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After watching Jurassic Park in fifth grade, Greg Newby wrote an essay for school about his aspiration to become a genetic engineer and bring back the dinosaurs. But instead of creating prehistoric creatures, he became a different kind of genetic engineer — one who develops genome editing technologies to treat genetic diseases.

As an undergraduate student at Carnegie Mellon University, Newby initially wavered between majors in engineering, computer science, and biology. His first research experience studying Drosophila and bacteriophage during his freshman year cemented his appreciation for laboratory research and he decided to pursue molecular biology.  

After graduating, he received a Fulbright Scholarship and worked at the University of Zürich in Switzerland developing biosensors to track post-translational modifications of proteins. In 2010, he moved to Boston to pursue a PhD at the Whitehead Institute in the lab of the late Susan Lindquist, where he developed methods to find and control proteins that aggregate and fold incorrectly. In 2017, he joined the ӳ����ý of MIT and Harvard as a postdoctoral fellow in the lab of ӳ����ý core institute member David Liu. 

As Newby wraps up his postdoc at ӳ����ý, we spoke with him about the genome-editing tools he has helped develop, the value he’s found in supportive mentors, and his goals for the lab he’ll be starting at Johns Hopkins University this month.

What are some of the questions you're trying to answer with genome editing?

There are dozens of genetic diseases that I've gotten to explore to see if they can be potentially treated with genome editing. In each case, we need to figure out which cells and what proportion of cells we need to correct with editing, and whether we can do that outside of the body and then give those cells back to the patients, or whether we need to do the editing inside the body. Then, we determine the best delivery format to get the genome editor into cells. And while we work on this delivery problem, we also need to  identify exactly which editor and guide RNA have the best balance of activity and specificity in the genome.

What has your work with genome-editing tools been focused on?

In 2016, the year before I came to ӳ����ý, the Liu lab published the . Using this editor, you can change one single nucleotide to another without insertion and deletion mutations being the predominant outcome and with good efficiency, even in non-dividing cells. 

At that time, most of these tools had been tested mostly in human cancer cell lines, and plasmids were used to deliver the editors. The problem is that plasmids don't work very well in most human cells, so we had to make different forms of the editor to deliver it. A lot of my research at the start was developing different formats for the delivery of base editors. We’d test different editor enzymes, then deliver these into cells as DNA, mRNA, or protein. We also used viral vectors to get efficient transduction of genes into human cells.

Then, in 2019, Andrew Anzalone in our group led the development of , which is much more flexible in terms of rewriting the genome. Rather than making base changes from one nucleotide to another, you can rewrite entire stretches of DNA. The process comes with some unique challenges, though — the enzyme is larger and less efficient, so I’m working towards more efficient delivery tools to achieve the same level of editing.

How is your research helping to develop prime editing?

Our group and others have used base editing and prime editing in vivo to treat mouse models of disease and study aspects of mammalian biology. We're working on making all of those aspects more efficient and reaching a point where we can treat genetic diseases. For example, in 2021, our group along with our collaborators published base editing treatments that could address sickle cell disease and . Now, we’re working on correcting a mutation that causes hypertrophic cardiomyopathy and preventing the disease’s onset. 

Adapting the tools we developed in those studies for prime editing will allow us to treat many more categories of disease and more patients who have genetic mutations that aren't amenable to base editing.

What have you learned from your mentors?

One of my undergraduate mentors at Carnegie Mellon, Beth Jones, said, “The most important thing in science is the people.” The archetype of one person getting their own results and learning something impactful doesn't happen in the absence of a community where people help you understand other fields of science, discuss ideas and experiments, and write compelling papers. And the most exciting results in the world don’t mean anything unless they are understood by others and used for even greater applications, tools, and discoveries in the future.

One thing I love about Susan and David is that they have this infectious enthusiasm for science and a vision for what it can mean for the world. Most of my job is doing experiments at the bench; you may sit  and pipet all day only to get an inconclusive result that brings you no closer to understanding what's going on. It's very easy to lose sight of the larger goal when you're spending hundreds of hours working on the smallest detail for a paper. Having a mentor who will keep in mind the total sum of your research and how it can end up changing the world is really special, and I hope that I'll be able to do the same for my trainees.