On the Path to Treating Sickle Cell Disease, Greg Newby Relies on Colleagues and Lessons Learned

Nachi Pendse, PhD - October 01, 2021

Greg Newby, PhD, talks about his start in science, using base editing to treat sickle cell disease, and the future of gene therapy and base editing in the clinic.

Greg Newby received his PhD in 2017 from the MIT biology department, where he developed methods to detect and control protein aggregation and prion formation. Newby is currently a postdoctoral fellow in the laboratory of David Liu, PhD, at the Broad Institute and Harvard University working towards developing base editor and prime editor technologies and applying them to treat models of genetic disease. He is also a lead scientist and author on the recent study published in Nature, Base editing of hematopoietic stem cells rescues sickle cell disease in mice.

Newby’s contributions to the field of genome engineering include:

  • Developing base editing tools to treat sickle cell disease and assessing them in animal models as part of a multi-institute collaboration
  • Assessing genome editing of diverse models of disease throughout the development of new genome editing tools
  • Interfacing with other groups to hasten the application of these tools to cystic fibrosis, progeria, blindness, deafness, and epidermolysis bullosa by designing and producing editors and conducting on- and off-target editing analyses 

In this Q&A, Newby spoke with me about how he got started in the field, his research and challenges in genome engineering, and his advice for young scientists. 

Nachi Pendse (NP): How did you get into science and who are the people that most influenced you on this path?

Greg Newby (GN): My parents and my undergraduate mentors are likely the ones who influenced me the most on my path in science. I had been interested in science from a young age, largely thanks to the many fun places my parents took me and their incredible patience and insight in carefully answering every question. What really set me on my current path of biomedical research was my undergraduate research experience and close interactions with many faculty members at Carnegie Mellon University. They not only taught us laboratory techniques but also showed us a vision of what science can achieve for humanity, conveyed the joy of discovery, and instilled the ability to endure hard work and failure.

I have always been inspired by Thomas Edison’s quote, “I’ve succeeded in finding 1,000 ways to NOT make a lightbulb.” Though I’m aware that Thomas Edison likely had many character flaws, I think he got the spirit of this idea spot on. It usually takes a lot of failure before anything worthwhile is achieved in science. Keeping in mind that each of those failures is itself a useful piece of knowledge that we can learn from and use to design a better experiment next time has certainly been helpful and inspiring to me through the many failures I’ve experienced.

It usually takes a lot of failure before anything worthwhile is achieved in science.

Greg Newby, PhD

NP: How is it to work with one of the most famous and brilliant scientists of our time, Dr. David Liu?

GN: Working with David has been absolutely inspiring, and I am constantly reminded of what a privilege it is to work where I do. I sometimes wonder if his full name is David Liu-nardo da Vinci, on account of the many fields of science and art in which he is an expert. His insights and suggestions have been invaluable to my work, and somehow David manages to be constantly generous with his time despite juggling the needs of his 30+ trainees as well as his teaching role. His deep care for advancing the capabilities of science and humanity through our rigorous research comes across each time we meet with him. A key perk of being in David’s laboratory is the opportunity to work alongside the diverse, collaborative, and all-around amazing people he attracts. The presence of this large group of fun and creative people working side-by-side with me has been helpful for every aspect of this job.

NP: Tell us about base editing and how you used it to tackle sickle cell disease?

GN: Base editors can make precise, single-nucleotide changes with pure editing outcomes. We combined two recent advances in the base editor toolkit to develop a customized editor with capabilities particularly well-suited to modifying the sickle cell mutation, which is caused by a single nucleotide change. The key question was whether this editing strategy worked in patient blood stem cells, which is the cell type that could potentially be modified to treat this devastating disease. We transplanted the edited cell population into mice and assessed the editing that was maintained after four months in the mouse bone marrow, by which time non-stem cells would have been lost and only stem cells and cells derived from stem cells remain. We observed that 68% of sickle cell genes had durably been converted to a healthy variant. Approximately 80 to 90% of cells contained at least one edit and therefore, we anticipated, would be free of disease. This experiment was necessary to learn about the longevity of edited human cells, but these human cells cannot populate the entire mouse hematopoietic system so do not provide information on the correction of disease symptoms.

In order to assess the rescue of disease symptoms, we edited blood stem cells from a mouse model that harbors the sickle cell mutation and transplanted those cells in mice. We found that we could achieve editing in about 50% of the sickle cell genes in mice, and that editing just 20% was sufficient to restore normal blood parameters such as the concentration of hemoglobin and counts of red blood cells and white blood cells. Editing also rescued abnormalities in the spleen, which is typically damaged in sickle cell patients.

We found that we could achieve editing in about 50% of the sickle cell genes in mice, and that editing just 20% was sufficient to restore normal blood parameters.

Greg Newby, PhD

NP: How do you envision the delivery of base editing components as a therapeutic?

GN: Initially, an approach very similar to the one used in our study could be employed. Blood stem cells could be collected from a sickle cell patient, then electroporated with base editor mRNA to edit the sickle cell disease genes into healthy ones. These cells can then be transplanted back into the patient using existing clinical hematopoietic stem cell transplantation (HSCT) methods. This method should eliminate the risk of graft-versus-host disease that may (in some rare cases) occur when a sibling donor or otherwise matched donor provides healthy stem cells to the patient. It also permits anyone to receive the therapy without requiring a suitable donor to be found.

In the long run, I hope that more efficient methods to deliver base editors to blood stem cells will be developed in the future so that they can be used to precisely modify a patient’s cells with a single injection. This would make the process most painless for the patient and readily distributed around the world.

NP: If you were to choose between AAVs, lentivirus, LNPs, or other currently used delivery technologies, which one would you choose and why?

GN: Many of these current technologies may be equally suitable to curing sickle cell disease. However, for the purposes of minimizing any potential detrimental outcome, I would favor a lipid nanoparticle (LNP) approach. These can be used to directly deliver editor mRNA or RNP, which will quickly conduct its editing job and then be degraded by the cell. Most other delivery tools, including lentivirus and AAV approaches, place DNA into the cell. Since DNA encodes our generationally-long-term cellular instructions, it persists in the cell more durably and could possibly lead to more unwanted off-target editing. The introduction of new DNA may itself be mutagenic in some rare cases. Any tool that efficiently delivers base editor mRNA or RNP to blood stem cells would be particularly attractive for future development.

I hope that more efficient methods to deliver base editors to blood stem cells will be developed in the future so that they can be used to precisely modify a patient’s cells with a single injection.

Greg Newby, PhD

NP: What is your vision for gene therapy and base editing and its future in the clinic?

GN:  I hope that future developments in gene therapy methods will include better targeting to all parts of the human body, control over the duration of expression, and methods to limit expression of delivered cargo to certain cell types. The base editors and prime editors that our laboratory developed can theoretically be used to correct 90% of human disease mutations. Right now, a primary challenge is in safely delivering enough editors into the necessary cell type to treat the disease. With the improvements listed above, we would be able to quickly advance many new editor therapeutics to the clinic.

It has been such a great experience to learn from and work on this project with our collaborators at St. Jude Children’s Research Hospital: Mitch Weiss, Shengdar Tsai, Jonathan Yen, Kaitly Woodard, Thiyagaraj Mayuranathan, Cicera Lazzarotto, Yichao Li, and many others, including those from other institutions as well. And of primary importance, all of this work is done in the hopes that sickle cell patients, and all of humanity, will be better off on account of the new tools and knowledge we gained. I often think back to something that my undergraduate department head, Beth Jones, told me: “the most important thing in science is the people.” Beth was right – nobody could do this work alone.

Dr. Pendse is senior project lead scientist at Novartis and a member of ASGCT's Communications Committee.

Share This Page