Pseudophosphatase research looked like a dead end, but it didn’t stop the Hinton lab
Shantá D. Hinton calls herself a daredevil, but she’s careful to add that it doesn’t mean that she’s reckless.
She is a thorough and careful researcher, leading a lab of William & Mary undergraduates probing the mysteries of a class of proteins. Hinton’s group is one of the few laboratories in the United States studying pseudophosphatases, proteins whose very name makes many researchers shy away.
“The word was going around,” Hinton explained. “Anything with ‘pseudo’ in it is going to be a grant-killer.”
The specter of a grant-killer floating over pseudophosphatase research left the field wide open; Hinton was daring enough to concentrate on pseudophosphatases, focusing on a particular molecule called MK-STYX. Her disregard of the word that was going around paid off recently in the form of a $900,000 National Science Foundation grant. She was also awarded a Reves Faculty Fellowship this year.
Hinton is an associate professor in William & Mary’s Department of Biology. She explained her lab’s work with MK-STYK to a packed house at the university’s semiannual Tack Faculty Lecture in 2017. She explained the biochemical functions of various enzymes: kinases add a phosphate group to a protein, while phosphatases remove it. The removal/addition of phosphates changes the function of the protein — it’s just one part of the protein mix and synthesis that is the busy life of a cell.
Then there are the pseudophosphatases, like MK-STYX. These proteins do part of the job of phosphatases. They “grab on” to the phosphate group, but don’t consummate the removal. That’s where the “pseudo” comes from.
Hinton says that the study of kinases, the phosphate-adding enzymes, is quite advanced. (“Because, frankly, kinases are not as challenging to study,” she notes.) On the other hand, the research community had largely written off pseudophosphatases as do-nothings. They seemed to have no function and maybe were a biochemical evolutionary artifact.
But a number of years ago, Hinton’s lab found that MK-STYX was not a cellular freeloader after all. It reduced the number of stress granules in a cell. When a cell is under environmental stress, it protects itself by halting the translation of messenger RNA. The messenger RNA’s job is to transfer genetic data from the DNA. That genetic data is necessary for the synthesis of proteins.
When the messenger RNA stalls, it clumps up into stress granules. The clumps choke the transmission of genetic information to the cell’s protein-synthesis job sites. The cell can’t make proteins, because it doesn’t have the genetic message.
Hinton’s research on cells from the “immortal” HeLa cell line, obtained many years ago from a cervical cancer in a woman named Henrietta Lacks, indicated that MK-STYX can free up the transmission of genetic information by reducing both the size and number of stress granules.
And Hinton’s research discovered that MK-STYX was not just a one-function protein. She found that it also spurs neuronal growth and development. The NSF funding will allow her to drill down deeply into the functions and mechanisms of MK-STYX and similar molecules.
“This new funding will allow my lab not only to be expert in pseudophosphatases, but I think people also will come to look to us for expertise in pseudo enzymes in general,” she said. “It will allow me to take the time to tease out something that is supposed to be an inactive member of a family and find out how it really functions.”
Hinton plans to use the funding to bring on a lab technician and expand the scope of her lab beyond MK-STYX. She’s particularly interested in another phosphatase called tensin, a homolog of a tumor suppressor. The NSF funding will open up opportunities for biochemical assays and mass spectrometry: “Mass spectrometry might allow me to investigate how MK-STYX is really doing its job,” she said.
And, she says, much of the money will be used to support her students. Like many labs at William & Mary, much of the research in the Hinton Lab is done by undergraduate students. There are students working most of the year, including a cohort of a dozen or so who spent the summer session learning the skills and procedures of basic research. Many of them find themselves as co-authors on peer-reviewed journal papers outlining discoveries that may one day be part of clinical approaches to the fight against a whole slate of neurological disorders ranging from confusion to delusion to Parkinson’s.
“These are students who may or may not go on to work in research labs as a profession, but they'll at least begin to understand the research environment and so become more informed citizens,” she said.
Many of the students get experience beyond the considerable basic research conducted at Hinton’s lab in the Integrated Science Center. Hinton says she wants certain of her students to get a taste of life in some of the world’s leading biomedical facilities. She has an arrangement with a colleague at Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital in Toronto.
“Each summer I like to send two — or at the most, three — students to Mount Sinai. I go up for a week to acclimate them to the research environment and get them started on being trained in a high-throughput lab,” Hinton said. “You are moving fast! It's exciting! They ask questions all day every day.”
She also likes to give students in her Cell Signaling and Associated Disease course the opportunity to visit Cold Spring Harbor Laboratory on Long Island.
“They can interact with scientists at the top of their field,” Hinton said. “There's also a good chance if they'll be able to witness a doctoral defense.”
Hinton was a postdoctoral fellow at Cold Spring. She described how one of her students asked her how she could give up such a life. The student pointed out that research at the Hinton lab at William & Mary is carried on at a much slower, more deliberate pace.
“Why did you leave this?” the student asked, captivated by the energy, the pace, the air of impending discovery that permeates high-throughput research labs. “Why did you give this up…for us?”
“I looked at her and I said, but every faculty member at William & Mary gave this up. If you look at all of us, and all our pedigrees, you'll see that we all gave this up,” Hinton said. “But then we can produce these people like you — who ask us why we gave this up.”
