Not So Everyday Medicine The Future Of Medicine … CRISPR

Charlotte Lawrence (right) speaks to Jessica Alson, PhD., a Manchester resident and partner at a venture capital firm focused on CRISPR, the gene editing technology.

This edition of “Not Your Everyday Medicine” is a bit more technical than usual, as we get a primer on the revolutionary gene-editing technology, CRISPR, and the future of personalized medicine in my interview with Dr. Jessica Alston, a Manchester resident, and partner at Cambridge venture capital firm F-Prime Capital.  

Welcome Dr. Alston, can we start with you sharing a bit about your background, and how you got involved in gene editing?

I am a scientist by background.  I did my Ph.D. in genetics and did lab-based work at both Harvard and The Broad Institute.  After working in management consulting, I came to the venture capital firm F-Prime Capital seven years ago, where I am now a partner.  F-Prime invests in healthcare and technology and I work primarily in the life sciences fund, which invests in therapeutics, devices, diagnostics, and research tools.

Gene editing is an area of focus for us, which I’m able to get a unique look at through the investment lens to see how we can help move these technologies from the lab to the clinic. We've been fortunate to work with academics, other investors, and teams to build and support several companies in the gene-editing space.

Gene editing brings to mind CRISPR. Can you tell us what CRISPR is, and how it was discovered?

CRISPR is two things: first, it’s a bacterial immune system, and second, it is a gene-editing platform.  The original observation of CRISPR was in 1987 when researchers noticed curious-looking sequences in bacterial genomes that consisted of series of repeats, in between which there appeared to be random sequences of DNA.  At the time, it was not understood what the sequences did, but the CRISPR name - which came later - describes this observation, and it is an acronym that stands for: Clustered Regularly Interspaced Palindromic Repeats. 

What should our readers understand about the importance of CRISPR?

In nature, CRISPR is a mechanism bacteria use to combat the viruses that infect them.  Much like how the flu infects us, a bacteriophage infects bacteria.  It was eventually noted that the random sequences in the CRISPR sites in bacterial DNA—which appeared to be useless when first discovered—actually matched the DNA of bacteriophages.  This tells us that bacteria stored a catalog of bacteriophages that had previously infected them so that they could recognize and fight them if they ever showed up again.  The way they do this is that the bacteriophage sequences stored in the CRISPR sites help guide an associated protein, called “Cas,” to the genome of an infecting bacteriophage, and then Cas cuts the bacteriophage’s DNA, essentially inactivating it.

So CRISPR matters because it can target specific areas of one’s DNA?

Yes, CRISPR/Cas can be used as a gene-editing system.  You can direct Cas to a specific site on a DNA strand to make a cut.  The cell, of course, will respond to cuts in its genome, which it sees as damage—it will sense and repair these types of breaks.  It’s actually the process of the cell repairing the break that leads to a sequence change at the site where the cut was made.  There were previous gene editing systems that worked in a similar way, by making cuts at specific, programmable (meaning that you can choose them) sites in DNA.  However, CRISPR/Cas is different because of the way that it is guided to the site where it is going to make the cut.  It is easier to "program" or direct to sites of your choosing than other systems, and that is why it is the most popular and widely used editing system today.

Could you share how recent developments have changed CRISPR's capabilities?

As I mentioned, the process of the cell repairing the DNA break is what leads to a change in the DNA sequence, and the outcome of this process can be hard to control.  It works very well if what you want to do is disrupt a gene, but often for therapeutic purposes we want to make a specific change in the DNA.  For example, many genetic diseases are caused by single-letter changes in DNA. While it would be optimal to simply be able to correct these one-letter mutations, that is difficult to do efficiently with the basic CRISPR/Cas mechanism.

Two techniques - base editing and prime editing—were introduced to address this challenge; both of these build on CRISPR/Cas but introduce additional elements to enable different types of edits.  Base editing allows you to directly convert one letter of DNA to another, though there are some limitations to the letters you can change and what you can change them to.  Prime editing goes a step further and allows you to change any DNA letter to any other letter and also lets you make small insertions and deletions.

Think of CRISPR/Cas editing as scissors, base editing as a pencil and eraser, and prime editing as a word processor: it really enables search-and-replace gene editing in a way that we haven't been able to do before. 

What is next on the horizon for CRISPR?

There are a few areas of active exploration.  First, work is underway to develop methods that will allow for larger fragments of DNA to be inserted into the genome in a targeted way.  Today, you can do smaller insertions and deletions, but it’s harder to do larger, gene-sized pieces. 

The second area is delivery, which means methods or technologies to get the editors to the tissues and cells where you want them to act.  Right now, we have solutions for a handful of tissues – for example, the blood (where cells are actually removed from the patient, edited, and then returned to the body), the liver, and the eye. Researchers are currently looking to develop more delivery systems or even expand the scope of the existing ones so treatments can be available for all tissues and parts of the body. 

What stage of clinical trials are these genetic treatments in currently? And what is your company's role in bringing them there?

Programs that are using the CRISPR/Cas mechanism are currently in early clinical trials (Phase I/II), and there is already some data emerging. Base editing is about to enter the clinic later this year, and prime editing, which was developed more recently, is still pre-clinical.  

In addition to being used to treat genetic diseases, CRISPR/Cas is also being used to make edited cell therapies for oncology, and some of these programs are in clinical trials as well.  In these therapies, immune cells are engineered to recognize proteins or antigens that might be on the surface of cancer cells: the immune cells are actually armed to attack cancer.  The initial versions of these therapies (which were not created with CRISPR/Cas) have been very successful in treating liquid tumors (such as leukemia and lymphoma) and there are several therapies that are FDA approved.  CRISPR/Cas can be used to make additional edits to the cells to improve various features, creating next-generation cell therapies. 

A venture firm’s role is about supporting these companies with financing as they work to develop these therapies through the early preclinical and clinical stages.  For F-Prime specifically, we were an investor in one of the early CRISPR/Cas editing companies, and we also helped found the companies advancing base editing and prime editing.

Can you tell us more about how a company gets founded? Does a group of people come to you with an idea and you think, "This could make an incredible company"? Or do you seek them out?

It can happen in a couple of different ways.  In the case of base editing, for example, we saw the potential of the science and started discussions with the inventor (Dr. David Liu from Harvard and the Broad Institute) to build a company around it.  We then worked with Dr. Liu to license the intellectual property for the approach out of Harvard.  We worked with other investors to fund the company and recruit a team to start developing the strategy and ultimately the therapies.  We were also fortunate to have several of the scientists from Dr. Liu’s lab who originally worked on the technology decide that once they finished their training, they would come to the company and continue developing the technology there.

Do you have any guidance or advice for students who have an interest in pursuing a career at the intersection of science and business?

First, get exposure to different environments.  Try working in an academic lab, at a smaller company, or try working purely on the business side, perhaps in something like investing.  I suggest pursuing extracurricular opportunities to get exposure to different career paths. For example, there are things like “pitch” events, where students generate ideas and think about how to build a company around them.  There are consulting clubs where you can work on mock engagements and think about strategy.

Second, I recommend exploring courses, like Biotech classes at your high school or, once in college, there may be business classes on commercializing science (these might be at the business school, but accessible to undergrads). 

Lastly, I encourage students to reach out to people that are working in areas that you think are exciting.  People are genuinely excited to help young students that are interested in science, and related fields.  In the Greater Boston Area, we have an incredible ecosystem of universities, companies and investors—it's truly one of the best places in the world to pursue your interest in science.

Charlotte Lawrence is a junior at Manchester Essex Regional High School.  As the school district’s student health ambassador, she seeks to raise awareness about issues that impact the health of our students and community.