Richard Sherwood

Richard Sherwood

Genetics is a fast-developing field, and Richard Sherwood, PhD, an investigator in the Brigham’s Division of Genetics, takes full advantage of recent advancements in his research.

“The field of genetics used to be observational and focused on looking at how different mutations in the genome correlated with disease,” said Sherwood. “Now, with recent developments spurred by the discovery of CRISPR, we can actually manipulate genes to create mutations and see how these mutations affect how cells and animals behave. The ability to create mutations also opens up the possibility of gene therapy, which is the closest you can get to a cure when dealing with genetic disease.”

Sherwood began working at the Brigham as an independent postdoctoral fellow in 2010 and now works as an assistant professor in the same department. He appreciates the benefits of working at an institution where there is a strong relationship between clinical practice and research and where clinical observations can drive the questions his lab asks.

Using and Improving CRISPR

Sherwood’s research focuses on refining, improving and using CRISPR technology. CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 is a genome editing technology known for its ability to break things. With precision, these scissor-like tools can be sent to any location in the genome to make a snip, break a gene, and remove, add or alter a specific stretch of DNA.

Last year, Sherwood and his colleagues discovered that the double-strand breaks that CRISPR-Cas9 makes are predictable, and they developed a machine learning model that can predict insertions and deletions with high accuracy. The team demonstrated that this approach could be used to edit and repair mutations related to three diseases in human cell lines — Hermansky-Pudlak syndrome, Menkes disease and familial hypercholesterolemia – with a predictable repair outcome in more than half of instances. The team published its findings in Nature.

One research project Sherwood is currently working on investigates why certain mutations cause high cholesterol. There have been huge international efforts to collect genomic data. With these vast data pools available, people can see how mutations correlate with disease. This does not always translate to understanding why a certain mutation causes a disease. Sherwood’s lab uses CRISPR to create mutations in cells that are known to be linked to high cholesterol in an effort to understand how these mutations function to raise cholesterol levels.

Skipping Ahead

Sherwood is also heading a project on exon skipping, one of the few Federal Drug Administration (FDA) approved gene therapies on the market. In exon skipping, a molecular patch known as an antisense oligonucleotide is layered over a stretch of RNA that encodes a faulty piece of a gene, allowing cellular machinery to skip over this stretch to produce a more functional protein. Duchenne muscular dystrophy and spinal muscular atrophy were the two diseases that originally led the way in garnering FDA approval for this technology, but little has been done to explore its benefit for other diseases.

“We’re very interested in exon skipping,” said Sherwood. “This an exciting time for the field. The first gene therapies have emerged, but there’s been no systematic effort to look at what other diseases this new technique can be applied to. We want to understand what other genetic diseases may benefit from this therapy.”

Less Hype, More Help

While CRISPR-Cas9 technology could be used in gene therapy to directly edit human genes, Sherwood sees this type of application becoming common only in the distant future. He is focused on leveraging it now as a tool to improve our understanding of how genetics contributes to human disease.

“We’re at this unique point in time where we can collect more types of data than we know what to do with,” said Sherwood. “Already, genome sequencing is routinely used by oncologists to tailor treatment for cancer patients. In the next 10 years, it will be the case that everyone’s genome is sequenced, probably from birth. We will have all this valuable health information for every patient, but how to use it give actionable medical advice is still lagging. Trying to figure out how we can use this valuable information to improve human health motivates me.”


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