Lecture Series and Co-sponsors:
The 2019 Arrow Lecture Series on Ethics and Leadership is co-sponsored by Stanford’s Center for Biomedical Ethics, Center for Ethics in Society, and Center for Law and Biosciences.

Background on the Arrow Lectures:
The Arrow Lectures were established in 2005 and have become prestigious lectures at Stanford University. Past lecturers include renowned scholars such as Esther Duflo, Paul Collier, Robert Reich, Thomas Piketty, and Nobel laureate Amartya Sen. The lectures are named after Stanford’s Emeritus Professor Kenneth Arrow, a Nobel Prize winner in Economics.

Kenneth Arrow’s Legacy:
Arrow was a renowned scholar and one of the most influential economists of the 20th century. He received the Nobel Prize in Economics at the age of 51, making him the youngest recipient ever. Five of Arrow’s students have gone on to win the Nobel Prize in Economics.

Jennifer Doudna and the Promise and Peril of Genetic Editing:
The lecture will focus on the CRISPR technique for editing the human genome, discovered by Dr. Jennifer Doudna. CRISPR allows humans to control evolution and may lead to the rewriting and reformulation of what it means to be human. Recent news includes the birth of the first CRISPR-edited human baby by Dr. He in China.

Format of the Evening:
The lecture will be followed by a Q&A session with the audience.

Background on Jiwoo Lee:
Jiwoo Lee is a sophomore at Stanford majoring in computational biology. She began working on CRISPR in high school and has won numerous awards for her research. She was nominated for the Wired Magazine 25 Prize by Jennifer Doudna. She is involved in various extracurricular activities, including being a sorority member, a dance team member, and a health educator.

Introduction to Jennifer Doudna:
Jennifer Doudna is a professor at UC Berkeley and the Gladstone Institute. She is an investigator at the Howard Hughes Medical Institute and the Executive Director of the Innovative Genomics Institute. She has received numerous prestigious honors for her work on CRISPR.

Overview of the Presentation:
Jennifer Doudna will discuss the science of genome editing and the discovery of CRISPR. She will share her perspective as a biochemist who knew little about genome editing before her involvement. She will emphasize the importance of curiosity-driven scientific projects and following clues to make sense of the natural world.

Discovery of CRISPR:
Doudna and her lab discovered CRISPR, a bacterial adaptive immune system, in 2012. CRISPR presented itself as a powerful technology for genome editing, different from its natural function in bacteria. Doudna highlights the common occurrence of scientists stumbling upon natural phenomena that provide clues for laboratory applications.

Introduction:
Jennifer Doudna, a renowned scientist, shares her journey of discovering and developing CRISPR-based genome editing technology. CRISPR is a bacterial adaptive immune system that protects cells from viral infections by storing viral DNA fragments and using them to guide Cas proteins to cleave matching DNA sequences.

Emergence of CRISPR:
Jill Banfield’s research on bacteria in natural settings revealed distinctive DNA sequences in bacterial chromosomes, suggesting an adaptive immune system against viruses. Scientists identified these sequences as CRISPR arrays, containing repeated DNA segments and unique viral DNA fragments.

CRISPR Mechanism:
CRISPR systems detect viral infections, store viral DNA fragments in the CRISPR array, and use Cas proteins to cut up matching DNA sequences. The CRISPR array is transcribed into RNA molecules, each containing a unique viral address label. Cas proteins form complexes with CRISPR RNA and search the cell for matching DNA sequences. Upon finding a match, the Cas proteins cut the DNA, providing protection from future viral infections.

Diversity of CRISPR Systems:
CRISPR systems vary widely among different bacteria, with different types of Cas genes and RNA address labels. Studying the functions of these diverse CRISPR components became a focus of research for scientists like Jennifer Doudna.

Collaboration with Emmanuelle Charpentier:
Doudna met Emmanuelle Charpentier at a scientific conference and discovered their complementary expertise. They collaborated to investigate the function of Cas9, a single large protein essential for CRISPR immunity in a particular bacterium.

Deciphering Cas9 Function:
Doudna and Charpentier’s collaboration aimed to understand the molecular function of Cas9. They worked with Martin Jinek and Chris Chylinski, postdoc and graduate student, respectively, in their labs. The team used various techniques to study Cas9, including biochemical assays and structural analysis.

Applications of CRISPR-Based Genome Editing:
The discovery of CRISPR-based genome editing has revolutionized genetic research and holds immense potential for therapeutic applications. Scientists can now precisely edit DNA sequences, enabling the correction of genetic defects, modification of genes for research, and development of new therapies. CRISPR-based gene editing offers promising avenues for treating genetic diseases, developing personalized medicine, and advancing agricultural research.

Discovery and Mechanism of CRISPR-Cas9:
CRISPR-Cas9 is a bacterial defense system that recognizes and cuts viral DNA. Cas9 is a protein that uses a guide RNA molecule to recognize a specific DNA sequence and cut the DNA at that location. The Cas9 protein can be engineered to target any DNA sequence, making it a powerful tool for genome editing.

Applications of CRISPR-Cas9:
CRISPR-Cas9 can be used to edit genes in cells, which has applications in: Fundamental research: studying gene function and disease mechanisms Healthcare: developing new treatments for diseases Therapeutics: correcting genetic defects that cause disease Agriculture: improving crop yields and resistance to pests and diseases Diagnostics: developing new tests for diseases and genetic disorders

Ethical Considerations:
The power and simplicity of CRISPR-Cas9 raise ethical questions about its use. Some concerns include: The potential for unintended consequences of genome editing The use of CRISPR-Cas9 to create “designer babies” with enhanced traits The potential for CRISPR-Cas9 to be used for bioterrorism

Research Example: CRISPR-Cas9 for Neurodegenerative Diseases:
Researchers are exploring the use of CRISPR-Cas9 to treat neurodegenerative diseases such as Huntington’s disease. CRISPR-Cas9 can be modified to penetrate the brain and target specific genes involved in the disease. Animal studies have shown promising results, with CRISPR-Cas9 successfully editing genes in the brain and improving disease symptoms.

CRISPR-Cas9 and Organ Donor Animals:
Some researchers are engineering animals to be better organ donors for humans. This involves using CRISPR-Cas9 to modify animal genes to make their organs more compatible with the human immune system. Ethical questions arise regarding the welfare of the animals and the potential risks and benefits of this technology.

Animal Genome Editing:
Jennifer Doudna discusses the use of CRISPR-Cas9 genome editing in animals, particularly in pigs and monkeys. CRISPR-Cas9 is used to remove endogenous viral DNA sequences from pig genomes, making them safer for organ transplantation into humans. Additionally, gene editing is employed to create humanized versions of pig genomes, enhancing organ acceptance by patients.

Agriculture Applications:
CRISPR-Cas9 has shown promising applications in agriculture, specifically in crop improvement. A study by Zach Lipman from Cold Spring Harbor Laboratory demonstrated the use of CRISPR-Cas9 in tomatoes to alter a regulatory sequence, allowing for precise control over the number of fruits produced. This technology has the potential to revolutionize crop production and address global food challenges.

Diagnostic Uses:
CRISPR-based systems are being explored for diagnostic purposes. CRISPR enzymes can be used not only for cutting DNA but also for detecting DNA and RNA molecules. This enables the development of simple, cost-effective, and point-of-care diagnostic tests. Potential applications include detecting viruses, bacteria, and other pathogens in clinical settings, similar to home pregnancy tests.

Commercialization of CRISPR:
CRISPR has sparked a surge of commercial interest, raising questions about ownership, profit distribution, and regulations.

Somatic vs. Germline Editing:
CRISPR editing in somatic cells results in non-heritable changes, while germline editing affects the entire organism and can be passed on.

Editing in Mammals:
CRISPR editing in mammals, including humans, has become increasingly feasible, prompting discussions about its potential applications and ethical implications.

Germline Editing in Humans:
In 2018, a Chinese scientist announced germline editing in human embryos and subsequent implantation, leading to the birth of babies.

Responsible Use and Regulation:
The international community recognizes the need for serious discussions and regulations to ensure responsible use of CRISPR technology and prevent ethically challenging applications.

Advancements in CRISPR Technology:
Researchers worldwide are harnessing CRISPR’s power for fundamental research and developing products based on this technology.

Collaboration and Support:
Jennifer Doudna acknowledges the contributions of her research team, collaborators, and funding agencies in the development of CRISPR technology.

The Innovative Genomics Institute (IGI):
IGI, a partnership between UCSF, Berkeley, and Gladstone Institutes, aims to advance genome editing research and facilitate discussions on education and ethics.

Response to Germline Editing Announcement:
Doudna received a surprise email from the scientist responsible for the germline editing announcement, prompting her to inform the conference organizers.

Meeting with Ho Chi Minh:
Jennifer Doudna met with Ho Chi Minh, the scientist behind the CRISPR announcement, in Hong Kong before the conference began. Ho Chi Minh appeared young and naive about the potential public backlash to his work. He seemed to expect international acclaim and accolades, rather than the negative reactions that ensued.

Doudna’s Prior Interactions with Ho Chi Minh:
Doudna had encountered Ho Chi Minh at previous professional gatherings. She had no indication that he intended to apply CRISPR to clinical settings. She believes she would have advised against such a move if he had revealed his plans.

CRISPR as a Revolutionary Technology:
CRISPR is a revolutionary technology that allows for simple editing of genes in any species. It is a powerful tool with the potential to alter the genetic makeup of organisms.

Accessibility and Low Barrier to Entry:
CRISPR technology has a relatively low barrier to entry compared to other scientific fields, making it accessible to individuals with advanced high school-level knowledge. Setting up a CRISPR editing lab in a garage requires significantly less financial investment compared to nuclear physics research.

Germline Editing and Profound Implications:
CRISPR technology allows for germline editing, passing genetic modifications to all future generations. This profound aspect of CRISPR raises ethical concerns about playing God with the genetic sequence.

Positive Therapeutic Uses and Potential Misuse:
CRISPR technology holds immense potential for positive therapeutic applications, including in plants and animals. However, there is a risk that the technology could be used for less beneficial or even harmful purposes.

Ethical Concerns and Unintended Consequences:
The accessibility of CRISPR technology raises concerns about its potential misuse by individuals with malicious intent. Germline editing, in particular, could have far-reaching and irreversible consequences, affecting the genetic makeup of future generations.

Regulatory Challenges and Balancing Innovation:
The ease of access to CRISPR technology poses challenges for regulation and governance. Balancing the potential benefits of innovation with the need to mitigate potential risks and unintended consequences is a crucial task for policymakers and the scientific community.

Democratization of CRISPR Technology:
CRISPR technology has become widely available and accessible due to its low cost and distribution through organizations like Addgene. Scientists and individuals can easily obtain the Cas9 protein and necessary constructs for genome editing at a cost of approximately $65. DIY science initiatives, such as Indiegogo, offer CRISPR kits, although their effectiveness may vary. CRISPR kits are being developed for educational purposes, allowing students to learn about the technology and its applications.

Ethical Considerations:
The democratization of CRISPR raises concerns about the potential misuse and irresponsible use of the technology. The low barrier to entry and the absence of legal frameworks increase the risk of CRISPR being used for unethical or harmful purposes. Balancing the potential benefits of CRISPR with the risks associated with its widespread use is a significant challenge. Striking a balance between scientific progress and responsible use is crucial, and international cooperation is necessary to address these ethical implications.

The Importance of Ethical Education:
Ethical considerations should be an integral part of scientific research and education. Scientists should receive training and support to develop a comprehensive understanding of the ethical implications of their work. Engaging scientists in discussions about the ethical, societal, and environmental impacts of their research is essential.

Advocating for Responsible Use:
The scientific community should actively promote responsible and ethical use of CRISPR technology. Scientists should speak out against unethical practices and advocate for regulations and guidelines to ensure the safe and responsible application of CRISPR. Public awareness and education about CRISPR and its potential implications are crucial for informed decision-making.

Scientists’ Focus on Their Own Work:
Scientists are often focused on their own experiments, publishing papers, finishing theses, and securing jobs and tenure. This mindset may limit their exposure to the broader implications and potential impacts of their work.

Lack of Training in Ethics:
Graduate programs and training programs for scientists often do not adequately address the ethical considerations and potential societal impacts of scientific research. Scientists may not be equipped with the knowledge and skills to think critically about the ethical dimensions of their work.

Need for Better Education and Collaboration:
There is a need to improve the education of scientists in ethics, including exposing them to the realities of how their work might be used and its potential impact on other fields and society as a whole. Collaboration between scientists and bioethicists can be beneficial in fostering a deeper understanding of the ethical implications of scientific research and developing ethical guidelines.

Challenges in Ethical Education:
Striking a balance between providing scientists with ethical guidance without stifling innovation and progress can be challenging. Bioethicists may sometimes be perceived as obstacles to scientific research, rather than collaborators working towards ethical advancements.

Promoting Ethical Collaboration:
Finding ways to work together as a team, where scientists and bioethicists collaborate to move science forward in an ethical manner, is crucial. This can involve open and respectful dialogue, mutual understanding of perspectives, and a shared commitment to responsible and ethical research.

Understanding the Human Aspect of Science:
Speaker 08 highlights the importance of recognizing the human aspects of scientific research, questioning why moral considerations should be separated from one’s professional life.

Bioethics in Medical Schools vs. Engineering Schools:
Bioethics is a well-established field in medical education, but there is no equivalent emphasis on ethical considerations in computer science and engineering schools.

The Tension Between Innovation and Ethics:
The ethicist’s role is often perceived as slowing down progress and innovation, leading to the “let scientists be scientists” response.

Jennifer Doudna’s Responsibility and Challenges:
Jennifer Doudna acknowledges her responsibility to address the ethical and social implications of CRISPR technology, beyond her role as a scientist focused on discovery.

Public Awareness and Engagement:
Speaker 08 asks Doudna about her experience in raising public awareness of CRISPR’s challenges, given her efforts to break out of the traditional scientist mold.

Doudna’s Observations:
Doudna acknowledges the excitement and interest in CRISPR, but recognizes that there is still work to be done in fostering public understanding and engagement with the technology’s ethical and social implications.

Scientists’ Role in the Conversation:
Scientists should be involved in discussions about the responsible use of CRISPR technology, rather than dismissing concerns or claiming superiority. Encouraging more scientists to engage in discussions about CRISPR is crucial to facilitate a broader conversation. Scientists often hesitate due to a perceived lack of expertise, but it’s important to participate even if one doesn’t have all the answers.

Three-Legged Stool of Responsibility:
Personal responsibility: Individual scientists have a duty to consider the ethical and societal implications of their work. Professional responsibility: Scientific societies and organizations have a responsibility to guide their members and promote responsible conduct. External regulation: Government bodies or supranational organizations may need to implement regulations to ensure the safe and ethical use of CRISPR technology.

Challenges in Regulation:
Enforcement: Regulations need to be enforceable to be effective, which can be challenging. Hong Kong Wake-Up Call: The CRISPR-edited babies case highlighted the need for more robust guidelines and regulations. He Jiankui’s Response: He Jiankui claimed to have followed the criteria set forth by the National Academies, indicating the inadequacy of existing guidelines.

Ethical Dilemmas and the Need for Clearer Criteria:
He Jiankui’s actions highlighted the lack of clear criteria for assessing the ethical implications of gene editing technologies. A broader consensus and clearer guidelines are necessary to prevent misinterpretations and potential abuses.

Role of Scholarly Journals in High-Profile Cases:
He Jiankui’s apparent goal was to publish his work in a prominent journal to gain international attention and professional approval. The role of journals in such cases is a topic of debate, with some advocating for publication to allow for evaluation, while others question the appropriateness of providing a platform for controversial research.

High-Stakes Meeting and Real-Time Criticism:
During a meeting in Hong Kong, He Jiankui was scheduled to present his work, despite criticism from the head of the FDA, Scott Gottlieb. The organizers defended their decision to allow He Jiankui to present, emphasizing the importance of scientific evaluation and open discussion.

Different Perspectives on Publication and Presentation:
The incident raised questions about whether He Jiankui should be allowed to publish his work in a scholarly journal, given the ethical concerns surrounding his research. Different viewpoints exist on this issue, with some arguing for the value of open evaluation, while others emphasize the need to prevent the promotion of unethical or potentially harmful practices.

The Right Conditions for Gene Editing:
Jennifer Doudna believes that gene editing should initially focus on diseases with clear genetic causes and well-documented studies. Practical considerations, such as the ability to deliver gene editing molecules to specific cells, also play a role in selecting treatable conditions. Blood-related disorders, where cells can be edited outside the body and reintroduced, are currently more feasible targets than conditions like Huntington’s disease, which require editing neurons.

Scientists vs. Patients: Who Drives the Choice?
Currently, scientists largely decide which diseases to prioritize for gene editing based on technical feasibility and research interests. The pressing medical needs of patients and families are not always the primary driving factors. Wealthy individuals and family foundations sometimes sponsor research on rare diseases affecting their families, raising ethical questions about funding biases.

Therapeutic vs. Enhancement: A Blurred Line
The distinction between therapeutic and enhancement uses of gene editing is challenging to define. Conditions like hypercholesterolemia, which significantly reduce the risk of heart disease, raise questions about whether they should be considered enhancements or medical interventions.

The Future of Human Evolution:
Gene editing could lead to the emergence of “Human 2.0” with enhanced capabilities and reduced susceptibility to diseases. Ethical considerations surrounding this transition are often overlooked, particularly regarding the role of the current generation in shaping the future of humanity. The drive to cure diseases and improve human traits will likely continue, potentially leading to a wide range of societal changes and ethical dilemmas.

Human 2.0 and the Need for Ethical Discussions:
Jennifer Doudna emphasizes the inevitability of human enhancement technologies like Human 2.0 and calls for open forums to discuss their ethical implications. She highlights the need to address how society will transition into this new era and deal with the potential consequences.

Ethical Challenges Posed by Rogue States:
A hypothetical scenario is presented where North Korea uses CRISPR to create designer babies, raising geopolitical and ethical concerns. Doudna acknowledges the difficulty in regulating rogue states and the need for international efforts to establish regulations. She emphasizes that these concerns are not limited to CRISPR-Cas9 but apply to any technology with the potential for misuse.

Balancing Ethics and Innovation:
Megan Palmer questions the depth of ethical engagement among scientists and engineers, citing instances where ethical principles are used for justification rather than critique. Doudna suggests establishing detailed criteria for human germline editing that the international community agrees upon. She believes that precise guidelines will help prevent individuals from interpreting existing guidelines loosely.

Addressing Intentional Misuse and Worst-Case Scenarios:
Doudna expresses discomfort with publicly discussing unethical applications of CRISPR-Cas9 and publishing papers on how to misuse the technology. She believes such discussions are counterproductive and should be limited to appropriate forums like government agencies.

Advice for Young Scientists:
In response to a question about what advice she would give to a young scientist who has access to powerful technologies like CRISPR, Doudna emphasizes the importance of considering the ethical implications. She encourages young scientists to be aware of the potential risks and benefits, to engage in thoughtful discussions, and to seek guidance from experts in the field.

Responsibility of Scientists:
Jennifer Doudna emphasizes the significance of considering the broader context of one’s research, including potential uses and misuses. Scientists should not shy away from expressing their opinions and engaging in debates, even if they are not experts in bioethics or law. Engaging with colleagues who have expertise in ethics and law can lead to valuable learning and insights.

Addressing Concerns about Weaponization:
Rob Reich expresses concerns about the potential weaponization of CRISPR technology, given its capacity to alter people’s genomes. Reich raises the ethical responsibility of scientists to develop counter-technologies or antidotes to prevent weaponization.

DARPA’s Role in Developing Countermeasures:
Jennifer Doudna acknowledges the concerns about weaponization and highlights that agencies like the Department of Defense (DOD) are taking proactive measures. DARPA, an organization within the DOD, has issued calls for proposals aimed at controlling CRISPR and ensuring its safe use. DARPA’s focus includes developing anti-CRISPR technologies and exploring ways to limit the spread of CRISPR-based modifications.

Transparency and Collaboration:
Doudna stresses the importance of transparency and collaboration among scientists, policymakers, ethicists, and the public. She believes that open dialogue and collective efforts are essential in shaping regulations and policies around CRISPR technology. Doudna emphasizes the need for continuous monitoring and evaluation of CRISPR’s applications to address emerging ethical concerns.

Safety Switch Concerns:
Rob Reich suggests that gene-editing therapies should have an antidote or a safety switch to reverse their effects if necessary.

Government Involvement:
Jennifer Doudna highlights the role of government funding in supporting fundamental research and directing it toward specific areas.

Company Responsibilities:
Doudna acknowledges that companies have fiduciary responsibilities to shareholders and focus on bringing products to market, which may not prioritize safety switches.

FDA Regulations:
Doudna emphasizes the importance of FDA regulations requiring safety switches for gene-editing therapies to ensure their approval.

Asilomar Conference Parallels:
A participant draws parallels between the current discussions on CRISPR and the Asilomar Conference in 1975, which addressed the risks of molecular cloning.

Historical Context:
Doudna explains the Asilomar meeting, where scientists discussed the potential dangers of molecular cloning and the creation of dangerous proteins using recombinant DNA technology.

Self-Regulation and Model for CRISPR:
Doudna suggests that the self-regulation model adopted by the scientific community after the Asilomar Conference could be applied to address the ethical considerations surrounding CRISPR technology.

Innovative Genomics Institute Meeting:
Doudna mentions a meeting convened by the Innovative Genomics Institute in 2015 to discuss the future of genome editing, especially in humans and the human germline.

Involvement of Paul Berg and David Baltimore:
Doudna acknowledges the contributions of Paul Berg and David Baltimore, who were part of the Asilomar Conference and have been engaged in the discussions on CRISPR ethics.

Relevance to Human Germline Editing:
Doudna points out that CRISPR raises ethical issues beyond those of engineering bacteria, as it involves the potential engineering of humans.

Asilomar as a Blueprint:
Doudna concludes that the Asilomar Conference serves as a valuable blueprint for shaping the current conversation on the ethics of gene editing.