Like a sculptor’s hand steering a chisel toward a stone, guide RNAs direct CRISPR’s Cas9 protein to cut a piece of DNA. With multiple CRISPR gene therapies in clinical trials and some on track for FDA approval, CRISPR has come a long way from its humble origin as a bacterial defense system.
When it comes to gene editing, questions of safety, ethics, and potential off-target effects follow. If scientists could make CRISPR safer, then lifesaving CRISPR-based therapeutics could reach the patients who need them sooner.
Samira Kiani, a biologist at the University of Pittsburgh School of Medicine, is up to the task. By melding her background in medicine with her passion for art and design, Kiani uses synthetic biology to engineer safety directly into the CRISPR gene editing system in both her academic lab and biotech company, Genexgen. By creating safe CRISPR systems, she hopes to accelerate the delivery of CRISPR-based therapies into patient hands.
As a scientist and storyteller, Kiani doesn’t stop at safety. She uses filmmaking and video games to center the ethical concerns surrounding CRISPR and gene editing. By bringing scientists and the public together in creative spaces, Kiani wants to disrupt the scientific status quo and facilitate discussions around the consequences of scientific discoveries for both science and society.
How did you become interested in science?
I came to science from a nontraditional entryway. I went to medical school and was doing science in a liver research lab in the evening. I enjoyed my medical training, but I felt like there was something in it that was not for me. Then one day I sat with myself and said, “Part of me is always a scientist slash medical doctor. I can't really remove that from myself, but I also like design and storytelling and being creative.” I wondered if there was any way of combining these interests, and I came across the field of synthetic biology. The idea of designing organisms from scratch, coming up with an idea for a function, and then building that function into that organism was very interesting. It was equivalent to a piece of art, painting, or poetry for me.
What made you want to use synthetic biology to make CRISPR-based therapies safer?
My serious work in synthetic biology began when I worked with Ron Weiss at the Massachusetts Institute of Technology Synthetic Biology Center in 2012. At that point, it was the birth of the CRISPR technology for gene editing. Ron tasked me with combining the principles of synthetic biology with CRISPR technology. He wanted me to build new genetic circuits using CRISPR to activate, repress, or develop certain functionality in cells.
After two years into my research there, my dad was diagnosed with pancreatic cancer. Pancreatic cancer is deadly, and the current treatment regimens are not very effective. Many patients resort to new experimental therapies in clinical trials. I was really determined to get my dad into one of these clinical trials, but because my dad didn’t live in the US, we couldn't get him onto one. That experience made me think; we spend a lot of time evaluating the safety of these therapies in phase one and two clinical trials, while patients need these treatments now. What if we could engineer safety into these new treatments from the get go?
That's when I zoomed out and looked at what I was doing with synthetic biology and CRISPR. I was controlling Cas9 and the guide RNA. What if I could use these tools to build safety and controllability into CRISPR-based gene therapies?
How do you make CRISPR safer?
For one, we looked at the Cas9 protein structure, and through bioinformatics, we determined which part of the Cas9 protein elicits an immune response in the body (1). We wanted to figure out if there was any way to engineer Cas9 so that it would be more immune silent.
We’re also interested in moving away from CRISPR’s function as a DNA cleaving agent. Instead of creating a permanent change in DNA, we use a “dead” Cas9 protein that is mutated so that it cannot cut DNA. We can still send it to any part of the genome we want, but when it gets to the destination, it just sits on the DNA. We fuse proteins that activate or repress gene expression to the dead CRISPR system, and it carries these proteins with it to the target gene. Once there, they do their natural job, which is either to activate the gene or repress it (2). This is a safer way of applying CRISPR to treat conditions that don't necessarily need us to disable the gene permanently.
What kind of research questions are you working on at Genexgen?
Genexgen is a next generation immunotherapy company focusing on how we can bring epigenetic editing to immunotherapy. Nature engineered the immune system to fight a number of diseases, so I’m interested in bringing in what I know about synthetic biology and gene editing to manipulate the immune system. For instance, we could use the CRISPR system that helps dial down and up the expression of genes that are responsible for the immune response such as the production of antibodies, inflammatory signals, or cytokines (3).
How do you integrate your interest in storytelling and art into science?
I'm realizing more and more that genetic technologies have a profound effect on society. These technologies are not going to be confined to our research labs, conferences, or peer to peer communications. They will readily impact the lives of many people.
I want to explore how we can innovate differently. Instead of just asking questions from a scientist’s perspective, we should integrate the points of view of people from other disciplines including art, social sciences, and behavioral sciences and collectively start asking questions that lead to new types of innovations. Through filmmaking, theater, and collaborations with game designers, I want to expose scientists to other points of view and have them reflect on the ethics and societal impact of the research that we do.
We recently collaborated with Carnegie Mellon University Entertainment Technology Center to develop a virtual museum called Unmute that houses information about CRISPR and its benefits and harms. Through a collaboration with the Center for Game Design, we’re developing residency programs for artists and scientists to come together.
Samira Kiani collaborated with the Carnegie Mellon University Entertainment Technology Center to develop a virtual museum called Unmute to teach people about CRISPR.
What is your documentary film “Make People Better” about?
The film is about the future and where we are heading in terms of genetic technology. It zooms into that higher question of what our responsibilities are as human beings and as scientists to each other and to the general population. We use the case of He Jiankui, the scientist who created the twin CRISPR babies back in 2018, as an example to discuss why and how this happened. I see the film as a way to start conversations about what our responsibilities as scientists are. The film should come out by the end of this year or early next year.
Did making this film change how you think about your own research?
Absolutely. One important aspect that this film touches on is the mentor-mentee relationship in science and how there are certain norms in our field that are not necessarily working. There is a lot of emphasis on pushing forward, breaking the glass, and being first in science. I had been doing that to my students, but I've been rethinking that. The more important thing is to think about what type of future we’re going to build for the next generation. Science needs to be more compassionate toward the people we are serving and to each other in the scientific community. It requires us to reflect more of our souls as human beings. Let's revisit the process of innovation and how we do science.
- Ferdosi, S.R. et al. Multifunctional CRISPR-Cas9 with engineered immunosilenced human T cell epitopes. Nat Commun 10, 1842 (2019).
- Yeo, N.C. et al. An enhanced CRISPR repressor for targeted mammalian gene regulation. Nat Methods 15, 611-616 (2018).
- Moghadam, F. et al. Synthetic immunomodulation with a CRISPR super-repressor in vivo. Nat Cell Biol 22, 1143-1154 (2020).