzed one of the most exciting waves of research activities in recent years.” Her “particularly elegant and impactful” experiment exhibited thoughtful design and careful troubleshooting. “[I]n one fell swoop, Ann was able to demonstrate that the microbial CRISPR system can be transplanted into eukaryotic cells and can be used to facilitate simultaneous editing of multiple locations in the human genome" – something that has long been “a tantalizinig dream.” He noted that over 2,000 laboratories have received reagents developed through these studies, and Ran has published a protocol in Nature Protocol to make it easy for other labs to use.” He also said that she is an engaging communicator whose career is off to a “meteoric” start.

In support of Ran’s nomination, Professor Gregory Verdine wrote that her “spectacular results…represent a quantum leap forward for the field of precision genome-editing and that set the stage for therapeutic genome manipulation in human subjects.... These experiments pave the way for highly efficient, targeted disruption of genes, and also for correction of disease-causing defects in cells… If these are not beautiful experiments, I do not know what are.”