Jennifer Doudna (UC Berkeley Professor) – UC Berkeley Lecture (May 2019)


Chapters

00:00:12 CRISPR and the Journey of Scientific Entrepreneurship
00:02:43 CRISPR Gene Editing: From Bacteria to Genome Engineering
00:11:41 CRISPR-Cas9: A Novel Technology for Genome Engineering
00:17:16 CRISPR-Cas9: From Scientific Discovery to Exponential Growth
00:22:32 Early CRISPR Technology and the Founding of Caribou Biosciences
00:31:22 Founding and Funding of Caribou and Intelia Therapeutics
00:33:53 CRISPR-Cas9 Technology: Applications and Development Strategies
00:36:47 CRISPR-Cas Technologies: From Academic Research to Commercial Opportunities
00:44:34 Navigating Ethical Challenges in CRISPR Technology
00:49:30 Navigating Ethical Challenges of Genome Editing
00:55:11 Genome Editing: Applications, Challenges, and Societal Implications
01:05:11 Genome Editing: Considerations for Modifying Multiple Genes

Abstract

CRISPR-Cas9: Revolutionizing Biotechnology and Navigating Ethical Frontiers

CRISPR-Cas9, a groundbreaking gene-editing technology, has emerged as a cornerstone in biotechnological innovation, transforming medicine, agriculture, and scientific research. Spearheaded by Dr. Jennifer Doudna, this technology, initially inspired by bacterial immune systems, offers unprecedented precision in DNA manipulation. Doudna’s journey from curiosity-driven research to entrepreneurship exemplifies the intersection of science and business, leading to the founding of Caribou Biosciences and other ventures. As CRISPR-Cas9 paves new pathways in various fields, it also brings to the fore critical ethical considerations, particularly in human and agricultural genome editing. This article delves into the origins, impact, and ethical landscape of CRISPR-Cas9, highlighting Doudna’s significant contributions and the ongoing dialogues shaping the future of gene editing.

The Genesis of CRISPR-Cas9:

Jennifer Doudna, a trailblazer in molecular biology, began her exploration into CRISPR technology by studying bacterial immunity against viral infections. The discovery of the CRISPR-Cas system, a natural defense mechanism in bacteria, laid the foundation for developing CRISPR-Cas9. This simplified system, crafted by Doudna and colleagues, enables targeted DNA modifications, marking a significant leap in genome editing.

Scientific Breakthrough and Its Impact:

CRISPR-Cas9’s ease of use and versatility have positioned it as a transformative tool in biological sciences. Published in 2012 by Doudna and Emmanuelle Charpentier, their research unveiled Cas9’s potential for gene editing, sparking global interest. Within a year, multiple studies demonstrated its efficacy across different organisms, signaling a new era in genomics.

Exponential Growth and Entrepreneurial Shift:

Reflecting the scientific community’s enthusiasm, CRISPR-Cas9 publications and applications have grown exponentially. Doudna’s transition from academia to entrepreneurship was driven by her vision to harness this technology for practical applications. She co-founded Caribou Biosciences, focusing initially on research tools and later expanding into therapeutic and agricultural applications.

Caribou Biosciences: Pioneering Applications:

Caribou Biosciences, co-founded by Doudna and Rachel Horwitz, embarked on applying CRISPR-Cas9 in diverse domains. From studying genetic diseases to enhancing crop resilience, the company has been at the forefront of utilizing genome editing for real-world solutions.

Caribou’s Milestones and Contributions:

Rachel Horwitz, Caribou’s co-founder, played a significant role in the company’s success. Caribou’s work contributed to the development of CRISPR-Cas9 as a therapeutic tool for human diseases. The company also made strides in applying CRISPR to agriculture, with a focus on improving crop resilience and yield. Caribou’s success, resulting in a market capitalization exceeding a billion dollars, allowed it to become a publicly traded company and forge significant corporate partnerships, notably with DuPont Pioneer, for the application of CRISPR-Cas9 technology in agriculture.

Founding Caribou Biosciences:

Jennifer Doudna and Rachel Horwitz founded Caribou Biosciences in 2011, making it the first company Doudna had ever co-founded. The company’s name, Caribou, was derived from Cas (C-A), ribonucleic acid (Ribo), and the need to turn it into a word. Caribou’s initial focus was on developing CRISPR-Cas9 as a research tool to discover genes involved in cancer and genetic diseases. Doudna emphasized the importance of CRISPR-Cas9 as a tool that allows scientists to easily and accurately change genes in a targeted manner, filling a critical gap in the biotech toolbox.

Addressing the Need for a Gene Editing Tool:

The potential of CRISPR-Cas9 to solve real-world problems beyond academic settings opened up entrepreneurial avenues for its application. However, translating CRISPR-Cas9 technology into clinical applications requires significant funding, expertise, and collaboration beyond academic capabilities. Caribou focused on developing its own versions of CRISPR-Cas9, which would be patented by the company, providing it with an in-house suite of protected technology for diverse applications. The company also explored different delivery methods for CRISPR-Cas9, including DNA or RNA molecules to encode the editing molecules or directly delivering preformed protein RNA complexes (ribonucleoproteins or RNPs) into cells.

CRISPR-Cas9’s Impact on Genome Editing and Entrepreneurship:

The CRISPR-Cas9 technology has enabled groundbreaking advancements in fields beyond medicine and agriculture, such as environmental science and energy production. Doudna’s pioneering work in CRISPR-Cas9 gene editing has garnered significant recognition, including being named a MacArthur Fellow in 2015 and receiving the 2020 Nobel Prize in Chemistry alongside Emmanuelle Charpentier. The ongoing discussions surrounding the ethical implications of CRISPR-Cas9 have led to the development of international guidelines and regulations aimed at ensuring its responsible and ethical use.

CRISPR-Cas9 in Agriculture and Medicine:

The applications of CRISPR-Cas9 in agriculture and medicine are vast. In agriculture, it promises more resilient and productive crops. In medicine, it holds the potential for curing genetic diseases, with Caribou Biosciences actively exploring these therapeutic avenues.

Doudna’s Inspirational Journey:

Jennifer Doudna’s path to science, marked by perseverance against societal biases and skepticism, serves as an inspiration. Her commitment to following her passion and her resilience in the face of challenges have been pivotal in her achievements and in shaping the CRISPR-Cas9 landscape. Throughout her career, Doudna faced criticism and naysayers but persevered by seeking support from encouraging individuals. Her French teacher in college advised her to stick with chemistry, recognizing her potential in the field.

Ethical Considerations and Addressing Ethical Challenges:

CRISPR-Cas9 technology raises critical ethical considerations, particularly in human and agricultural genome editing. Jennifer Doudna identifies three major ethical challenges in the field:

– Germline Editing: Editing the genes of sperm, eggs, or embryos raises concerns about heritable changes that could be passed on to future generations.

– Designer Babies: The potential to select specific traits or characteristics in offspring raises concerns about social inequality and discrimination.

– Unintended Consequences: The complexity of biological systems makes it difficult to fully predict the long-term effects of CRISPR editing, leading to concerns about unintended consequences.

Doudna emphasizes the importance of engaging in open and transparent discussions about the ethical implications of CRISPR technology. She calls for international collaboration and regulation to ensure responsible use of the technology. Doudna also highlights the need for public education and engagement to foster a deeper understanding of the technology and its potential impact.

Ethical Challenges and Concerns Surrounding Gene Editing Technology:

* Agriculture and Regulation: Gene editing in agriculture faces ethical challenges due to the potential for both beneficial and harmful applications. Different governments have varying regulations for gene editing in plants, creating challenges for companies and researchers.

* Gene Drives and Environmental Impact: Gene drives using gene editing tools can be used to spread specific genetic traits quickly through populations, such as creating mosquito strains that cannot spread disease. This raises ethical questions about weighing human health benefits against potential environmental harm and the impact on other species.

* CRISPR Babies and Heritable Changes: The idea of using gene editing in the human germline to create heritable changes (CRISPR babies) is a profound ethical concern. Such changes become part of a person’s entire genetic makeup and can be passed on to their offspring.

* Ongoing Efforts to Address Ethical Issues: Scientific societies and regulatory bodies are working on guidelines and regulations to minimize potential harm from gene editing in various settings.

* Hong Kong Announcement and Scientific Community Response: The announcement of the birth of baby girls with CRISPR-edited genomes in Hong Kong sparked a crisis within the scientific community, leading to discussions on how to manage and regulate such practices.

* Importance of Open Discussion and Public Education: Open dialogue and public education are crucial to raise awareness about gene editing technology and its potential impact on food, medicine, diagnostics, and other aspects of life.

* Navigating Ethical Discussions and Engaging Stakeholders: Navigating ethical discussions and engaging with civil society and policymakers requires expertise from various fields, including law, business, and public policy. Collaboration and input from experts in these areas are essential for developing effective regulations and rules.

* Evolving Nature of Ethical Considerations: The ethical landscape surrounding gene editing is constantly evolving, requiring ongoing discussions and adaptations to address new developments and applications of the technology.

Doudna’s Insights on CRISPR and Its Societal Implications:

* Ethical Concerns and Government Involvement: Doudna realized the potential ethical issues of using CRISPR in human embryos and organized meetings to discuss the topic. This led to international meetings, government involvement, and public discussions. Doudna was contacted by government representatives, including senators and California Governor Jerry Brown, seeking information about CRISPR’s dangers and business opportunities. Senator Feinstein’s office is drafting a resolution to prevent the clinical use of genome editing in human embryos due to ethical and safety concerns.

* Cost Considerations: Doudna discussed the potential high cost of CRISPR-based treatments with senators, acknowledging the need to make it affordable and accessible to those in need.

* Challenges and Perseverance in Scientific Research: Doudna emphasized the challenges and setbacks commonly faced in scientific research, including numerous failed experiments and ideas. She highlighted the importance of perseverance, resilience, and willingness to continue working even when things fail. Doudna shared a story of a colleague who lost three months of work due to a shattered glass flask but returned to the lab the next day to start over.

* Impact Areas of CRISPR Technology: Doudna identified agriculture, human medicine, and synthetic biology as key areas where CRISPR is expected to have a significant impact. She mentioned potential applications in engineering organisms for commercial use, producing useful chemicals, and developing biofuels.

* Balancing Scientific Research and Societal Concerns: Doudna expressed her desire to stay involved in discussions about the ethical and societal implications of CRISPR technology, despite her preference for focusing on scientific research. She emphasized the importance of considering the broader implications of new technologies and engaging in conversations with policymakers and the public.

* Importance of Diverse Interests and Hobbies: Doudna shared her personal experience of pursuing gardening and other hobbies outside of the lab to maintain balance and find rejuvenation when facing setbacks in scientific research.

How Gene Editing Works in Stem Cells:

– Editing entire tissues, plants, or animals requires modifications in proliferating stem cells.

– In plants, a small ball of tissue with totipotent abilities is used for gene editing.

– In humans, gene editing can be done in blood stem cells, which are then replaced to repopulate the blood supply.

Addressing Multiple Genes in Gene Editing:

– Current technology primarily focuses on single genetic changes for well-documented diseases.

– Editing multiple genes simultaneously is possible in animals and plants and may become easier in humans in the future.

– Genes can have multiple functions, leading to potential detrimental effects in areas other than the intended beneficial change.

Ethical Considerations in Gene Editing:

– Risk and benefit analysis is crucial in determining the appropriateness of gene editing interventions.

– Acute diseases may warrant higher risk tolerance compared to traits that are not diseases.

– Ongoing research aims to understand gene interactions and genetic pathways for diseases and traits, aiding ethical decision-making.

Future Applications of CRISPR:

– CRISPR’s increasing presence in our lives is anticipated.

– Diagnostic applications, point-of-care treatments, and genome-edited plants are among the expected developments.

– Public understanding of the technology is important for informed choices and societal discussions.



Dr. Jennifer Doudna’s journey from exploring bacterial immunity to spearheading CRISPR-Cas9 technology encapsulates the essence of scientific inquiry and its potential to reshape the world. As CRISPR-Cas9 continues to evolve, it brings with it a constellation of opportunities and challenges, demanding a balanced approach between technological advancement and ethical consideration. The story of CRISPR-Cas9 is not just about a scientific breakthrough; it is about the human endeavor to understand, manipulate, and responsibly use the very code of life.


Notes by: OracleOfEntropy