Toward the end of her Ph.D. training, Amanda Whipple (née Ward) faced a dilemma: She could continue to satisfy her curiosity through basic research or adopt an industry role with more potential to improve human health. Whipple chose industry and soon “stumbled into” a research project that would renew her penchant for discovery. That research on non-coding RNA in a genetic disorder called Angelman Syndrome still motivates her ongoing work as a newly minted MCB professor.
Whipple studies a set of genes that underpin a handful of currently untreatable genetic disorders. The genes in question are imprinted—meaning that cells inherit two copies, one from each parent, but only express one. “Normally, [in non-imprinted genes] your cells cannot distinguish between the two parental copies of a gene. So if a particular gene is ‘on,’ then both your maternal and paternal copy are on,” Whipple explains.
But imprinted genes are different. They carry a molecular mark that allows cells to distinguish the two parental copies and regulate them separately. For some imprinted genes, the maternal copy is expressed or “on,” while the paternal copy is silenced or “off.” For others, the silencing pattern is vice versa. This silencing means that individuals effectively have only one copy of imprinted genes.
The neurodevelopmental disorders Angelman Syndrome and Prader-Willi Syndrome both stem from mutations in imprinted genes. Whipple believes that studying the transcriptional regulation of imprinted expression and the function of imprinted genes will open new avenues for treating conditions like Angelman and Prader-Willi.
During her industry postdoc at the biotech company Ionis Pharmaceuticals, Whipple experienced firsthand the speed with which a “basic science insight” can be translated into a treatment. Ionis specializes in RNA-targeting molecules called antisense oligonucleotides or “ASOs” as treatments for genetic disorders, and Angelman was on the docket..
Most people with Angelman inherit both a mutant and an intact copy of the gene, but, due to imprinting, the intact copy is never turned “on”. “There are not a lot of options to genetically correct the mutated gene copy,” Whipple explains. But researchers thought it might be possible to un-silence the silenced copy.
In 2011, soon after Whipple’s arrival at Ionis, researchers at Baylor College of Medicine identified a long non-coding RNA responsible for silencing the intact copy of the Angelman gene. The finding spurred work at Ionis on an ASO that would target and shut down the silencing RNA. “It was exciting to witness the progression of a basic science discovery from an academic lab working on this non-coding RNA in neurons to its application to human disease,” Whipple recalls.
Prior to this postdoc, Whipple’s path to becoming a scientist was fairly straightforward. Born in California, Whipple spent most of her childhood in Tulsa, Oklahoma. “I really enjoyed Oklahoma as a kid, because it was a safe place to play outside,” she says. “My siblings and I just had to be back at the house for family dinner.”
Her first immersion in science wasn’t until her undergraduate years at the University of Oklahoma. The process of discovery soon drew her in.
When she began grad school at Baylor College of Medicine, Whipple chose to pursue questions with bearing on human health. She joined Thomas Cooper’s lab. “Part of the lab investigated fundamental questions regarding RNA splicing,” Whipple says. “But it was connected to the other part of the lab, which worked on [a] human disease with aberrant RNA splicing called myotonic dystrophy.”
In patients, myotonic dystrophy causes muscle wasting and potentially fatal heartbeat irregularities. The disorder traces to a type of mutation called a trinucleotide repeat expansion, where a repeating sequence of three base pairs is aberrantly copied in a gene many times over. Most people only have a few copies of the repeat, but myotonic dystrophy patients carry hundreds to thousands of back-to-back repeats. Whipple’s task as a graduate student was to identify proteins that mediate the toxic effect of repeat-laden RNA. It entailed many hours of coaxing mutant mice onto treadmills and looking for signs of muscle wasting in their gait.
This grad school experience solidified her interest in RNA’s roles in the etiology of genetic disorders. That interest led her to Ionis, where she championed the Angelman project from initial idea through preclinical trials in mice.
However, Whipple wasn’t sure whether she wanted to stay in industry. “The company has one particular technology–in this case, ASOs–that’s the core of who they are,” she explains. “They can study any disease potentially treatable by an ASO…At the end of the day, I am most interested in the biological question and want to use any approach necessary to answer the question.”
She adds that leaving the Ionis Angelman Syndrome project after successful proof-of-concept studies in mice was a difficult decision. Still, she sought out an academic postdoc where she could more broadly explore the function of imprinted, non-coding RNAs and found such a position in Phil Sharp’s lab at MIT.
Whipple arrived in Boston on January 1, 2015—just in time for the record-breaking winter known as Snowmageddon. Despite the cold and the deep snow drifts, relocating to Boston and MIT proved to be a good move both personally and professionally. She met the man who would become her husband, a shop teacher at MIT, through their church. The two married in 2016.
Meanwhile, in the lab, Whipple refined her research focus, zeroing in on imprinted genes that yield non-coding RNAs rather than proteins. Many imprinted non-coding RNAs occur in neurons, so she spent much of her time in the Sharp lab developing a method for culturing mouse neurons and identifying the effects of mutations in imprinted genes.
These lines of research have carried over to her new lab at Harvard. Whipple says that relocating her lab has gone smoothly, thanks largely to MIT and Harvard’s proximity. Her team already includes a research technician and an MCO graduate student who simply moved their benchwork about two miles up the street to the Biolabs building.
“It’s great to have another fellow RNA biologist as a colleague in MCB,” says MCB faculty Sean Eddy. “She’s studying RNA phenomena that I think are super interesting, and I’m hoping we have the opportunity to join forces with Amanda.”
Whipple’s lab will focus on three types of imprinted non-coding RNAs. The first are “long non-coding RNAs” (lncRNAs), which often inhibit expression of other genes. The RNA that silences paternal copies in Angelman Syndrome is one such lncRNA. The second group are the much smaller “microRNAs,” many of which also act as gene repressors.
The third set of imprinted genes code for “small nucleolar RNAs” (snoRNAs). “Probably the most unexplored area and the thing I’m most excited about doing in my lab is to work on understanding the function of these [imprinted] snoRNAs,” she says. Non-imprinted snoRNAs congregate in a region within the nucleus called the nucleolus and add tiny chemical tags to other RNAs, altering downstream gene expression. Imprinted snoRNAs may behave similarly, but their functions are uncharted territory.
So far, imprinted snoRNAs have only been found in neurons, a fact that intrigues Whipple. “Most [non-imprinted] snoRNAs are expressed everywhere, and they have this known function where they direct RNA modifications to specific targets,” she says. “But the snoRNAs we study are peculiar for three reasons: One, they are imprinted; two, they are only found in the brain; and, three, they have no known targets.”
Because Whipple is an RNA biologist who works mostly in neurons, she is thrilled to join a department with many world-class neurobiology labs, including the Dulac Lab, which is only a few doors from Whipple’s lab space.
“It is wonderful to have Amanda Whipple join MCB,” says MCB chair Venkatesh Murthy. “Her exciting and creative work on non-coding RNA in relation to the fascinating phenomenon of genomic imprinting brings a unique dimension to our department; at the same time, her research has strong and obvious links to the work of numerous colleagues here.”
“I feel incredibly blessed to be a part of the Harvard MCB community,” Whipple says. “I look forward to learning from my colleagues and trainees with both distinct and complementary research interests.”
by Diana Crow
