Jennifer Doudna (UC Berkeley Professor) – Opportunites and Ethics of Editing Genomes (Feb 2019)


Chapters

00:00:05 Promise and Peril of Genetic Editing
00:03:41 Origins and Applications of CRISPR Technology
00:12:00 CRISPR-Based Genome Editing: Unveiling the Adaptive Immune System of Bacteria
00:20:58 CRISPR Technology: Applications and Ethical Implications
00:33:52 CRISPR-Cas9: Applications in Medicine, Agriculture, and Diagnostics
00:37:20 Germline Editing in Humans: Ethical Challenges and Considerations
00:44:19 CRISPR's Global Impact: Controversy and Ethical Considerations
00:46:59 CRISPR Technology: Accessibility and Ethical Concerns
00:49:40 Global Challenges and Ethical Considerations in CRISPR Technology
00:55:31 Challenges and Opportunities in Bioethics Education
00:57:36 Ethical and Social Dimensions of CRISPR Technology
01:01:33 Scientists' Engagement in Ethical Conversations Regarding Genetic Engineering
01:04:36 Ethical Considerations in Gene Editing Controversies
01:07:04 Ethical Considerations for Genetic Enhancement
01:14:36 Navigating Ethical Dilemmas in Human Enhancement
01:22:12 Ethical Considerations and Preparedness for CRISPR Technology
01:24:58 History and Implications of Gene Editing Safety Precautions

Abstract

Navigating the Future of CRISPR: Ethical, Scientific, and Regulatory Challenges

An Introduction to the 2019 Arrow Lecture Series on Ethics and Leadership

The 2019 Arrow Lecture Series on Ethics and Leadership, co-sponsored by Stanford’s Center for Biomedical Ethics, Center for Ethics in Society, and Center for Law and Biosciences, will feature renowned scientist Jennifer Doudna, who will discuss the promise and peril of genetic editing. The Arrow Lectures, established in 2005, have hosted prestigious lecturers such as Esther Duflo, Paul Collier, Robert Reich, Thomas Piketty, and Nobel laureate Amartya Sen. Named after Stanford’s Emeritus Professor Kenneth Arrow, a Nobel Prize winner in Economics, these lectures emphasize the importance of ethical considerations in scientific advancements.

Jennifer Doudna and the Promise and Peril of Genetic Editing

Dr. Doudna’s lecture will focus on CRISPR-Cas9 technology, a revolutionary tool for editing the human genome that she discovered. CRISPR allows humans to control evolution and may lead to the rewriting and reformulation of what it means to be human. The recent news of the birth of the first CRISPR-edited human baby by Dr. He in China underscores the urgency of addressing the ethical, scientific, and regulatory challenges associated with this technology.

The Promise and Perils of CRISPR-Cas9

Jennifer Doudna’s journey with CRISPR technology began from a scientific curiosity, leading to the discovery of CRISPR as a powerful tool for genome editing. This technology, initially part of a bacterial immune system, now allows precise genetic modifications in various organisms, including humans. The implications of this are profound, as Yuval Harari notes, combining information technology and biotechnology to shape humanity’s future. CRISPR’s applications range from treating neurodegenerative diseases and cancer to enhancing agricultural productivity and developing rapid diagnostics for pathogens.

CRISPR-Based Genome Editing: A Revolutionary Discovery and Its Applications

Jennifer Doudna 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. CRISPR systems detect viral infections, store viral DNA fragments in the CRISPR array, and use Cas proteins to cut up matching DNA sequences. 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 functions by recognizing and cutting viral DNA. It involves Cas9, a protein that uses a guide RNA molecule to identify a specific DNA sequence and make precise cuts at that location. This mechanism is fundamental to the technology’s editing capability.

Applications of CRISPR-Cas9:

CRISPR-Cas9 has diverse applications. It can edit genes in cells, which is significant for fundamental research, healthcare, therapeutics, agriculture, and diagnostics.

Ethical Considerations:

The simplicity and power of CRISPR-Cas9 technology raise substantial ethical questions. Concerns include potential unintended consequences, the creation of “designer babies,” and risks associated with bioterrorism.

Ethical and Societal Impacts

The ethical implications of CRISPR are profound, especially highlighted by the birth of the first CRISPR-edited babies in China. The potential for creating ‘designer babies’ and the ramifications of germline editing pose significant ethical questions. Jennifer Doudna has expressed concerns about the ethical use of CRISPR, particularly in human genome editing. The technology’s simplicity and accessibility further exacerbate these concerns, as it lowers the barrier to entry for potential misuse.

Animal Genome Editing, Agriculture Applications, and Diagnostic Uses of CRISPR

CRISPR has been 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. In agriculture, CRISPR-Cas9 has shown promising applications in crop improvement, allowing precise control over traits like fruit production. Furthermore, CRISPR enzymes can be used for detecting DNA and RNA molecules, enabling the development of simple, cost-effective diagnostic tests.

Collaborative and International Research Efforts

The development of CRISPR technology exemplifies the power of international and collaborative research. Doudna’s partnership with Emmanuelle Charpentier and their work with diverse CRISPR-Cas systems highlight the collaborative nature of modern scientific research. This international effort underscores the need for global dialogue and consensus on the ethical and regulatory aspects of CRISPR technology.

Regulatory and Legal Challenges

Regulating CRISPR usage is complex due to the global nature of scientific research. Establishing legal frameworks to balance scientific progress with ethical considerations is a key challenge. The incident involving He Jiankui in Hong Kong, where he claimed to follow guidelines for gene-editing human embryos, illustrates the inadequacies of existing regulations and the need for clearer criteria and international consensus.

CRISPR: Ethical and Practical Concerns

The commercialization of CRISPR raises questions about ownership, profit distribution, and regulations. 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, including humans, has become increasingly feasible, prompting discussions about its potential applications and ethical implications. In 2018, a Chinese scientist announced germline editing in human embryos and subsequent implantation, leading to the birth of babies. The international community recognizes the need for serious discussions and regulations to ensure responsible use of CRISPR technology.

Scientists’ Focus on Their Own Work:

Scientists often focus intensely on their experiments, publications, theses, and securing jobs and tenure. This focus may limit their awareness of the broader implications and potential impacts of their work.

Lack of Training in Ethics:

Graduate and training programs for scientists often neglect to address the ethical considerations and societal impacts of scientific research. Scientists may lack the knowledge and skills to critically assess the ethical dimensions of their work.

Need for Better Education and Collaboration:

Improving 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, is essential. Collaboration between scientists and bioethicists can foster a deeper understanding of the ethical implications of scientific research and help develop ethical guidelines.

Ethical and Social Dimensions of CRISPR: Jennifer Doudna’s Reflections and Challenges:

Speaker 08 highlights the importance of recognizing the human aspects of scientific research and questions why moral considerations should be separated from one’s professional life. Bioethics is well-established in medical education, but there is no equivalent emphasis on ethical considerations in computer science and engineering schools. The ethicist’s role is often perceived as slowing down progress and innovation, leading to the “let scientists be scientists” response. Jennifer Doudna acknowledges her responsibility to address the ethical and social implications of CRISPR technology beyond her role as

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

The Role of Scientists and Education

Doudna and other scientists argue for the need to engage more actively in discussions about the societal implications of their research. There’s a consensus that scientists should not shy away from voicing their opinions on ethical matters, even if they are not experts in bioethics or law. Additionally, integrating bioethics into science education is seen as crucial for fostering responsible innovation.

Future Directions and Considerations

As we venture into the era of “human 2.0,” where gene editing might lead to enhanced human capabilities, the ethical and societal impacts need careful consideration. Balancing individual autonomy with societal values, and ensuring equitable access to these technologies, are paramount. The international community must collaborate to establish criteria for responsible use, particularly in sensitive areas like human germline editing. The precedent set by the Asilomar Conference on molecular cloning offers a blueprint for current conversations on genome editing, emphasizing the need for self-regulation and ongoing dialogue among scientists, policymakers, and the public.

Jennifer Doudna’s Encounter with Ho Chi Minh and the Unveiling of CRISPR’s Ethical Quandaries

In the lead-up to the 2019 Arrow Lecture Series, Jennifer Doudna met with Ho Chi Minh, the scientist behind the CRISPR announcement, in Hong Kong. Doudna had encountered Ho at previous professional gatherings but had no indication of his plans to apply CRISPR to clinical settings. During their meeting, Ho appeared naive about the potential public backlash to his work and seemed to expect acclaim rather than the negative reactions that ensued. Doudna expressed her concern that if Ho had shared his plans with her, she would have advised against such a move due to its profound ethical implications.

CRISPR Technology – Accessibility and Ethical Considerations

CRISPR technology has a relatively low barrier to entry, making it accessible to individuals with advanced high school-level knowledge. Setting up a CRISPR editing lab requires significantly less financial investment compared to other scientific fields. This ease of access raises concerns about potential misuse by individuals with malicious intent, particularly in the context of germline editing, which has far-reaching and irreversible consequences. Balancing the potential benefits of CRISPR with the need to mitigate risks and unintended consequences is a crucial task for policymakers and the scientific community.

Exploring the Accessibility and Ethical Considerations of CRISPR Technology

The democratization of CRISPR technology has made it widely available and accessible, with organizations like Addgene distributing the Cas9 protein and necessary constructs for genome editing at a low cost. DIY science initiatives offer CRISPR kits for educational purposes, although their effectiveness may vary. The low barrier to entry and the absence of legal frameworks increase the risk of CRISPR being used for unethical or harmful purposes. Balancing scientific progress with responsible use is crucial, and international cooperation is necessary to address these ethical implications. Ethical considerations should be an integral part of scientific research and education, with scientists receiving training and support to understand the ethical implications of their work. Scientists should actively promote responsible use of CRISPR technology, advocate for regulations and guidelines, and engage the public in discussions about CRISPR’s potential impacts.

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.

Deciding Which Medical Conditions Should Be Treated with Somatic Germline or Germline 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.

Ethical Considerations and Societal Implications of Human Germline Editing

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.


Notes by: oganesson