Jennifer Doudna (UC Berkeley Professor) – CRISPR Biology and Technology (Jun 2019)


Chapters

00:00:04 CRISPR Biology and Technology: The Future of Genome Editing
00:02:57 The Science and Future of Genome Editing
00:12:45 Genome Editing: A Revolutionary Tool for Manipulating DNA
00:16:10 CRISPR Technology and Its Applications in Public Health, Agriculture, and Biomedicine
00:23:09 Genome Editing: Public Health, Agriculture, and Germline Editing
00:34:53 Designer Babies: Genetic Editing and Its Ethical Implications
00:39:02 Ethical Considerations for Human Germline Editing
00:44:35 CRISPR Research and Its Importance
00:47:14 CRISPR: Beyond Human Applications
00:51:40 CRISPR Ethics: Somatic vs. Germline, Medical vs. Enhancement
00:58:11 Germline Gene Editing: PGD vs. Gene Editing
01:02:02 Ethical Debates Surrounding CRISPR and Human Genetic Enhancement
01:09:15 Ethical and Practical Challenges of Widely Accessible Genome Editing
01:11:16 Ethical and Societal Considerations in Scientific Innovation
01:21:14 Ethical and Practical Considerations in Human Genome Editing
01:26:41 Navigating Uncertainty: Ethical Considerations in Genome Editing
01:32:12 Ethical and Policy Challenges in Human Embryo Editing
01:42:41 Cultural Relativism and Universal Ethics in CRISPR Gene Editing

Abstract

CRISPR-Cas9: Revolutionizing Genetic Engineering and Facing Ethical Dilemmas

Abstract

CRISPR-Cas9 technology, a groundbreaking invention by Jennifer Doudna, has revolutionized genetic engineering, offering precise and targeted DNA editing. Its potential in medical advancements and agricultural improvements is immense, but its rapid development and wide-ranging implications have sparked intense ethical debates, particularly around human germline editing and unintended consequences.

Introduction to CRISPR-Cas9

Derived from a bacterial defense system, CRISPR-Cas9 uses RNA-guided proteins to make specific changes in DNA. This technology enables scientists to efficiently edit genomes, presenting opportunities to correct disease-causing mutations, develop pest-resistant crops, and explore new medical treatments. Its ease of use and accuracy surpassed previous gene-editing methods.

Introduction to Professor Jennifer Doudna:

Professor Jennifer Doudna, a renowned chemist, molecular and cell biologist, is known for her 2012 article in Science, co-authored with Emmanuel Charpentier, which presented a simple method for editing DNA using an RNA-guided protein found in bacteria. This procedure was recognized as a groundbreaking advancement in genome editing.

Origins in Bacterial Research:

CRISPR, an adaptive immune system in bacteria, involves acquiring viral DNA fragments and integrating them into the bacterial genome as a genetic vaccination card. CRISPR-associated proteins use RNA address labels to guide DNA destruction, protecting the cell from viral infections.

Diversity of CRISPR Systems:

CRISPR systems vary in complexity. Jennifer Doudna’s lab studied simpler CRISPR systems, focusing on the function of Cas9, a single enzyme providing RNA-guided protection.

Cas9: A Precise DNA Cleaver:

Cas9, guided by RNA, finds and destroys viruses. It uses a 20-letter RNA sequence to recognize a matching sequence in DNA, unwinding the DNA double helix and generating a break.

Single Guide RNA: A Technological Breakthrough:

Martin Yinek, a postdoc in Doudna’s lab, linked two RNA molecules in nature to form a single guide RNA. This allowed for the design of single guide RNAs with different address labels, enabling Cas9 to find and cut any desired DNA molecule. This discovery opened up the possibility of genome editing in eukaryotic cells.

Genome Editing Applications:

Double-stranded DNA breaks in eukaryotic cells can be repaired, resulting in either small disruptions or larger changes to the DNA sequence. This enables targeted gene correction, insertion, or deletion, with potential applications in medicine, agriculture, and basic research.

Ethical Challenges and Human Germline Editing

The potential of CRISPR-Cas9 extends to human germline editing, where changes can be passed on to descendants. This prospect has raised significant ethical concerns, especially following the controversial experiment by He Jiankui, who edited human embryos to confer HIV resistance. The incident underscored the need for careful ethical consideration and stringent regulations to prevent misuse and ensure responsible application of the technology.

Ethical and Social Implications

Ethical and Social Implications:

CRISPR in humans raises ethical concerns categorized along two axes: somatic vs. germline and medical vs. enhancement. Somatic changes affect only the body cells and are not passed on to descendants, while germline changes affect both body cells and germ cells (eggs and sperm) and can be passed on to offspring. Medical uses aim to cure or prevent diseases, while enhancement uses aim to improve traits beyond the normal range. Ethical issues in somatic medical use include safety, efficacy, accessibility, and prioritizing diseases to target. Ethical issues in germline use include potential unintended consequences, moral and religious objections, and concerns about eugenics.

The human germline genome is not static but constantly changes through random mutations and human-directed changes. Germline genome changes can be either beneficial or harmful. Germline treatment may be necessary for couples who both carry genetic diseases and want to have a healthy child. Preimplantation genetic diagnosis (PGD) is a safe and effective method to select healthy embryos for implantation, avoiding diseases like cystic fibrosis.

Germline fears are often overblown. Discriminating against couples who want to use germline treatment because of these fears is unfair. Enhancement issues are real concerns that need to be addressed.

Public Health and Environmental Impacts

Regulatory and Societal Considerations:

Beyond medical applications, CRISPR-Cas9 has implications for public health and the environment. Gene drives, for instance, could help control mosquito-borne diseases but pose ecological risks. In agriculture, genome-edited crops face regulatory debates similar to GMOs, while in animal health, it could improve organ donor compatibility.

Tissue Delivery:

Simply injecting a protein into the thigh is insufficient for genome editing to work effectively. The challenge of tissue delivery arises due to the complexity of the process.

Wide Availability and Accessibility:

CRISPR genome editing is easily accessible and relatively easy to use, raising concerns about controlling access to prevent potential misuse.

Ethical Challenges:

The widespread availability of CRISPR technology poses ethical challenges. There is a need to address potential misuse, such as unsafe or ineffective applications or unethical and dangerous uses.

Comparison to Other Technologies:

The challenge of controlling access and use is not unique to CRISPR genome editing. It applies to various technologies that are widely available, such as software engineering and hacking.

Rapid Technological Advancement:

Technologies are advancing rapidly, enabling various applications, but regulating their use remains a challenge.

Future Directions and Responsible Use

Shifting Vocabularies:

There is a shift in vocabularies between silicon-based and carbon-based life forms. Terms like “hacking” and “viruses” are used in both contexts.

Josiah Zaner as an Example:

Josiah Zaner, a Bay Area resident, injected himself with CRISPR technology and is not considered crazy despite his unconventional actions.

As CRISPR-Cas9 continues to evolve, the focus is on ensuring its responsible use, managing ethical dilemmas, and addressing technical challenges like delivery methods and predicting outcomes. Education and public engagement are crucial in navigating these issues, as is the role of scientists in guiding regulation and application. The technology, while transformative, must be approached with caution, considering its far-reaching impacts on humanity and the environment.

Supplemental Information:

Common vs. Rare Alleles:

In genetic engineering, changing a common disease-causing allele to a common non-disease allele is relatively safe. However, changing a common allele to a rare allele or a completely new allele raises more uncertainty and safety concerns.

CRISPR in Agriculture:

Genetically modified salmon with a single change to enhance growth and size may help solve declining fish stocks. Labeling such products as GMO may lead to unjustified rejection despite their potential benefits.

GMO Labeling:

Labeling GM products may provide consumers with desired information, but it also risks misleading or deterring them from safe and beneficial products. The California’s Proposition 65 warning for carcinogens is often ignored due to its widespread use, suggesting a potential outcome for GM labeling.

International Registry vs. Local Authorities:

There is a debate on whether to create an international registry for CRISPR experiments or to trust local authorities to make ethical decisions. No definitive model has emerged yet, and the ideal approach is still under discussion.

Pre-existing Treatments vs. Genetic Solutions:

Balancing genetic interventions with existing non-genetic treatments for diseases depends on risk-benefit analysis. Genetic solutions should be weighed against well-established treatments and the severity of the condition.

HIV and Social Stigma:

In certain regions, HIV infection carries a strong social stigma. He Jiankui’s intentions to address this stigma through gene editing raised ethical questions about his motivations.

Access to Assisted Reproduction:

China’s restrictions on assisted reproduction for HIV-positive individuals may have influenced He Jiankui’s decision to use gene editing as an alternative. The press release from the investigation suggests potential coercion and deception in recruiting participants.

Prior Knowledge and Reporting Responsibilities:

Scientists faced with knowledge of unethical research may lack clear guidelines on whom to report to or how to proceed. Mechanisms for reporting and addressing questionable research practices need to be created.

Ethical Considerations and Risk-Benefit Analysis:

Ethical aspirations should include the responsibility to report unethical practices, while also providing practical mechanisms to do so. Risk-benefit analysis should be the guiding principle in balancing genetic and non-genetic treatments.

Hot, Sexy Things vs. Effective Solutions:

The allure of exciting and novel approaches can overshadow more effective but less captivating solutions. The media, the public, and the stock market often prioritize sensationalism over practical and evidence-based solutions.

Ethical Challenges and Cultural Relativism in Genetic Engineering:

The legality of homosexuality in China raises questions about the ethical implications of genetic engineering in different cultural contexts. Societies have varying moral codes, leading to diverse perspectives on the acceptability of genetic interventions. Limited knowledge about genetic determinants of traits like sexual preference and neurodiversity poses challenges in regulating genetic modifications. The debate between universal human rights and cultural relativism presents a fundamental ethical dilemma. Determining the validity of universal human rights and their origins remains a complex and unresolved issue. The intersection of genetic engineering and cultural relativism presents profound ethical challenges that require careful consideration and further exploration.

In conclusion, CRISPR-Cas9 represents a significant advancement in genetic engineering, offering unprecedented opportunities for medical and agricultural improvements. However, its rapid development necessitates a careful and ethical approach to harness its benefits while mitigating risks and addressing societal concerns. As the technology continues to evolve, a collaborative and informed approach involving scientists, ethicists, policymakers, and the public will be essential in realizing its full potential responsibly.


Notes by: oganesson