Welcome and Introductions:
President Matthew Scott of the Carnegie Institution for Science welcomed the audience to a packed hall and thanked them for coming. He highlighted the ongoing free public lectures and events at the institution and encouraged attendees to sign up for updates. Scott expressed delight in the new partnership with the Council of Scientific Society Presidents (CSSP) and emphasized the significance of working with such distinguished scientists. He mentioned the connection to the Kavli Institute and the annual celebration of Kavli awardees.

Carnegie Institution Video:
A short video showcased the Carnegie Institution’s scientists, their research, and the institution’s history of remarkable discoveries. The video highlighted the unique freedom and support that Carnegie scientists receive, allowing them to pursue bold and groundbreaking research. It showcased the institution’s contributions to astronomy, geophysics, geochemistry, ecology, and life sciences.

Council of Scientific Society Presidents (CSSP):
Dave Penrose, current chair of the CSSP, addressed the audience. He recalled the enthusiastic public interest in science during the 1970s and expressed encouragement at seeing a large audience for the presentation. Penrose provided an overview of the CSSP, emphasizing its role as a center for national science leadership development, a strong advocate for science, and a forum for policy development. He highlighted the CSSP’s commitment to advancing leadership in science and technology and ensuring a bright future for science in the 21st century.

Introduction of Dr. John Holdren:
Penrose introduced Dr. John Holdren as the next speaker, praising his lifelong dedication to securing a bright future for science.

Dave Penrose’s Introduction of John P. Holdren:
Dave Penrose introduces John P. Holdren, recipient of the CSSP Supportive Science Award, the highest honor bestowed by the Council of Scientific Society Presidents (CSSP). Holdren is recognized for his outstanding support of U.S. science, free science communication, and the support of basic research. Holdren’s accomplishments during his seven years as science advisor to President Obama have advanced the U.S. and global scientific enterprise.

John P. Holdren’s Background and Achievements:
Holdren’s distinguished career prior to becoming President Obama’s Science Advisor includes: Professor of Environmental Policy at Harvard Kennedy School. Director of the science, technology, and public policy program at Harvard’s Belfer Center for Science and International Affairs. Professor of environmental science and policy at Harvard’s Department of Earth and Planetary Sciences. Director of the Woods Hole Research Center. Co-leader of the Interdisciplinary Graduate Program in Energy and Resources at UC Berkeley. Chair of the Executive Committee of the Pugwash Conference in Science and World Affairs. Nobel Peace Prize Acceptance Lecture on behalf of the Pugwash Conferences. Chair of the Committee on International Security and Arms Control of the National Academy of Sciences. Co-chair of the bipartisan National Commission on Energy Policy.

Awards and Honors:
Holdren has received numerous awards and honors, including: MacArthur Prize Fellowship. Volvo Environment Prize. Kavli Foundation Award in Science and Environmental Policy. Tyler Prize for Environmental Achievement. Heinz Award in Public Policy.

Membership in Prestigious Academies:
Holdren is a member of several prestigious academies, including: National Academy of Sciences. National Academy of Engineering. American Philosophical Society. American Academy of Arts and Sciences. Royal Society of London. Indian National Academy of Engineering.

Holdren’s Farewell Remarks:
Holdren acknowledges that this is likely his last opportunity to address the Council of Science Society presidents. He briefly discusses the Obama administration’s efforts in science and technology policy and identifies areas where further work is needed. Holdren emphasizes the importance of restoring science to its rightful place in the administration and highlights various initiatives undertaken to promote scientific integrity, STEM education, open data, and international cooperation in science and technology.

President Obama’s Contributions to Science and Technology:
Promoted science, technology, and innovation by appointing experts and organizing events. Launched initiatives in STEM education, healthcare, energy, and international collaboration. Invested over $100 billion in the Recovery Act and protected science budgets during tough times. Recruited top talent to government positions, including five Nobel laureates.

Obstacles to Progress:
Inadequate funding for research and development. Insufficient translation of research advances into practical applications. Underrepresentation of women and minorities in STEM fields. Lack of science, technology, and innovation talent in government agencies. Poor public and policymaker understanding of science and its role in society.

Opportunities for Future:
Harnessing partnerships across government, sectors, and internationally. Continuing to integrate science and technology talent into government. Applying research on effective STEM inspiration and training to increase participation. Exploiting advances in biomedical sciences and big data to improve healthcare. Building on the momentum of climate change initiatives and renewable energy growth.

President Obama’s Science Savviness:
Considered the most science-savvy president since Thomas Jefferson. Awarded the Kavli Prize for his contributions to science and technology. Demonstrated a deep understanding of science’s role in solving societal challenges.

Dr. Jennifer Doudna’s Background and Contributions:
Fred Kavli Science at the Frontiers lecturer, presented by the Council of Scientific Society Presidents. Li Ka Shing Chancellor’s Chair in Biomedical and Health Sciences at UC Berkeley. Professor of Chemistry and Molecular and Cell Biology at UC Berkeley. Investigator with the Howard Hughes Medical Institute since 1997. Received numerous prestigious awards and honors for her research. Pioneered CRISPR-Cas9 genome engineering technology, revolutionizing genetics and medicine. Named one of Time Magazine’s 100 Most Influential People in the World.

DNA as the Code of Life:
DNA is the fundamental molecule that encodes the information for cellular growth, division, and development into tissues and organisms. The structure of DNA consists of two strands of chemical letters twisted around each other, forming a double helix. The chemical letters in DNA pair with each other in a specific manner, allowing for the copying of one strand into the other.

Curiosity-Driven Research in Bacterial Adaptive Immunity:
Jennifer Doudna’s research interests lie in understanding the fundamentals of biology, particularly in the context of bacterial adaptive immunity. The goal is to uncover pathways that can be harnessed for exciting technologies, such as CRISPR, for modifying DNA within cells.

Uncovering Bacterial Adaptive Immunity and CRISPR Technology:
Doudna’s research journey led to the discovery of a pathway in bacteria that fights viral infection. This pathway, known as CRISPR-Cas9, can be utilized as a technology for genome engineering, allowing for precise changes to DNA inside cells. CRISPR-Cas9 enables the targeting of specific DNA sequences and the introduction of desired genetic alterations.

CRISPR Technology as a Powerful Tool for Genetic Manipulation:
CRISPR-Cas9 has emerged as a powerful tool for genetic manipulation, revolutionizing the field of genome engineering. It allows researchers to study gene function, develop new therapies for genetic diseases, and potentially modify crops and other organisms. CRISPR technology has sparked ethical and societal discussions due to its potential impact on human health, agriculture, and the environment.

Origins of DNA Editing Technology:
* Jennifer Doudna discusses the possibility of altering DNA within cells, akin to editing text in a word processor.
* Decades of biological research, including Barbara McClintock’s work, have contributed to understanding DNA’s dynamic nature.
* A novel technology allows precise control over DNA at the level of a single letter within a human cell’s 3 billion base pair DNA sequence.

The Inspiration from Bacterial Defense Mechanisms:
* The development of this technology emerged from an unexpected source: understanding how bacteria fight off viral infections.
* Bacteria, like other organisms, encounter viruses in their environment.
* When a virus infects a bacterial cell by injecting its DNA, the virus’s program takes over the cell’s machinery, leading to virus production and cell destruction.

CRISPR: A Novel Pathway for Bacterial Defense against Viruses:
Bacteria have evolved defense mechanisms to combat viral infections, and one such pathway is called CRISPR.

Identification of CRISPR by Jillian Banfield:
Jillian Banfield’s research focused on studying bacteria in unique environments, such as extreme pH, temperature, and pressure conditions. Banfield collected samples from these environments, sequenced the DNA, and reassembled the circular chromosomes to analyze the DNA code and interacting viruses.

Unique DNA Sequence Pattern in Bacterial Chromosomes:
Banfield and other researchers observed an interesting pattern of DNA sequences within bacterial chromosomes. Repeated sequences (black diamonds) were interspersed with unique sequences in between. These sequences were termed CRISPRs (clusters of regularly interspaced short palindromic repeats).

Background:
Jennifer Doudna’s research focuses on the function of RNA molecules inside cells. Jill Banfield discovers CRISPR sequences in bacterial DNA samples and suggests their involvement in an immune system.

CRISPR as a Genetic Vaccination Card:
CRISPR sequences are unique DNA patterns representing genetic vaccination cards for cells. These sequences are derived from viruses and serve as a record of past viral infections. The CRISPR system allows cells to pass this information to their progeny for future protection.

CRISPR and Cas Genes:
Cas or CRISPR-associated genes are typically found near CRISPR repetitive loci. These genes encode proteins that are involved in the CRISPR pathway.

Central Dogma of Molecular Biology:
DNA stores genetic information and is copied into RNA molecules. RNA molecules can be translated into proteins or function independently.

CRISPR as an Adaptive Immune System:
CRISPR-containing bacteria can adapt to viruses that infect them. The system involves three steps: detection, incorporation, and interference. Bacteria acquire immunity to viruses by storing their DNA in the chromosome.

Chance Meeting and Collaboration:
Doudna meets Emmanuelle Charpentier, a medical microbiologist studying a CRISPR system with a single Cas9 gene. Their collaboration aims to determine the function of Cas9.

Cas9 Function:
Cas9 protein, along with RNA molecules, forms guided complexes that search for matching DNA sequences. Upon finding a match, the complex cuts the viral DNA, providing immunity against the virus.

The Role of Cas9 Protein in DNA Recognition and Cleavage:
Cas9 protein binds to DNA at specific sequences matching a 20-nucleotide sequence in an RNA molecule. The Cas9 protein unwinds the DNA double helix, allowing two molecular blades in the protein to make a cut in each strand of the DNA. This DNA cleavage triggers the destruction of DNA in bacteria.

The Importance of Two RNA Molecules:
In addition to the guide RNA sequence, a second RNA molecule called tracer is required for forming a structure essential for the targeting complex to assemble. This structure binds to the Cas9 protein and enables the complex’s assembly.

Martin Jinek’s Discovery:
Martin Jinek’s experiments led to the realization that the CRISPR-Cas9 system could be simplified compared to its natural form. The idea was to link the DNA recognition information and the DNA cleavage machinery into a single RNA molecule.

Harnessing the Power of CRISPR-Cas9:
CRISPR-Cas9 technology allows for precise and easy programming of the Cas9 protein to target and cut any desired DNA sequence by modifying the sequence of the guide RNA.

3D Model of Cas9 Protein:
A 3D printed model of the Cas9 protein demonstrates its structure, including the white protein and the orange guiding RNA molecule.

DNA Recognition and Cleavage:
The Cas9-guide RNA complex searches for a DNA sequence matching the sequence on the guide RNA and grabs onto the DNA. An RNA-DNA helix forms inside the protein, displacing the other strand of DNA and positioning molecular blades to make a precise double-stranded break in the DNA.

Connection to Genome Engineering:
Cells have evolved sophisticated machinery to repair double-stranded DNA breaks, including mechanisms for rejoining the ends or integrating new DNA segments at the break site.

Significance for DNA Sequence Alteration:
Scientists recognized that introducing double-stranded breaks at specific locations in DNA could enable DNA sequence alteration. Various strategies were being developed to achieve this, including the use of CRISPR-Cas9.

Single Protein Reprogramming:
Unlike earlier technologies requiring complex protein engineering, Cas9 can be reprogrammed for different DNA sequence recognition and cleavage by simply changing the short sequence of guide RNA. This simplifies the process and makes it accessible to researchers without specialized expertise in protein engineering.

Software versus Hardware:
Earlier genome editing technologies were hardwired, requiring new protein engineering for each experiment. Cas9 is more analogous to software, a single protein reprogrammable by short sequences of RNA. This flexibility enables various applications and rapid adoption across different systems.

Rapid and Accurate DNA Targeting:
Cas9’s rapid and accurate DNA targeting mechanism makes it suitable for harnessing as a technology. The enzyme searches through the cell’s DNA to find a single sequence matching the guide RNA, binds to it, unwinds it, and cuts the DNA. Repair machinery in the cell then fixes the break, allowing researchers to make precise changes to the DNA.

Widespread Applicability:
Cas9 operates in effectively any kind of cell where it has been employed, making it a democratizing technique. This widespread applicability enables researchers to make precise DNA changes in various cell types for research and other applications. The ease of use and low cost further contribute to its broad adoption.

CRISPR’s Wide-Ranging Use:
CRISPR technology has been applied in diverse systems, including plants, animals, and microorganisms, for various purposes. Examples include engineering crops with improved traits, developing animal models for disease study, and engineering organisms for sustainable biofuel production.

USDA’s Decision on CRISPR-Edited Mushrooms:
A recent article in Nature highlighted a CRISPR-edited mushroom developed by a company in the Midwest. The USDA deemed this mushroom non-GMO as it lacks foreign DNA, opening the way for non-regulated agricultural applications. This decision led to excitement in the agricultural sector, with companies planning to release CRISPR-edited plants soon.

CRISPR in Biomedicine:
CRISPR holds promise for treating diseases by engineering stem cells, modeling human diseases in animals, and potentially treating patients. Recent publications in Science Magazine demonstrated the correction of a mutation causing muscular dystrophy in a mouse model using CRISPR. These studies indicate the potential for clinical applications, though further research is needed.

Germline Editing:
Germline editing involves making changes to DNA in developing organisms, affecting future generations. An example is Russell Vance’s work at UC Berkeley, where he used CRISPR to edit DNA in a fertilized mouse egg. Germline editing raises ethical and societal considerations due to its potential impact on future generations and the environment.

Ethical Considerations:
CRISPR-Cas9’s capability for germline editing raises ethical concerns due to its potential to modify inheritable traits and impact future generations.

Example of Germline Editing Experiment:
In an experiment, CRISPR-Cas9 was used to target a gene responsible for black coat color in mice, resulting in albino mice with genetic changes that could be passed on to offspring.

Global Discussions on Responsible Use:
Jennifer Doudna and colleagues organized discussions involving scientists from around the world to address the ethical implications of germline editing.

Prudent Path for Employment of Genome Editing Technology:
A proposal emerged to voluntarily refrain from using CRISPR-Cas9 or similar technologies in human embryos for clinical purposes until ethical considerations are thoroughly examined.

National Academies Summit:
The National Academies of several countries convened a summit to deliberate on the issue of germline editing and its ethical implications.

International Approval for Research Purposes:
As of the time of the presentation, four countries (Sweden, the UK, China, and South Korea) have approved the use of CRISPR-Cas9 for human embryo editing specifically for research purposes.

Doudna’s Closing Remarks:
Jennifer Doudna acknowledges her team’s contributions and emphasizes the importance of collaboration and funding in scientific research.

Questions from the Audience:
The audience is eager to ask questions, with one person referring to Doudna as a “rock star” for her groundbreaking work.

Timeline for Clinical Applications:
Doudna clarifies that her discussion focuses on clinical applications in adults and children, excluding germline editing. She suggests that sickle cell trait, a blood disease, might be an early target for therapeutic applications. Editing can be done outside the body, with blood cells removed, edited, and reintroduced to the patient.

Progress in Clinical Trials:
Academic labs and companies are actively working towards clinical trials. Colleagues mention a possible timeline of 12 to 18 months for filing an investigational new drug (IND) request with the FDA. This approval would allow human clinical trials to commence.

Significance of Monkey Studies:
Doudna highlights the relevance of monkey studies in providing insights into the potential of CRISPR technology.

Ethical Considerations for Human Genome Editing:
Doudna emphasizes the need for caution and ethical considerations when applying gene editing to the human genome, particularly in the context of human germline editing. She highlights the importance of a global pause on human germline editing to allow for further scientific research and consensus building.

Accessibility and Potential Misuse of Gene Editing Technology:
Doudna expresses concern about the ease of obtaining gene editing reagents and kits, making the technology accessible to individuals with varying levels of expertise and potentially leading to inappropriate or dangerous applications.

Balancing Scientific Advancements and Ethical Responsibility:
Doudna recognizes the potential benefits of gene editing in revolutionizing medicine and agriculture, such as personalized medicine, disease prevention, and crop protection. However, she emphasizes the importance of navigating ethical and societal issues to ensure responsible and safe use of the technology.

Precedents for Navigating Ethical Challenges in Science:
Doudna draws parallels between the current discussions on gene editing and the Asilomar meeting in 1975, which addressed ethical concerns related to molecular cloning. She stresses the need to actively grapple with these issues and seek guidance from historical precedents.

Rapid Pace of Scientific Advancement and Public Understanding:
Doudna reflects on the disconnect between the rapid pace of scientific advancements and the public’s understanding of these technologies. She emphasizes the importance of engaging the public in discussions about gene editing and its potential implications to ensure informed decision-making.

Examples of Potential Applications:
Doudna highlights potential applications of gene editing in agriculture, such as protecting crops from pathogens and environmental changes. She also discusses the concept of gene drives, which could be used to control populations of disease-carrying organisms but raise concerns about unintended consequences.

Balancing Benefits and Risks:
Doudna acknowledges the potential benefits of gene editing but emphasizes the need for careful consideration of the risks and ethical implications before implementing these technologies. She calls for a thoughtful approach that balances the potential for advancements with the responsibility to ensure safety and appropriateness.

Gene Editing’s Potential and Risks:
Jennifer Doudna emphasizes the great potential and great risks associated with gene editing. She highlights the need for grownup conversations about this profound and difficult topic in a time when such conversations are lacking.

Scientists’ Role in Public Discourse:
Doudna stresses the importance of scientists taking a serious position on gene editing and engaging in public discourse. She acknowledges her own reluctance to do so, given scientists’ natural inclination to focus on lab experiments.

Public Perception of Science:
Doudna laments the disconnect between scientists and non-scientists, citing examples such as the recent incident where a scientist was mistaken for a terrorist on a plane. She points to public reactions to climate change, vaccinations, and genetically modified food as instances of this disconnect.

Public Response to Gene Editing:
Doudna describes the amazed and interested reactions she has encountered at PTA meetings and public events. She acknowledges that people struggle to understand gene editing and are trying to grasp its implications.

Desperation for Therapeutic Applications:
Doudna reveals that she is frequently contacted by parents, patients, and individuals with genetic diseases who are desperate to know when gene editing can be used to help them. She emphasizes that therapeutic applications are still years away, but the prospect of future benefits is exciting for many.

Designer Humans and Enhancements:
Doudna discusses the possibility of designer humans and enhancements through gene editing. She acknowledges the potential for such changes but expresses caution, emphasizing the limited understanding of the long-term consequences.

Intellectual Property and Profit:
Academic researchers’ intellectual property is owned by their universities. Universities file patents to protect commercialization opportunities. Commercial entities are essential for developing therapeutics due to resource limitations in academic labs. The question of how publicly funded science profits should benefit the public remains.

Countermeasures and Regulation:
Groups are researching ways to regulate CRISPR, including shutting down or reversing its activities. The bleeding edge of research focuses on controlling the function of CRISPR proteins.

Global Standards for Ethical Use:
Martin Apple suggests prioritizing medical applications in humans before developing ethical standards. Enforcing ethical standards globally is challenging due to differing views and varying levels of transparency and accountability.

Understanding DNA Repair Mechanisms:
After CRISPR cuts DNA, loose ends can be connected through a designed bridge sequence. This bridge sequence can be introduced externally by the experimenter or naturally by the cell using matching DNA sequences.

Temporary Fixes and Gamete Stage Editing:
CRISPR-based treatment of sickle cell syndrome may involve removing blood, treating it, and returning it to the patient, offering temporary relief. Editing at the gamete stage is a potential future possibility.

Using CRISPR to Edit Blood Stem Cells:
Editing blood stem cells, rather than circulating blood cells, is more therapeutically valuable due to their proliferative properties and ability to repopulate the blood system.

Editing Gametes:
Editing gametes, such as sperm, is possible and offers exciting opportunities for therapeutic changes. However, extensive research is required.

Epigenetic Effects on Edited Genes:
The effects of epigenetics, particularly methylation, on edited genes are not fully understood and require further research. Anecdotal evidence suggests that epigenetic modifications may turn off inserted genes.

Innovations and Businesses in Gene Editing:
New businesses will emerge, including technology companies building on the CRISPR platform and application-specific companies in agriculture, therapeutics, and other fields.

Regulation of Gene Editing:
Regulation of gene editing is challenging due to the lack of clear guidelines. Federal funding cannot be used for human embryo modification in the United States, but private funding or state money could be employed. Ongoing conversations are necessary to address the ethical and regulatory challenges.

Reflecting on the Discovery of CRISPR:
The discovery of CRISPR’s incredible machine for recognizing and destroying viral DNA was a pure joy of discovery. Connecting this basic understanding to its potential as a technology was a moment of realizing the unexpected possibilities of scientific research.

Sharing the Sense of Wonder:
Encouraging students and researchers to share the sense of wonder and excitement in scientific discovery.