Jennifer Doudna (UC Berkeley Professor) – Director’s Distinguished Women in Science Speaker Series (Jan 2018)

Chapters

Abstract

Revolutionizing Biology and Ethics: The Journey of Jennifer Doudna and CRISPR-Cas9

Jennifer Doudna, a renowned pioneer in gene editing and co-discoverer of CRISPR-Cas9, has revolutionized both the study of biology and the ethical landscape of scientific research. From her early indifference to being a “woman in science” to later recognizing the unique challenges faced by women in the field, Doudna’s career is a testament to perseverance and passion. Balancing a rigorous scientific career with personal life, she has traversed a non-linear path from studying bacterial communication to groundbreaking work in RNA biochemistry, leading to the discovery of CRISPR-Cas9. This technology not only opened doors for targeted gene editing but also ushered in complex ethical discussions and the necessity for regulatory frameworks. Engaging with public policy, Doudna’s journey reflects the evolving role of scientists in addressing the societal implications of their work.

Jennifer Doudna: A Trailblazer in Science

Jennifer Doudna’s journey in science started in Hilo, Hawaii, and led her through Pomona College, Harvard, and Yale. Influenced by her father’s love for puzzles and a high school chemistry teacher, Doudna was drawn to the challenges of science. She chose to pursue biochemistry, a field combining chemistry and biology, a decision that laid the foundation for her later achievements. Doudna’s initial research at Yale focused on the 3D structures of RNA molecules, investigating their potential role in the origin of life. This focus on RNA eventually steered her towards CRISPR-Cas9 research.

The Genesis of CRISPR-Cas9

Doudna’s foray into CRISPR research began with a collaboration with Jill Banfield at UC Berkeley, where they studied CRISPR sequences in bacteria. Initially, this project was a small part of Doudna’s work, but it quickly became the dominant focus due to its potential. The discovery of CRISPR-Cas9, a collaboration with Emmanuelle Charpentier, involved understanding the function of Cas9, a protein capable of making targeted DNA cuts, revolutionizing the field of gene editing.

Early Research Interests:

Doudna’s research journey before CRISPR-Cas9 was marked by diverse interests. Initially, she pursued studies on bacterial communication and protein methylation at Pomona College. Upon entering Harvard Medical School, she explored various research areas through laboratory rotations.

Jack Szostak’s Influence:

Doudna’s path to RNA research began with joining Jack Szostak’s lab, where she worked on recombination in yeast and eventually shifted her focus to the evolution and origin of life. Szostak’s interest in RNA as a primordial molecule sparked Doudna’s fascination with RNA’s potential role in the origin of life.

Transition to RNA Structure and Function:

Realizing the need for understanding the structures and functions of RNA molecules, Doudna pursued a postdoc with Tom Cech, a renowned RNA biochemist. She focused on crystallizing RNA and solving three-dimensional structures to gain insights into their catalytic mechanisms.

Yale and Beyond:

Doudna established her own academic lab at Yale, where she continued her research on RNA structure and function. Her interest in RNA persisted throughout her career, eventually leading her to the development of CRISPR-Cas9 gene-editing technology.

Serendipity and the Path to CRISPR-Cas9:

Doudna’s research trajectory highlights the role of serendipity and open-mindedness in scientific discovery. While her initial research interests differed from the CRISPR-Cas9 project, her persistent curiosity and willingness to explore new avenues ultimately led to her groundbreaking work in gene editing.

Origins of the CRISPR-Cas9 Discovery:

A chance conversation between Jennifer Doudna and Jill Banfield at Berkeley’s Free Speech Movement Cafe sparked the journey to CRISPR-Cas9’s discovery.

Doudna’s Research Focus:

While at Yale, Doudna’s research primarily focused on catalytic RNAs. However, upon moving to Berkeley, she shifted her focus to understanding how RNA molecules control genetic information flow in cells.

CRISPR-Cas9 Inspiration:

Doudna and Banfield’s shared interest in RNA, despite their differing perspectives, led to discussions that inspired the CRISPR-Cas9 research.

Banfield’s Metagenomics Work:

Banfield’s metagenomics research on bacteria aimed to unravel the diversity of microbes and viruses in various environments.

CRISPR Observation:

Banfield’s work led her to observe a unique phenomenon in many bacteria: arrays of sequences with viral fragments inserted between repetitive DNA elements, known as CRISPR.

Collaboration at Lawrence Berkeley Lab:

Doudna and Jill Banfield began collaborating to investigate CRISPR in bacteria. Discussions about the observations and potential mechanisms of an adaptive immune system in bacteria ensued. Conversations with other lab members, particularly those studying soil bacteria and CRISPR sequences, fueled a growing interest and led to regular meetings among researchers.

LDRD Funding:

The Lawrence Berkeley Lab provided initial funding through an LDRD grant to support the CRISPR research project. This funding enabled the hiring of Blake Wiedenheft, a postdoc with expertise in microbes and CRISPRs.

Blake Wiedenheft’s Enthusiasm and Charisma:

Wiedenheft’s passion for the CRISPR project and his captivating presentation convinced Steve Holbrook to recommend using the LDRD money to bring him on board.

LDRD Explained:

LDRD (Laboratory Directed Research and Development) is discretionary funding allocated to laboratory directors for innovative and high-risk research projects that might not receive funding through traditional channels.

Emergence of CRISPR Research:

Initially, CRISPR research represented a small part of Doudna’s research focus. Doudna felt a sense of guilt for diverting resources from her primary research funded by the Howard Hughes Medical Institute.

Meeting Emmanuelle Charpentier and the Discovery of Cas9:

At a conference in 2011, Jennifer Doudna met Emmanuelle Charpentier, a microbiologist studying a CRISPR system in Streptococcus pyogenes. This CRISPR system had a single gene, Cas9, associated with adaptive immunity.

Collaboration between Doudna and Charpentier:

Doudna and Charpentier combined their expertise to study the function of Cas9. Their work revealed that Cas9 is an RNA-programmed protein that can be directed to cut DNA sequences of any desired sequence.

Development of a Simpler Guide RNA:

Doudna and her colleagues developed a simpler guide RNA that uses a single piece of RNA to hold onto the protein and provide the sequence information for DNA cutting. This discovery paved the way for the use of CRISPR-Cas9 as a gene editing tool.

Convergent Evolution of CRISPR Research:

Several labs worldwide were working on CRISPR systems, driven by various interests. Francisco Mojica identified integrated viral sequences in CRISPR arrays, suggesting an adaptive immune system. Denisco, a yogurt company, sought to protect their bacterial cultures from phage infection using CRISPR. Labs in the Netherlands studied the biochemistry of CRISPR enzymes.

CRISPR-Cas9 as a Tool for Biologists:

CRISPR-Cas9’s ability to make directed cuts in DNA revolutionized biological research. It allowed scientists to break DNA, insert or modify genes, and study the effects of these changes on cell behavior.

Jennifer Doudna’s Achievements, Research, and Impact

Doudna, along with Emmanuel Charpentier, is credited with the groundbreaking discovery that CRISPR-Cas9 can be utilized for programmable DNA editing. This achievement earned her the prestigious Alan Waterman Prize from the National Science Foundation. She holds professorships at UC Berkeley in Chemistry and Molecular and Cell Biology and is an investigator with the Howard Hughes Medical Institute. Doudna is also a co-founder of Carbon Biosciences and Intellia Therapeutics, companies exploring research applications and disease treatments using CRISPR technology. Her book, “A Crack in Creation,” delves into the profound ethical and philosophical questions raised by this technology.

CRISPR-Cas9’s Broader Impact

CRISPR-Cas9’s implications extended beyond basic research. Labs worldwide, including Doudna’s, delved into the practical applications of this technology. CRISPR research was a convergent effort, involving multiple labs with diverse interests. The ability to edit genes opened up possibilities for treating diseases and improving human health, attracting significant attention from various fields.

Ethical Challenges and Public Policy Engagement

With the realization of gene editing’s transformative potential came the responsibility to address its social implications. In early 2013, Doudna shifted her focus from pure research to engaging with the public policy arena of gene editing. This involved establishing the Innovative Genomics Institute and participating in pivotal meetings to discuss the ethical and societal implications of gene editing. Communicating the complexity of CRISPR to non-experts and addressing ethical concerns, especially regarding germline editing, became central to her work.

Regulatory and Policy Challenges

The rapid pace of scientific advancements in gene editing often outpaced ethical considerations, creating a need for regulation. Government agencies began to engage in policy discussions, though progress was hindered by the lack of a dedicated regulatory body. The case of human germline editing in Oregon, funded by non-federal money, highlighted the complexities and the necessity for state involvement in research funding and regulation.

A Call for Responsible Science

Jennifer Doudna’s journey from a curious student in Hawaii to a leading figure in gene editing exemplifies the dynamic nature of scientific research and the importance of ethical responsibility. As CRISPR-Cas9 continues to open new frontiers in biology, the need for careful ethical consideration, public engagement, and policy development remains critical. This story not only celebrates scientific innovation but also underscores the evolving role of scientists in society, where the implications of their work extend far beyond the laboratory.

Supplemental Information:

Transition from Basic Research to Practical Applications:

Jennifer Doudna’s lab continued to investigate the fundamental mechanisms of CRISPR-Cas9 while others explored its practical applications. The discovery of CRISPR-Cas9 marked a significant turning point in biology, with implications for medicine, agriculture, and beyond.

Jennifer Doudna’s Recognition of Gene Editing’s Impact and Responsibility to Address Its Ethical Implications:

Widespread adoption of gene editing technology led to a surge in publications, presentations, and inquiries.

George Church’s prediction of a coming tidal wave:

Doudna’s meeting with George Church revealed his expectation of a significant impact from gene editing.

Grappling with the social implications of gene editing:

Doudna felt compelled to address the ethical implications of gene editing.

Founding the Innovative Genomics Institute:

Doudna, Botchan, and others established the Innovative Genomics Institute to educate non-scientists about gene editing.

Discussion with Jacob Korn and Mike Botchan:

Doudna, Korn, and Botchan considered writing an op-ed about the ethics of gene editing.

Meeting in the Napa Valley with Paul Berg and David Baltimore:

Doudna organized a meeting with scientists to discuss the ethical dimensions of gene editing.

Responsibility to engage the public in the conversation:

Doudna realized the importance of engaging the public in discussions about gene editing ethics.

Ethical Implications of Germline Editing and the Challenges of Responsible Governance:

Communicating Gene Editing to Non-Scientists:

Jennifer Doudna emphasizes the importance of finding helpful analogies and avoiding jargon to explain gene editing to non-scientists. Effective communication focuses on the principles and potential applications of the technology rather than the technical details.

Ethical Issues of Germline Editing:

Germline editing raises significant ethical questions, including who should decide on heritable changes, who pays for and regulates it, and who has access to the technology. Concerns about eugenics and the potential impact on human identity and our understanding of what makes us human arise when we can tinker with the code of life.

Balancing Responsible Discussions and Practical Implications:

Despite responsible discussions and calls for moratoria on germline editing, the reality is that research and applications may still proceed independently. The challenge lies in enforcing ethical guidelines and preventing the technology from outpacing societal discussions and regulations.

International Differences in Oversight:

Different countries have varying levels of oversight and regulations for gene editing, leading to potential disparities in ethical practices. In some countries, researchers may have more autonomy and less stringent review processes, highlighting the need for international coordination and harmonization of guidelines.

Who Ensures Ethical Governance?:

The lack of a dedicated “lab police” to enforce ethical guidelines raises questions about how to prevent irresponsible or unethical applications of gene editing. Reliance on self-regulation and peer review may not be sufficient to ensure responsible governance. Establishing international oversight bodies or regulations could help address this challenge.

The Ethical and Policy Conundrums of Gene Editing Technology:

The Influence of the Perspective Piece:

– Jennifer Doudna and colleagues wrote a perspective piece in 2015 expressing concerns about gene editing in human embryos.

– The publication of this piece coincided with the submission of three manuscripts reporting gene editing in human embryos to scientific journals.

– Two of these papers, originating from China, were eventually withdrawn due to the backlash and ethical considerations raised by the perspective piece.

Ethical Implications of Gene Editing:

– Gene editing raises ethical challenges, particularly in the context of germline editing and potential misuse.

– Applications such as gene drives, which aim to rapidly spread a trait through a population, have positive implications for human health but also pose environmental risks.

– Agricultural applications of gene editing raise questions about GMO labeling and regulations.

Addressing Ethical Concerns:

– Doudna emphasizes the need for transparency and honesty about the potential risks and ethical implications of gene editing technology.

– She expresses concern about the rush to use the technology for attention or as a first-to-market strategy, which could lead to public backlash.

Policy and Regulatory Considerations:

– There is a need for policy discussions to keep pace with the rapid advancements in gene editing technology.

– Doudna’s involvement in policy discussions includes working with the National Institutes of Health, the Department of Energy, and the Department of Defense.

– Various countries and agencies are engaged in developing guidelines and regulations for the safe and responsible use of gene editing.

The Role of States in Gene Editing Policy:

– In the absence of a federal Office of Science and Technology Policy, states can play a role in shaping policy.

– Human germline editing is not fundable with federal money, but states can provide funding for such research.

– The Center for the CIRM in California, for example, could potentially fund research that leads to applications of gene editing in the human germline.

Engagement with State Funding Agencies:

– Engagement with state funding agencies becomes crucial in addressing ethical concerns and shaping policy for gene editing technology.

Notes by: Hephaestus