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In the second instalment of Technology Networks Explores the CRISPR Revolution, we interview the world-renowned American biochemist and co-developer of CRISPR, Professor Jennifer Doudna.



In 2012, Doudna and Professor Emmanuelle Charpentier were the first to describe the use of CRISPR as a genome editing technology – a breakthrough that is regarded as one of the most significant biological discoveries of all time.



In addition to making this discovery, Doudna is recognized as the "face of CRISPR" and is a vocal advocate for its safe and responsible use. In 2015, she was the first to call for a moratorium on using CRISPR technology to make permanent changes to the human germline.



Doudna is also credited with building the "CRISPR economy" which employs thousands of individuals, and she has helped to co-found and serves on the advisory panel of several companies in the CRISPR space.



In addition to her impressive list of publications and innovative research work, Doudna is also championing women in STEM. She actively promotes and mentors talented young female executives in CRISPR, with examples including Rachel Haurwitz, former Doudna Lab member and CEO of Caribou Biosciences, and Janice Chen, former Doudna Lab member and CRO of Mammoth Biosciences.



In this interview, Dounda recalls the original discovery, discusses the unique and exciting application of CRISPR technology and provides her thoughts on the future of the CRISPR field.



Molly Campbell (MC): Your work on CRISPR-mediated genome editing is now recognized as one of the most significant biological discoveries to date. Could you tell us about the research that led to this discovery, and describe to us how it felt when you realized the true potential of this technology?



Jennifer Doudna (JD): In 2006 while working in my lab at the University of California at Berkeley, I heard about an unexpected way that bacteria might be storing snippets of viral DNA sequences in “CRISPR” arrays.



These snippets are copied into RNA which are used like address labels to direct bacterial proteins to cut viral DNA in specific places. The arrays, together with CRISPRassociated (Cas) proteins, provide adaptive immunity that protects microbes from viral infections. Our team, including collaborator Emmanuelle Charpentier and our lab members Martin Jinek and Kryz Chylinski, investigated how a CRISPR-associated protein called Cas9 uses RNA guides to find and cut viral DNA, and how we might reprogram it to cut at other DNA sites.



On the day that Martin Jinek completed experiments showing how Cas9 can be programmed with engineered single-guide RNAs, I could not stop thinking about our results and about how Cas9’s RNA-programmed cutting activity could be used differently to make changes to a human cell’s DNA sequence.



While cooking dinner that night, I suddenly burst out laughing. “Why are you laughing Mom?” my son wanted to know. “Because bacteria have this amazing protein that can be programmed to find and cut any desired piece of DNA, like looking up and changing a single word in a book in the library!” I told him.



In 2012, we published our results and described how CRISPR-Cas9 could be used as a simple and effective system for genome editing in cells. The profound implications of this technology have been unfolding ever since.



MC: Aside from CRISPR, there are alternative methods to genome-editing. Why is CRISPR superior to other approaches, what benefits does CRISPR offer over other these other methods?



JD: Scientists have been curious about the possibility of making modifications to the genome for quite some time. Early tools for genetic manipulation include TALENs, ZFNs, and more recently, CRISPR-Cas9 and related RNA-guided proteins. Both TALENs and ZFNs are based on proteins that have an affinity for a particular gene sequence. Therefore, while they can target a specific gene, each requires a technically non-trivial protein engineering process in order to ensure specificity for the gene of interest.



In contrast, CRISPR-Cas9 doesn’t need this step as it uses RNA as a guide to find a desired DNA sequence. The same Cas9 protein can be programmed to target a new gene simply by providing it with a new RNA guide, which can be ordered online or made quickly in the lab.







﻿Video credit: TED.





MC: What is the most unique and exciting application of CRISPR technology that you have encountered thus far?



JD: I recently hosted an annual lab retreat with my research team. This was an opportunity for us to share novel ideas and brainstorm future research directions. One conversation initiated by a group of lab members centered around global warming. Ideas included editing agricultural crops to include a carbon-absorbing protein for moderate-term CO2 storage, editing the microbiome of cattle to reduce their methane production, and developing climate change resistant crop varietals.



While there may not be one direct fix for this societal challenge, I was delighted to hear some of the ideas that were presented about how CRISPR could potentially address this overwhelming problem.



MC: In a previous interview you mention that you have become the "face of CRISPR" almost by default because "nobody else wanted to do it". Why do you think this is?



JD: There’s a large time commitment involved with traveling and giving talks to the public. It’s hard to balance the demands of being available to speak on an important new development in a rapidly moving field, while also fulfilling the obligations of running a research lab and an institute, teaching courses, and continuing to perform other academic duties.



MC: What do you think the lay (non-scientific) audience’s perception of CRISPR technology is? Do you believe there is enough public understanding of CRISPR and gene-editing? If not, what do you think can be done to address this?



JD: Public awareness of CRISPR technology continues to expand. It is now rich source material for Hollywood scriptwriters and the public is aware of the potential for the technology to help but also harm if misused. We must continue a global conversation about how we apply this powerful technology responsibly.



MC: Your book “A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution” emphasizes the need for a global conversation on how CRISPR genome editing technology is applied. Since the book was published in 2017, have we come any closer to having this conversation? How has the controversial work of He Jiankui in 2018 impacted this?



JD: Yes, the number and the depth of conversations taking place across the world regarding medical therapeutics, elimination of genetic diseases, the availability of CRISPR foods, etc. is heartening. In particular, I am excited about the work of pgEd.org in the Boston area and of the dialogues at CRISPRcon every year. CRISPR remains an experimental technology, though, so we must proceed cautiously, deliberately and with transparency. He Jiankui’s reckless work highlighted the technical and ethical hurdles we still face, and the scientific community has re-doubled efforts to engage all stakeholders and develop stronger guardrails to avoid misuse.



MC: There is a patent dispute surrounding CRISPR that has received widespread media coverage over recent years. Are you able to provide any insight on this matter? Do you anticipate the issue being resolved in the near future? Has the ongoing issue impacted the progression of research within the CRISPR field?



JD: I focus on science, not patents. I’m pleased that important, potentially life-saving research continues to progress quickly in both academia and industry. You can read more about the current patent status here.



MC: What are the greatest challenges faced by researchers utilizing CRISPR technology?



JD: We need to understand how to safely and effectively deliver gene editing tools into patients. Before CRISPR-based therapies can be approved as safe to use, scientists will need to demonstrate how the CRISPR system can be delivered to patients in such a way that we can fix the relevant genetic material without making unwanted changes, and at a high enough rate to have a positive, long-term outcome for the patient.



MC: Fast-forward 10 years from now. What does the CRISPR mediated genome-editing field look like to you?



JD: In 10 years, we may have successfully developed CRISPR crops that will be widely available in grocery stores, new diagnostics to detect disease progression, and the first wave of approved medical therapeutics that can treat or even cure human genetic disease.



Professor Jennifer Doudna was speaking with Molly Campbell, Science Writer, Technology Networks.



Catch up on the first instalment of Technolology Networks Explores the CRISPR Revolution, an interview with Professor Francisco Mojica, here.