From her bright, sunny office with an expansive view of Mission Hill, Anna Krichevsky, PhD, of the Department of Neurology, speaks passionately about her research involving microRNA (miRNA) and its potential to help patients with neurologic diseases ranging from brain tumors to Alzheimer’s Disease (AD). On her wall, beside some striking yellow orchids, are framed images of human neurons that provide a daily reminder of the brain’s intrinsic beauty.
Krichevsky’s mother was a physician, but as a young woman, Krichevsky realized she was more interested in biomedical research. Krichevsky was fascinated by gene-regulating ribonucleic acids (RNA), and she decided to pursue a PhD in Molecular and Cellular Biology. During her Post-Doctoral Fellowship in Neurobiology, news broke about a recently discovered RNA molecule, and Krichevsky read the seminal papers about miRNA with great interest. She would go on to devote her career to studying them.
Noncoding miRNA are tiny nucleic acids that are expressed in most eukaryotic organisms and are present in all human cells. However, due to their small size, they were left undiscovered in humans until 2001, when three groups simultaneously published definitive data in Science showing that these small RNAs are expressed in various animals, including humans.
Around the same time, Krichevsky was pursuing her post-doctoral fellowship at BWH in the lab of Kenneth Kosik, MD, studying RNA neurobiology. She read these articles and was shocked; miRNA was a new class that contained hundreds of previously unknown molecules. This was a fundamental discovery – one of a few that may happen in a scientist’s lifetime.
“I immediately knew I needed to study this,” Krichevsky said. “Any questions you could ask about this could lead you to some interesting and totally unexpected answers.”
MiRNA play a regulatory role in the human body. Researchers have found that in certain disease states, production of specific miRNAs get ramped up or ramped down. Krichevsky’s lab identified a few key miRNAs that are paramount in the development of aggressive glioblastoma brain tumors, including one of the first oncogenic miRNAs called miR-21. The other key miRNA, miR-10b, is absent in normal brain tissue, yet widespread in glioblastoma tumors.
Setting Sites on a Target
Krichevsky’s face lights up as she talks about the potential of targeting miRNA in disease states. “If miR-10b is inhibited, it is possible to kill nearly any glioma cell,” she said. “This research has tangible implications for the development of therapeutic drugs for brain tumors.”
Krichevsky is also interested in understanding the miRNA regulatory micro-environment in Alzheimer’s Disease, the major dementia associated with aging. AD’s causes are largely unknown and the disease is notoriously difficult to study and treat. While previous AD research has focused on the neuro-proteins tau and amyloid-beta, Krichevsky is excited to provide a new angle for examining the disease. Her lab has shown that some miRNA are neuroprotective, while others have neurotoxic effects. She is currently conducting innovative studies to decipher which miRNAs may underlie AD progression, and develop miRNA-based therapies for AD.
Krichevsky is dedicated to uncovering the therapeutic potential of miRNA to help patients with neurological diseases. “BWH is one of the few institutions in the world where you can take a molecule through all stages of development. There are very few places where you can make a discovery and bring it to clinic.”
Krichevsky has now conducted her miRNA research at BWH for 18 years. “The huge advantage of being a researcher at BWH is that the best experts are around the corner or across the street from you (and sometimes right in your department),” she said. “The intellectual environment here is fantastic: you can find any collaborator here that is the best in a certain field.”
Krichevsky credits the collaborative BWH environment for the successes of many of her projects over the years. As an example of the powerful impact of collaboration, Krichevsky recalls when she submitted her first paper to the journal Neuron. “The reviewers wrote back and asked me to show electron-microscopy images of the specific phenomenon. But I didn’t know anything about electron microscopy,” said Krichevsky, who had two months to respond to Neuron with images of her work. Luckily, while she was at a luncheon, she met a post-doctoral fellow who knew a researcher who was an expert in electron microscopy and worked across the street. With the help of this newly established collaborator, her work was successfully published.
Another reason Krichevsky enjoys working at BWH is the affiliated Initiative for RNA Medicine – of which she is an executive board member – that draws a plethora of experts working in the field of RNA research.
“The vision is to establish expertise and collaboration at a level that will bring investment from various sources and enable us to translate our research studies to clinical trials,” Krichevsky said. Frank Slack, PhD, an original co-discoverer of the first human miRNA, is the director of the Initiative.
Despite these breakthroughs, there are some limitations in the young field of miRNA. In fact, it can take 20-30 years to bring a molecule from the discovery phase to clinical targeting. There are also technical limitations with targeting brain cells due to the blood brain barrier and complex uptake mechanisms within the brain. Even with these challenges, however, Krichevsky cannot help her excitement about the future potential of miRNA. “We have something that may be extremely helpful for patients with brain cancer or neurodegenerative diseases.”