Panel, Conference Presentation
Editing the Genome: Promise and Peril
Milken InstituteJonathan Thomas, David Agus, David Baltimore, Amander Clark, Hank Greely, John Thomas
- Context of the Era: The panel characterizes the current period as a "golden era" in biological research, driven by accelerated discovery rates compared to the 1980s and 1990s.
- President Jimmy Carter's recent melanoma remission, treated by a therapy blocking immune "don't eat me" signals, exemplifies this new capability to harness the immune system.
- Sequencing cancer genomes prior to treatment has become standard practice, allowing for real-time identification of cellular signaling pathways.
- Impact of Intellectual Property Changes: A pivotal shift occurred when the U.S. Supreme Court ruled that human genes cannot be patented, democratizing access to DNA testing.
- The cost of BRCA testing dropped from $5,000–$6,000 to under $200 following the ruling.
- Dr. David Agus notes that during the 15-year monopoly on gene patents, tens of thousands of people died because they could not afford the tests.
- Mechanism of CRISPR-Cas9: Gene editing involves locating a specific DNA sequence (e.g., one of 3 billion base pairs) and using a nuclease protein to cut the DNA strands.
- CRISPR utilizes a guide RNA molecule to recognize the target sequence via Watson-Crick complementarity and a Cas9 protein to execute the cut.
- Cell repair mechanisms triggered by the cut can either disable a gene or incorporate a specific correction if a guide is provided.
- The technology is primarily suited for monogenic diseases (single gene defects), whereas multi-gene traits like height or heart disease involve complex genetic interactions.
- Germline vs. Somatic Editing: Dr. Amanda Clark distinguishes between editing somatic cells (body cells, non-inheritable) and germline cells (sperm, eggs, early embryos, inheritable).
- Germline editing alters the DNA of a one-cell embryo outside the body, resulting in changes passed to all subsequent generations.
- Current non-clinical research in the UK involves editing embryos for study only, without implantation, to understand embryonic development and IVF optimization.
- Somatic cell editing is already used clinically for conditions like HIV and sickle cell disease, whereas germline editing remains non-therapeutic in the U.S.
- Ethical and Historical Precedents: The panel draws parallels between the 1975 Asilomar Conference on recombinant DNA and current debates on CRISPR.
- Asilomar established a scientist-led moratorium to ensure safety before widespread application, a model the panel hopes to replicate globally.
- Dr. Baltimore argues for an international consensus based on moral force rather than binding law, given the difficulty of global enforcement.
- Dr. Hank Greely notes that while "fixing" genetic diseases (like cystic fibrosis) has a strong ethical case, "enhancement" traits (e.g., height, intelligence) remains a contentious and likely long-term barrier.
- Technical Limitations and Risks: The panel acknowledges significant technical hurdles preventing immediate clinical application of germline editing.
- CRISPR has demonstrated "off-target effects" in human embryo studies (e.g., in China), causing unintended mutations in unanticipated genome locations.
- Data from non-viable embryos (three nuclei) used in Chinese studies may not accurately reflect outcomes in viable human embryos due to differences in repair machinery.
- Dr. Agus highlights the risk of a "flat world" scenario where a lack of global enforcement allows rogue actors or less regulated jurisdictions to bypass safety norms.
- Regulatory Landscape in the U.S.: U.S. progress is constrained by legislative barriers regarding federal funding and FDA oversight.
- Federal funds cannot be used for research that destroys human embryos, though private funding exists; the Dickey-Wicker Amendment effectively blocks much of this work.
- The FDA is legally prohibited from reviewing or approving any clinical trials involving edited human embryos.
- California's Prop 71 (2004) was enacted partly to circumvent federal bans on embryonic stem cell research, creating a state-level hub for regenerative medicine.
- Alternative Therapies and Applications: CRISPR is being applied to diverse fields beyond human germline editing.
- Mosquitoes are being gene-edited to carry a "drive" for maleness to suppress populations transmitting Zika, malaria, and dengue.
- Agriculture applications include engineering crops for pest resistance and extending shelf life to reduce the 30% of produce lost during transport.
- Research is underway to resurrect extinct species, such as the woolly mammoth, using gene editing on elephant embryos.
- Political and Future Outlook: The panel discusses the potential impact of the 2016 U.S. election and the timeline for adoption.
- Secretary Clinton is viewed as supportive of biomedical research, while the administration's specific stance on gene editing remains unclear.
- Dr. Greely predicts that disease-fighting applications will eventually become commonplace, while enhancement uses will remain controversial for decades.
- Dr. Baltimore advocates for using "precision" in medicine, noting that CRISPR represents the ultimate precision tool, though clinical application for complex diseases is decades away.
- Security and Non-Human Risks: Dr. Greely and Dr. Agus express concern that non-human applications (agricultural/biological) are easier to execute and harder to regulate than human trials.
- The low cost and accessibility of the technology allow for DIY experimentation (e.g., in a garage) with minimal oversight.
- Risks include the potential for malicious actors to engineer pathogens (e.g., converting benign E. coli or mouse pox into human threats).
- The panel calls for the immediate development of data standards and regulatory frameworks for non-human gene editing.