Welcome and Introductions:
Matthew Scott, President of the Carnegie Institution for Science, welcomed the audience to the event and expressed gratitude for their presence. He introduced the ongoing series of free public lectures and other events hosted by the institution and encouraged attendees to sign up for updates.

Partnership with the Council of Scientific Society Presidents:
Scott highlighted the new partnership between Carnegie Institution for Science and the Council of Scientific Society Presidents, emphasizing their delight in collaborating on projects. This event marked their first significant joint initiative.

Connection to the Kavli Institute:
The event was also connected to the Kavli Institute, which has had Kavli lecturers speak at Carnegie Institution numerous times over the years. Annual celebrations of Kavli awardees, often co-sponsored by the Norwegian Embassy, have become a tradition.

Theme of Homecoming, Partnership, and Friendship:
Scott emphasized the sense of homecoming, partnership, and friendship that characterized the event and welcomed the audience as part of this community.

Introduction to the Speaker:
The program would begin with a three-minute video about the Carnegie Institution, followed by the main presentation on fascinating science in a prominent area of biology.

Carnegie’s Scientific Focus and Approach:
Carnegie scientists are dedicated to exploring the universe, Earth, and life itself. The organization prioritizes research over teaching, administration, and grant pressures, allowing scientists to concentrate on their work. Scientists are chosen for their unique skills and boldness, leading to groundbreaking discoveries that underscore the power of freedom.

Carnegie’s Astronomical Discoveries:
Carnegie astronomers, astrophysicists, and planetary scientists seek answers about the universe. Notable discoveries include Edwin Hubble’s revelation of the universe’s expansion, as well as studies of star chemistry and exoplanet diversity. These investigations probe distant reaches of space and time, driven by curiosity and the pursuit of knowledge.

Carnegie’s Earth Science Contributions:
Geophysicists, geochemists, and ecologists use cutting-edge instrumentation to explore Earth’s history and dynamics. They venture into nature’s laboratories, including rainforests and ancient rock formations, to study Earth’s properties. Their work has implications for understanding Earth’s processes and guiding policies related to environmental issues.

Carnegie’s Biological Breakthroughs:
Carnegie scientists have made significant contributions to understanding life’s secrets and improving its quality. Barbara McClintock’s Nobel Prize-winning discoveries about chromosomes revolutionized biology and medicine. Researchers investigate the molecular basis of life, from computation and genomics to advanced microscopy and engineering. This work deepens our understanding of plant, animal, and microbial life, as well as ecosystem changes influenced by human activities.

Carnegie’s Role in Nurturing the Next Generation:
Carnegie scientists are mentors and trainers who guide the next generation of scientists. They encourage questioning, wonder, and creative pursuit of ideas across vast scales, from the universe to the subatomic world. These scientists redefine the boundaries of scientific possibilities for our planet and universe. Their work draws on the past to illuminate the present and inform the future.

Award Presentation:
Dr. Dave Penrose, Chair of the Council of Scientific Society Presidents (CSSP), introduced Dr. John Holdren, Assistant to the President for Science and Technology and Director of the White House Office of Science and Technology Policy, as the recipient of the CSSP Supportive Science Award. The award recognizes outstanding and dedicated support of U.S. science, free science communication, and the support of basic research.

Dr. Holdren’s Career and Accomplishments:
Dr. Holdren’s distinguished career includes serving as Teresa and John Hines Professor of Environmental Policy at Harvard University, Director of the Science, Technology, and Public Policy Program at Harvard’s Belfer Center, and Director of the Woods Hole Research Center. He co-led the Interdisciplinary Graduate Program in Energy and Resources at the University of California, Berkeley, and chaired the Executive Committee of the Pugwash Conference in Science and World Affairs. Dr. Holdren has received numerous awards, including the MacArthur Prize Fellowship, the Volvo Environmental Prize, the Kavli Foundation Award, the Tyler Prize for Environmental Achievement, and the Heinz Award in Public Policy. He is a member of several prestigious academies, including the National Academy of Sciences, the National Academy of Engineering, the American Philosophical Society, and the American Academy of Arts and Sciences.

Dr. Holdren’s Remarks:
Dr. Holdren expressed gratitude for the award and acknowledged the large audience attracted by the speaker before him, Dr. Jennifer Doudna. He characterized his remarks as a “valedictory,” reflecting on the Obama administration’s efforts in science and technology policy and highlighting areas where further work is needed. Dr. Holdren emphasized the President’s commitment to restoring science to its rightful place in the administration, focusing on scientific integrity, STEM education, open data, energy and climate change, and international cooperation in science and technology. He also highlighted the President’s support for science, technology, and innovation through the Recovery Act and his efforts to protect funding for these areas despite budgetary challenges.

White House Leadership in Science, Technology, and Innovation:
Recruited top talent, including Nobel laureates and members of national academies, to key positions. Used the presidential platform to promote science, technology, and innovation in speeches, meetings, and events.

Science Fair and Celebrations:
Established the White House Science Fair to celebrate young scientists and engineers. Hosted astronomy nights on the White House lawn and celebrated science and technology achievements in the Oval Office and East Wing.

Unprecedented Initiatives:
Launched a wide range of initiatives in STEM education, information technology, innovation, biomedicine, energy, environment, and international science. Set an extensive agenda for advancing science and technology, with many items yet to be completed.

Regret and Persistent Obstacles:
Expressed regret that President Obama could not serve a third term to continue his work in science and technology. Identified obstacles to progress, including inadequate funding, slow translation of research into practical applications, underrepresentation of women and minorities, and poor public understanding of science’s role in society.

Major Accomplishments:
Strengthened partnerships across levels of government, sectors of society, and internationally to overcome obstacles in science and technology. Increased the presence of science, technology, and innovation talent in the government through aggressive recruiting efforts. Applied research on effective STEM inspiration, teaching, mentoring, and training to increase participation in STEM careers and create a science-savvy citizenry. Exploited advances in biomedical sciences and big data to drastically improve healthcare. Built on the momentum of the Paris Conference and the rapid growth of renewable energy deployment worldwide to drive a revolution in clean energy.

Opportunities for the Future:
Harness the full potential of partnerships to overcome obstacles and achieve scientific and technological advancements. Continue to integrate science, technology, and innovation talent into the government to drive progress. Apply research on effective STEM education and inspiration to increase participation in STEM careers and create a scientifically literate society. Utilize recent advances in biomedical sciences and big data to improve healthcare significantly. Build on the momentum of international efforts to address climate change and promote clean energy to revolutionize the energy sector.

Introduction:
Jennifer Doudna’s Kavli lecture focuses on CRISPR biology and the groundbreaking era of genome engineering. Her research centers around understanding how RNA molecules regulate the expression of genetic information.

CRISPR-Cas9 Breakthrough:
Doudna’s investigations led to groundbreaking insights into CRISPR-Cas9-mediated bacterial immunity. In collaboration with Manuel Charpentier, they devised a system for precise genome engineering in animals and plants. This transformative technology revolutionized genetics, molecular biology, and medicine.

Science Breakthrough of 2015:
Science Magazine recognized the genome editing technology as the Science Breakthrough of 2015. Doudna and Charpentier were named among Time Magazine’s 100 most influential people.

Small Science with Profound Impact:
Doudna’s scientific journey began with fundamental questions about bacterial immunity. Her curiosity-driven research led to the discovery of a pathway that could be harnessed for DNA alteration.

DNA as the Code of Life:
DNA holds the genetic information essential for cell growth, division, and the development of tissues and organisms. The beautiful structure of DNA consists of two strands of chemical letters forming a double helix.

The Power of DNA Manipulation:
Scientists have long envisioned the potential of manipulating DNA to alter cells and organisms. Changes in DNA can impact cells, whole organisms, and even lead to genetic diseases in humans.

Discovery of CRISPR:
Interest in CRISPR emerged from studying bacterial defense mechanisms against viral infections. Bacteria have evolved pathways to fight off viruses, including a newly discovered pathway called CRISPR. CRISPRs are characterized by unique DNA sequences within repeated sequences in bacterial chromosomes.

The Vaccination Card of Cells:
CRISPRs contain sequences derived from viruses the bacteria have encountered, acting as a genetic vaccination card. This allows cells to keep a record of viral DNA and pass it on to future generations.

Potential Immune System:
CRISPRs are often found next to Cas genes, encoding proteins that neighbor the repetitive sites. This suggests the existence of a conserved system in bacteria with a specific purpose.

RNA Involvement:
Jillian Banfield’s research sparked interest in the potential role of RNA in employing viral sequences within cells. RNA molecules might aid in recognizing viral molecules that attempt to infect cells.

Further Research:
The speaker’s research focuses on the function of RNA molecules within cells. The speaker’s expertise in RNA research has led to collaboration with Jillian Banfield to investigate the role of RNA in CRISPR-mediated viral defense.

Central Dogma of Molecular Biology:
DNA stores genetic information and replicates it accurately to progeny cells. DNA information is copied into RNA molecules, which can enter proteins or be functional on their own.

Hypothesis of Bacterial Adaptive Immune System:
CRISPR sequences are converted into RNA molecules that recognize foreign DNA, such as viral DNA.

Adaptive Immune System Steps:
1. Detection of foreign DNA (e.g., from a virus) injected into the cell.
2. Incorporation of small bits of viral DNA into the CRISPR sequence.
3. Copy of viral DNA sequence is made into RNA, which assembles with proteins to form guided RNA-protein complexes.

Function of CRISPR-Cas System:
Guided RNA-protein complexes search for DNA sequences matching the RNA sequence (derived from viral DNA). A match allows the complex to grab viral DNA and make a cut in it, providing immunity to viruses.

Collaboration to Study Cas9 Function:
Jennifer Doudna and Emmanuel Charpentier collaborated to study the function of Cas9 protein, a key component of the adaptive immune system.

Cas9 Protein Structure and Function:
Cas9 protein (blue blocky structure) is guided by RNA to recognize and cut specific DNA sequences. This function enables the CRISPR-Cas system to target and destroy viral DNA.

Mechanism of DNA Recognition and Cleavage:
CRISPR-Cas9 is a molecular system that recognizes and cleaves DNA. A protein called Cas9 grabs onto DNA sequences that match a 20-nucleotide sequence in an RNA molecule. The RNA molecule, derived from the CRISPR region, acts as a guide for Cas9 to find its target DNA sequence. Upon finding a matching sequence, Cas9 unwinds the DNA double helix and makes a cut in each strand, leading to DNA breakage.

Requirement for Two RNA Molecules:
The CRISPR-Cas9 system requires two RNA molecules for efficient DNA targeting and cleavage. The first RNA, called the guide RNA, carries the DNA recognition information. The second RNA, called the tracer RNA, is essential for forming a structure in the RNA that allows the targeting complex to assemble.

Development of a Single Guide RNA:
Martin Jinek, a biochemist, simplified the CRISPR-Cas9 system by linking the parts of the guide RNA and tracer RNA into a single guide RNA molecule. This single guide RNA can bind to Cas9 and form the targeting complex, containing both the DNA recognition information and the assembly instructions.

CRISPR-Cas9 as a Programmable Molecular Scalpel:
The single guide RNA acts as a programmer for Cas9, directing it to specific DNA sequences for cutting. This programmability allows the CRISPR-Cas9 system to be easily repurposed to target different DNA sequences by simply changing the guide RNA.

Transition from Fundamental Research to Technological Harnessing:
The programmability of the CRISPR-Cas9 system led to its recognition as a powerful technology with broad applications. This realization marked a shift from fundamental research driven by curiosity to the exploration of CRISPR-Cas9 as a groundbreaking tool.

Introduction of CRISPR-Cas9 Technology:
CRISPR-Cas9 is a revolutionary genome engineering tool that allows precise and targeted changes to DNA sequences in cells. It utilizes a protein called Cas9, guided by a short RNA molecule, to search and cut DNA at specific sequences.

Mechanism of CRISPR-Cas9:
The Cas9 protein, when complexed with guide RNA, scans DNA for a matching sequence. Once a match is found, the protein binds to the DNA and unwinds it, forming a structure that allows precise double-stranded breaks in the DNA. The breaks are then repaired by cellular machinery, enabling insertion, deletion, or modification of DNA sequences at the target site.

Advantages of CRISPR-Cas9 over Traditional Methods:
CRISPR-Cas9 is highly versatile, allowing DNA editing in a wide range of organisms, from plants and animals to microbes. It is relatively easy to use, requiring only the design of a short guide RNA molecule complementary to the target DNA sequence. It is highly precise, enabling targeted changes to specific DNA sequences without affecting other parts of the genome.

Applications of CRISPR-Cas9:
CRISPR-Cas9 has been employed in numerous research and practical applications, including: Studying gene function and regulation Developing new therapies for genetic diseases Improving agricultural crops Engineering microorganisms for industrial purposes Creating new animal models for research

Challenges and Future Directions:
Ongoing research aims to address challenges such as off-target effects (unintended cuts at unintended DNA sites) and delivery methods to efficiently target specific cells and tissues. CRISPR-Cas9 technology continues to evolve, with new applications and discoveries emerging, promising further advancements in genome engineering and its impact on various fields.

The USDA’s Stance on CRISPR-Cas9 Modifications:
The USDA classified CRISPR-Cas9 modifications as non-GMO since they do not introduce foreign DNA. A prominent agricultural company expressed excitement over this decision, with plans to introduce 25 CRISPR-engineered plants soon.

CRISPR-Cas9 Applications in Biomedicine:
CRISPR-Cas9 holds promise for modifying stem cells for future disease treatments and modeling human diseases in animals. Researchers demonstrated the correction of a muscular dystrophy-causing mutation in a mouse model using CRISPR-Cas9.

Germline Editing:
Germline editing involves making DNA changes in developing organisms, affecting future generations. A successful experiment by Russell Dance in 2013 targeted a gene responsible for black coat color in mice, resulting in white offspring. The ethical implications of germline editing sparked discussions on the responsible use of this technology.

Global Discussions on Ethical Use of CRISPR-Cas9:
A one-day meeting was held to discuss the prudent employment of CRISPR-Cas9 in germline cells. The National Academies of several countries organized a summit to address ethical issues surrounding CRISPR-Cas9. Four countries (Sweden, UK, China, Japan) have approved CRISPR-Cas9 for human embryo editing in research.

Collaborations and Funding in Scientific Research:
Scientific progress relies on collaborations and expertise beyond individual laboratories. Jennifer Doudna expressed gratitude for both public and private funding that enabled her team to initiate their research.

Audience Q&A:
A question was raised regarding the timeline for clinical applications of CRISPR-Cas9 in humans.

Ethical Implications of Germline Editing:
Human germline editing raises concerns about transmissible changes to future generations. The scientific community mostly agrees that current knowledge is insufficient for germline editing in humans. A global pause on germline editing has been proposed to allow for further research and ethical considerations.

Clinical Applications of CRISPR:
Muscular dystrophy and sickle cell trait are potential early targets for therapeutic applications. Blood-based therapies may be feasible, allowing for editing outside the body. Initial human clinical trials may begin within 12 to 18 months.

CRISPR in Agriculture and Synthetic Biology:
Opportunities exist for creating plants resistant to pathogens and climate change. Industrially important organisms can be modified for sustainable chemical production. Gene drives can potentially eradicate disease-carrying organisms, but their environmental impact needs careful evaluation.

Media Coverage and Public Perception:
Gene editing has garnered significant media attention, offering hope for treating severe diseases. Scientists have a responsibility to engage with the public and explain the complexities of the technology. Public understanding of gene editing is crucial for informed discussions on its ethical and practical implications.

Therapeutic Use of CRISPR-Cas9:
Therapeutic use of CRISPR-Cas9 shows promising potential. People are eager to know when it can be deployed for their benefit. Excitement and hope surround the possibility of treating diseases and conditions.

Enhancements and Ethical Concerns:
CRISPR-Cas9 technology can potentially make changes to embryos to enhance certain traits. Limited understanding of the human genome and interactions pose challenges in making desirable enhancements. Research using CRISPR-Cas9 in embryos may advance our understanding and drive motivations for clinical use.

Intellectual Property and Profit:
Questions arise regarding intellectual property and potential profits from CRISPR-Cas9 research. Public investments raise concerns about whether corporations should solely benefit from the research. Considerations involve whether individuals might need to pay ongoing fees to maintain gene edits.

Background on Gene Editing:
CRISPR-Cas9 is a gene editing technology that enables precise changes to DNA, offering potential for disease treatment and crop improvement. Universities play a significant role in filing, defending, and licensing CRISPR-related patents. Patent protection is crucial for the commercialization of gene editing technology.

Ethical Considerations:
Potential for abuse of gene editing technology raises ethical concerns. Researchers are actively exploring ways to regulate CRISPR’s function and reverse its activity.

Universal Standards for Medical Applications:
Establishing universal standards for medical applications of gene editing is essential. Prioritizing medical applications in humans should be the primary focus before addressing other uses. Adequate time should be dedicated to developing ethical standards on a global scale.

Challenges in International Research:
Differences in ethical perspectives among jurisdictions present challenges for international research. Ensuring transparency and accountability in research conducted in regions with lax regulations is crucial.

Technical Questions and Answers:
The bridge sequence in gene editing can be introduced by the experimenter or naturally by the cell using a matching DNA sequence. CRISPR editing at the gamete stage holds potential for therapeutic changes, though extensive research is required. Epigenetic modifications can occur in edited genomes, affecting gene expression. However, the long-term effects of these modifications are not fully understood.

Future Innovations and Business Opportunities:
The next generation of research is expected to yield new technologies based on CRISPR and related proteins. Potential business opportunities include technology companies focusing on CRISPR-based products and services. Companies similar to 23andMe may emerge, offering gene editing-related products and services to consumers.

Diverse Application of Genome Editing Technology:
The potential of genome editing extends beyond medicine, encompassing agriculture, therapeutics, and even animal modification for organ donation. Companies specializing in applications will likely emerge, driving creative innovations in various fields.

Ethical Considerations and Potential Government Regulation:
The absence of abortion-related controversies in genome editing does not preclude the need for ethical considerations and potential government regulation. Currently, federal funding cannot be used for human embryo modification, but private foundations and state funds could potentially be employed for such purposes.

Ongoing Conversation on Ethical Implications:
The Office of Science and Technology Policy is actively engaged in discussions regarding the ethical implications of genome editing. The scientific community, represented by Jennifer, is encouraged to reflect on the personal and scientific significance of the joy of discovery in this field.

Humble Origins:
CRISPR technology originated from a small, curiosity-driven research project involving a few individuals in various laboratories.

The Discovery of CRISPR:
The realization that bacteria possess an intricate defense mechanism capable of recognizing and destroying viral DNA sparked a sense of wonder and excitement. The appreciation for the remarkable capabilities of nature’s creations.

Unexpected Connections:
The connection between the CRISPR system and the concept of gene editing was a moment of realization, linking seemingly unrelated areas of research. The discovery of this connection led to the development of a groundbreaking gene-editing technology.

Sharing the Sense of Wonder:
The importance of sharing scientific discoveries and insights with students and the broader community. Fostering a sense of awe and curiosity about the natural world.

Appreciation for Collaboration:
Acknowledgment of the contributions of colleagues and collaborators in scientific advancements. The value of collaboration in driving scientific progress.