Proceedings of a Workshop—in Brief

Third International Summit on Human Genome Editing: Expanding Capabilities, Participation, and Access

Proceedings of a Workshop—in Brief

On March 6–8, 2023, at the Francis Crick Institute in London, the UK Royal Society and Academy of Medical Sciences, the U.S. National Academy of Sciences and National Academy of Medicine, and UNESCO–The World Academy of Sciences held the Third International Summit on Human Genome Editing. A follow-up to earlier international summits held in Washington, DC, in 2015¹ and in Hong Kong in 2018,² the third summit examined scientific advances that have occurred since the previous summits and the need for global dialogue and collaboration on the safe and ethical application of human genome editing. The first two days of the summit focused largely on somatic human genome editing, where the cells being altered are non-reproductive cells—as a result genetic changes cannot be passed on to future generations. The third day of the summit broadened the discussion to include heritable human genome editing, in which genetic changes could be passed on to a person’s descendants.

Science, equity, access, and public and patient engagement were prominent themes in the planning of the summit, said Robin Lovell-Badge (Francis Crick Institute), chair of the summit planning committee, in his introductory remarks. As Linda Partridge (Royal Society) and Victor Dzau (U.S. National Academy of Medicine) pointed out, therapies based on genome editing need to be both available and affordable if the new technology is to benefit human health equitably. This requires international norms, careful governance, and engaging with a wide variety of perspectives, said Partridge, which is why the summit sought to bring together a diverse range of speakers, including “those with lived experience of genetic disease and from parts of the world that have not been represented at previous summits.”

Together, the three summits have laid the foundation for international coordination of the governance and regulation of human genome editing, a process dating from a 1975 meeting held at the Asilomar Conference Center shortly after DNA editing techniques were developed, said David Baltimore (California Institute of Technology), chair of the planning committees for the first two summits. “Our meetings represent the response that a concerned community can create that can help the larger society get the benefits of new technologies while mitigating the challenges that they inevitably bring.”

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As with the summaries of the 2015 Summit³ and the 2018 Summit,⁴ this summary of the Third International Summit on Human Genome Editing does not represent the conclusions of the organizing committee or of the summit participants. Rather, it highlights important points made during the summit to provide context for the statement released by the organizing committee on the summit’s final day, which appears at the end of this proceedings—in brief.

THE HUMAN FACE OF GENOME EDITING

On the first day of the summit, former sickle cell patient Victoria Gray gave a human face to the progress and potential of human genome editing. From an early age, she suffered from severe pain, and “trips to the hospital were as normal to me as lunchtime on a school day.” She received IV fluids, high-dose pain medicines, and blood transfusions and often returned from the hospital having lost so much weight that she looked different to her classmates. “The pain I was feeling in my body was like being struck by lightning and hit by a freight train all at once.”

Despite her difficulties, she graduated from high school on time and began pursuing a nursing degree. But her health deteriorated, and after a hospital stay from October 2010 through January 2011, she lost muscle control of her arms and legs. “I couldn’t feed myself. I couldn’t walk on my own. I needed physical therapy to help me regain balance and the use of my legs…My nursing dream was over.” At one point, she learned from her son’s teacher that her son thought she was going to die. “This news was devastating. I knew I had to fight to be here.”

She began to do research on bone marrow transplantation and made an appointment to be evaluated as a transplant candidate. When she, her husband, and her brother met with the physician, she learned that she had the option of participating in a genome editing clinical trial. “Needless to say, I said, ‘yes.’”

In June 2019, after her bone marrow cells were collected and edited, her new “supercells,” as Gray calls them, were ready. She underwent four days of chemotherapy followed by the implantation of the edited cells. “After everyone who was documenting the procedure left the room, I shed tears of joy. Somehow, I felt as though I was newly born that day.” While in isolation for 30 days due to the suppression of her immune system, she lost her hair and suffered from terrible mouth sores, but the care she received buoyed her spirits. “They not only treated my body, but they treated my mind.” She returned home to her family about seven months later—only to discover that “the entire world had shut down from COVID.” But the genome editing had worked. “I began to enjoy the life that I once felt was passing me by. I was able to run around with my children, attend their football games, cheerleading events, and enjoy family outings. I no longer experienced severe pain and had to stop my life to be in the hospital for long periods of time. My children no longer have the fear of losing their mom to sickle cell disease. I’m able to work a full-time job. At one point in my life, I stopped planning for the future because I felt I didn’t have one. Now I can dream again without limitations…I stand here before you today as proof that miracles still happen and that God and science can coexist.”

ISSUES IN SICKLE CELL TREATMENTS

The treatment that cured Victoria Gray’s sickle cell disease used the CRISPR-Cas9 gene editing system to

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alter the regulation of the genes that produce adult hemoglobin. This has the effect of increasing the level of fetal hemoglobin in the blood, which is produced by genes that do not have the mutation responsible for sickle cell disease. Other genome editing therapies to treat the disease are also being developed, observed Daniel Bauer (Boston Children’s Hospital, Dana-Farber Cancer Institute, and Harvard University), John Tisdale (National Institutes of Health), and Annarita Miccio (Paris City University). One seeks to add a functional adult hemoglobin gene to the genome; another would directly repair the mutation in the gene for adult hemoglobin. A major advance, said Tisdale and Miccio, would be to develop methods of modifying the genes of cells without having to extract them from the body, which would avoid the need for chemotherapy to destroy a person’s existing blood stem cells so that they can be replaced by edited cells. However, such an advance will require overcoming substantial technical obstacles so that specific genes can be altered in specific cells without causing genetic changes elsewhere.

Other life-extending treatments for sickle cell disease do not involve genome editing, including the use of penicillin as a preventative therapy, administration of the drug hydroxyurea to reduce the symptoms of the disease, and transfusion for stroke prevention. Administration of hydroxyurea, for example, is safe and effective across the entire lifespan, even in low-resource areas of the globe, said Alexis Thompson (Children’s Hospital of Philadelphia). However, the drug is still not available in some parts of the world, despite its effectiveness. About 1,000 babies are born with sickle cell disease every day, the majority in Africa, and many of these children will die before their fifth birthdays without interventions. “I don’t think we can ignore the fierce urgency of now,” said Thompson.

Gautam Dongre (National Alliance of Sickle Cell Organizations) reported that India has the second highest prevalence of sickle cell disease in the world after Africa, with more than 1.4 million people waiting for a cure. Bone marrow transplantation and gene therapy offer great promise, but they are not affordable for most people in India, and even hydroxyurea is not available for many people in the country. Indian researchers are working on how to minimize the costs of treatments so they can reach more people, Dongre said.

Ambroise Wonkam (Johns Hopkins University) and Melissa Creary (University of Michigan) discussed ways to achieve greater equity in the administration of both genome editing and other treatments for sickle cell disease. Today in Africa, bone marrow transplantation is routinely possible only in Nigeria and South Africa, and longstanding neglect of large groups of people in Africa and elsewhere has resulted in significant disparities in health care and health outcomes. “We have to have ethics and equity at the center of all these conversations for this summit and beyond,” said Creary.

Arafa Said (Sickle Cell Disease Patients Community of Tanzania), Kofi Anie (London North West University Healthcare NHS Trust and Imperial College London), and Daima Bukini (Muhimbili University of Health and Allied Sciences) discussed the need for sickle cell patients to know more about potential benefits and risks to make informed decisions about treatments. When sickle cell patients in England were asked, “From what you know so far, what are your concerns, if any, regarding gene therapy in sickle cell disease?” the most frequent response was that they did not know enough to have views on the issue, highlighting the need for patient education, said Anie. “We shouldn’t assume that talking to patients within the clinic setting would address the basics of health literacy,” he said. People need to be provided with “very simple lay information.” In Tanzania, hydroxyurea has become widely available just in the last few years, and bone marrow transplants are just starting to become available. People are generally willing to try new therapies, observed Said, but other patients’ stories of successful treatments nevertheless have a major influence on their opinions. Mechanisms are being developed in Africa to meaningfully engage with patients, which will help produce information that can be leveraged as research moves into clinical trials, said both Bukini and Said.

SOMATIC GENOME EDITING FOR OTHER DISEASES

The variety of genome editing approaches being taken to treat sickle cell disease reflects the tremendous advances that have been made in genome editing in recent years, observed Jennifer Doudna (University of California, Berkeley, Howard Hughes Medical Institute, and Innovative Genomics Institute). At the time of the summit, the treatment used to treat Victoria Gray’s sickle cell disease was close to being approved for use in the Europe and the United States. Other clinical trials were underway for liver disorders and congenital eye disease, and trials in the planning stage would use genome editing to target infectious diseases, cancers, diabetes, and various rare and neglected diseases. In all these cases, genome editing is being used to make changes in somatic cells, so the changes cannot be passed on to future generations.

As David Liu (Harvard University and Howard Hughes Medical Institute) observed, variants in human DNA are responsible for thousands of genetic diseases that collectively afflict hundreds of millions of people. “A longstanding goal of the life sciences has therefore been to develop the ability to install, correct, or otherwise modify all possible types of pathogenic mutations so that we can study or treat the broadest possible range of the resulting diseases.” The CRISPR-Cas9 system discovered by Doudna and Emmanuelle Charpentier is still a widely used tool in genome editing, but newer systems are even more powerful and precise. Techniques known as base editing and prime editing enable efficient and precise gene correction in a wide variety of cell types without requiring that both strands of the DNA molecule be broken, minimizing the possibility of DNA deletions, insertions, or rearrangements that can result from double-stranded DNA breaks. Many laboratories have used prime editing to treat diseases in animal models of human disease, and some of these techniques have been applied in clinical trials.

Current genome editing systems rely on large molecules that need to be delivered specifically to their target cells. Today, genome editing most often relies on removing the target cells from the body, treating them in the laboratory, and returning the altered cells to the body, which is known as ex vivo genome editing. However, the cells of relatively few tissues can be treated in this way. Researchers are therefore working on ways to deliver genome editors to cells in the body, known as in vivo genome editing, using viruses, lipid nanoparticles, or virus-like particles that avoid the drawbacks of viral vectors.

Amy Wagers (Harvard University) looked more closely at Duchenne muscular dystrophy as an example of in vivo genome editing’s potential to produce one-time, systemic, permanent therapies. Many challenges still need to be overcome, including increasing the efficiency of genome editors, ensuring that edits are durable, reducing the toxicity of the vectors used to deliver editing molecules into the body, and reducing immune reactions to introduced agents. Also, the availability of personalized therapies for a large number of individual mutations across the genome will require new regulatory strategies, said Wagers, especially if costs and distribution are to be equitable.

Eric Olson (University of Texas, Southwestern) discussed the potential of applying genome editing to the hundreds of devastating genetic diseases of the heart and muscle that currently do not have cures. Cardiac and skeletal muscle tissues are long-lasting, allowing for possible “one time” fixes. An obstacle to such treatments is the relatively small number of patients with the same mutation, which will necessitate strategies to optimize genome editors for different gene variants. Another challenge is incomplete penetrance of disease phenotypes, with some patients who have a particular mutation expressing full-blown disease phenotypes while other patients with the mutation are relatively unaffected.

Kiran Musunuru (University of Pennsylvania) described another potential “one and done” genome editing therapy to treat and prevent ischemic heart disease and

stroke, with a particular focus on low- and middle-income countries. By changing a handful of nucleotides in a base editing molecule, the therapy could be used for a variety of diseases while being manufactured locally in widely distributed facilities. Combined with universal newborn screening and routine testing of affected individuals, this approach could be a model for the worldwide treatment of genetic diseases, he said.

Inborn errors of immunity are another target for genome therapy, said Fyodor Urnov (University of California, Berkeley and Innovative Genomics Institute). However, as with heart and muscle diseases, a large number of different mutations cause the approximately 500 known types of immune system dysfunction, which raises obstacles to commercialization. A standardized, scalable, affordable, fast, and portable platform to correct deleterious mutations would reduce risks and speed applications, he said.

Joni L. Rutter (National Institutes of Health) and Claire Booth (UCL Great Ormond Street Institute of Child Health) addressed the challenge of rare diseases that individually affect relatively few people but collectively impose a heavy toll on human health. Worldwide, more than 350 million people have a rare disease, including about 30 million people in the United States. In the United States, the resulting economic burden is over $400 billion dollars in direct medical costs per year and upwards of a trillion dollars if non-medical costs are included. Gene therapies for rare diseases have the potential to be transformative, said Boothe, but effective therapies are not reaching patients for economic as well as scientific reasons. Despite over 150 clinical trials of gene therapies for rare diseases, only a handful of therapies have been licensed, and some therapies that have been approved have been withdrawn because of high costs, limited markets, and inappropriate cost-benefit analyses. New ways to commercialize and approve gene therapies for rare diseases are needed to achieve sustainable and affordable access to life-changing therapies for patients with rare diseases, she said. One promising approach is to create delivery platforms that can be adapted to different editing molecules while undergoing unified regulatory processes.

Genome editing techniques that can be adapted to many different diseases would be a powerful way to reduce costs and broaden the range of patients who can be treated. An example is the use of edited immune system cells to treat different cancers. As Rachel Haurwitz (Caribou Biosciences) explained, T cells in the immune system can be edited to target specific proteins on the surface of tumor cells, yielding off-the-shelf therapies that could be used with a much larger patient population than is the case today. Such an approach could even be used outside oncology to treat a wide variety of other diseases.

In a related area of research, a gene editing approach that would avoid the problem of immunosuppression is to create genetically engineered cells that do not generate immune responses in a patient, so that the same cells can be used in many different patients. As Sonja Schrepfer (University of California, San Francisco and Sana Biotechnology) pointed out, cells that avoid immune responses are now being studied and soon will be ready for use in humans.

Genome editing tools can also be used to alter the activity of genes without changing the genome. Epigenome editing can alter the proteins and other molecules that regulate the expression of genes, offering possible treatments for cancer, heart disease, and many other conditions, said Angelo Lombardo (San Raffaele-Telethon Institute for Gene Therapy and Vita-Salute San Raffaele University). This approach could yield valid and potentially safer alternatives to other genome editing techniques.

Somatic genome editing can also include therapies administered before birth. Fetal blood transfusions, developed in the 1960s to treat anemia caused by RH incompatibility, have opened the door to a host of other therapeutic modalities, including stem cell transplantation, enzyme replacement therapy, and, in the future, fetal genome editing, said Tippi MacKenzie (University of California, San Francisco). The fetal environment offers many advantages over postnatal therapies, including fewer problems with immune responses, rapid proliferation of stem cells, greater

ability to surmount the blood-brain barrier, and distribution of therapies to multiple organs. Routine screening for common conditions combined with genome editing would greatly expand the ranges of patients and conditions that could be treated. A unique issue in fetal genome editing is the uneven distribution of risks and benefits between mother and fetus, but a survey of parents conducted by MacKenzie and her colleagues indicated that the majority want these kinds of treatments to be available. “We’re trying to carve out a safe and ethical roadmap for a clinical trial,” MacKenzie said.

While all these forms of genome editing bear great promise, presenters also emphasized the many technical obstacles that must be overcome, especially for in vivo genome editing. Therapeutic edits need to be made in particular locations of cells without affecting other genetic locations in those cells or other cells. Especially important is avoiding changes in egg and sperm cells and their precursors so that somatic genome editing does not inadvertently change the human germline.

An interesting factor in the science of genome editing is the work of independent researchers outside of the traditional research enterprise. The practitioners, many of whom have PhDs, do this research in homes or community laboratories, often collaborating online with colleagues across global borders, explained Alex Pearlman (MIT Media Lab Community Biotechnology Initiative). Projects mentioned by Pearlman include efforts to develop COVID tests and sources of free insulin in connection with affordability projects in the United States. Thousands of people belong to this community, with representation in the Global South as well as the United States and Europe. “It is an activist movement that is driven in large part by altruism, transparency, and open access,” said Pearlman.

Independent researchers use a variety of mechanisms on a case-by-case basis for ethical oversight, reflecting the diversity and pluralism of the community. The community has made serious efforts to develop and promote biosafety standards for home and community laboratories, and inside the community a growing trust architecture parallels that of institutional ethics oversight systems, Pearlman said. What these researchers now want is translational pathways through largely inaccessible regulatory frameworks so that they can move the products of their work into clinics.

THE ACCESSIBILITY AND AFFORDABILITY OF SOMATIC GENOME EDITING

Current genome editing treatments for sickle cell disease and other conditions are very expensive—more than $2 million per patient in the case of sickle cell treatment, as Doudna noted. As a result, current genome editing treatments are inaccessible to the vast majority of people around the globe who could benefit from them.

The companies developing genome editing approaches may see market authorization in the United States and Europe as the finish line, but the real finish line will be when all patients in the world have access to safe and effective one-time curative therapies, said Matthew Porteus (Stanford University). Reaching that point will require addressing several categories of problems. Facilities and other infrastructure are needed in all parts of the world to enable treatments. Education and training are needed to produce a global network of solution makers and problem solvers. Various engineering problems persist, such as manufacturing treatments in closed and automated systems, but “when one can convert a problem into an engineering problem, we’re almost there,” Porteus said. Finally, local and regional regulatory systems need to be structured around the needs of local societies without compromising safety. Partners, allies, and advocates will be essential to solve all these problems.

As a specific example of infrastructure needs, Sofonias Kifle Tessema (Africa Centres for Disease Control and Prevention) observed that the ability to conduct genomic sequencing is limited in large parts of Africa due to

an inadequate data infrastructure, a lack of skilled workforce, deficient policies and coordination, and supply chain, cost, and regulatory challenges. The expansion of sequencing and other genomic technologies across the continent would enable better diagnoses, inform disease management, and strengthen genomic medicine.

Some organizations have focused specifically on reducing costs so that treatments can be more widely available. An example is an initiative funded by the Bill & Melinda Gates Foundation to accelerate the development of gene therapies that are safe and accessible for HIV and sickle cell disease, with a focus on resource-limited parts of the world. Creating a single-shot in vivo gene therapy for these diseases is a technically challenging and high-risk endeavor, said Emily Turner (Bill & Melinda Gates Foundation). But the foundation has established partnerships to engage key stakeholders in low- and middle-income countries and has obtained global access rights from multiple for-profit companies. Given the size of the market, the possible extension of the platform to other diseases, and anticipated decreases in production costs, widespread availability and affordable pricing are feasible goals.

In many countries, access to genome editing will face barriers due to insufficient health infrastructure, social inequities, the need for more training initiatives for health care providers, and the lack of diversity in genomic databases, observed Natacha Salomé Lima (University of Buenos Aires and National Scientific and Technical Research Council). In health care systems that are highly fragmented and have significant budgetary limitations, basic needs remain unmet, and the benefits of high-cost technologies are largely out of reach. Argentina, for example, has sought to address problems of equity through novel and broadly distributed financing mechanisms. But standard-of-care treatment, if available, is usually concentrated in urban areas.

Equity in the context of genome editing encompasses more than issues of cost, ownership, and access, said Jantina de Vries (University of Cape Town). Equity also needs to be considered in terms of the process of knowledge production. “If we do not include everyone in the science that we do, we simply will end up—and have ended up historically—with innovations that work for some and not for everyone.” Equity in knowledge production requires that genome editing research be conducted in part where it will be applied, which points to the need to strengthen research, policy, and implementation infrastructures. “If we are targeting diseases that affect people in Africa, then we need to ensure that at least some human genome editing research happens on the continent as well.” Engagement with patients and patient advocacy can advance this process, de Vries said.

Steven Pearson (Institute for Clinical and Economic Review) pointed out that the value of new therapies, as determined by governmental health technology assessment agencies, depends on a variety of factors, including health gains for patients over their lifetimes, the cost of the treatment, whether that treatment might reduce costs in the future, the degree to which a condition is disabling or life-threatening, spillover effects on the community or society, and the risks or uncertainties associated with a treatment. Decisions about pricing inevitably involve tradeoffs among such factors, both within the health care system and across all societal investments in well-being. Because of the number of factors involved, the costs of developing and producing a drug do not necessarily determine prices. The challenge, said Pearson, is to create pricing, payment, and intellectual property systems that can keep up with the scientific innovation that is going on. “Tradeoffs will be necessary—do we have the social competence within and across nations to manage them?”

Filippa Lentzos (King’s College London) warned that the vast expansion of genomic data produced through genomic science can be used not only for personalized diagnostics and treatments but also for such nefarious uses as surveillance, tracking systems, suppression of dissidents, and even targeted weapons. To cite two of Lentzos’s examples: According to a WikiLeaks release, the U.S. State Department has asked its diplomats in Central Africa and the Middle East to gather fingerprints, facial images, iris scans, and DNA from some key civilian political and military officials. And in recent

years, China’s surveillance web has been extended to cover not just facial, voice, and gait recognition but also genetic data, including genetic data from the families of dissidents and from ethnic minorities. “We need to gently, cautiously, and responsibly raise awareness of the security dimension of genomic science,” said Lentzos. “We need to put security concerns on the table as another risk that the community needs to grapple with.”

PATIENT AND PUBLIC ENGAGEMENT AND THE ROLE OF CIVIL SOCIETY

Patient groups bring the voice of the patient community to science and innovation, said Mathieu Boudes (Montsouris Consilium). Patient groups can finance research, advocate, communicate with policymakers and regulators, train and educate patients, facilitate clinical trials, and move debates about ethics forward. They need to be supported and empowered to advance the causes with which they are involved.

Beyond patient groups, civil societies in general need to be engaged in deliberations and decisions, said Bettina Ryll (Melanoma Patient Network Europe and European Commission). “We cannot come up with something new and expect this to go well if we’re not succeeding in taking our societies along into this change.” Civil society includes trained scientists, and scientists are part of civil societies, thereby furthering the two-way communication needed for genome editing to progress.

As an example of public engagement, a project conducted in New Zealand looked at Māori views on genome editing and similarities and differences between Māori and non-Māori in engaging with the science and its application. A major conclusion was that genome editing is as much a cultural issue as a scientific or technical issue, said Māui Hudson (University of Waikato). Support or opposition to genome editing depends on the context and the application, and that context is shaped by values. Indigenous communities have put together guidelines about how to work responsibly with such groups. These communities now need capacity building to get more people involved in these discussions, with objectives that include recognition of indigenous rights, collaboration around ethical use of data and other resources, and equitable outcomes from this use, including potential commercialization.

Researchers, clinicians, patients, and families do not all hold the same opinions, observed Kelly Ormond (ETH-Zurich and Stanford University). According to surveys, support for a given intervention among professionals depends on such factors as whether a condition is highly penetrant, has an early or late onset, impacts the entire lifespan, and produces greater or lesser degrees of disability. Similarly, how an individual patient views a medical condition depends in part on whether that condition is part of their identity or not. For example, attitudes about genome editing for blindness vary according to whether a person was born blind, the cost of a procedure, and the degree to which vision might improve. In the case of chromosomal abnormalities such as Down syndrome, people express concerns that individuals with particular conditions will receive less social services and support if genomic treatments become widespread, with a resulting loss of autonomy and decrease in quality of life. People make different decisions about treatment depending on these and other factors, Ormond said, and they should not be discriminated against regardless of the decisions they make.

Public engagement requires a portfolio of approaches involving a large number of groups, including professional groups, said Simon Niemeyer (Global Citizens’ Assembly on Genome Editing and University of Canberra). It also needs a deliberative component that is inclusive and consequential, with the latter implying that the process leads to norms of practice. The Global Citizen’s Assembly on Genome Editing is partnering with other organizations that are engaging with the public on particular issues, yielding a two-step process to generate public discussion on, ultimately, a global level. The goal is not so much consensus as mutual understanding achieved via a process of deliberation, said Niemeyer.

India is an example of a country where a portfolio approach is essential, observed Sarojini Nadimpally (Sama Resource Group for Women and Health). India has a diverse population with many different cultures, religions, castes, languages, gender identities, health-seeking patterns, ethnolinguistic communities, families, and refugee or migratory statuses. Moreover, with globalization, local publics have to be conceptualized in the context of the global pharmaceutical and biotechnology industry, global health governance, online spaces, and the global market. From this perspective, publics must be seen as coproducers of knowledge and agents of change, not just as the beneficiaries of technologies, Nadimpally said. A local-level bottom-up approach could combine local knowledge to feed into innovations and policymaking while enhancing autonomy and participation.

On a global scale, the Association for Responsible Research and Innovation in Genome Editing (ARRIGE) seeks to promote global governance of genome editing, advance reflections on the subject, foster the development of genome editing technologies, and disseminate reliable information regarding genome editing technology, explained Lluís Montoliu (Association for Responsible Research and Innovation in Genome Editing and National Centre of Biotechnology). ARRIGE has been focusing on the Global South and has directed attention not just to human genome editing but to biotechnological applications for plant and animal genome editing, including gene drive applications. Through its statements, newsletters, collaborations, and other forms of outreach, it endeavors to communicate both the benefits and the limitations of genome editing to the public.

On a somewhat smaller scale, the Global Observatory for Genome Editing has served the complementary role of helping to broaden the discussion around genome editing and other technologies that have the capacity to alter human nature. The observatory has specifically sought to examine the ideas of care and flourishing that are tacitly embedded in the scientific and technological goals of genome editing, said Sheila Jasanoff (Global Observatory and Harvard University) This requires many types of expertise, including from fields like theology or law, which represent “repositories of profound thinking about the meaning of human life.” In this way, the observatory is seeking to bring together disciplines, outlooks, sectors, and perspectives that do not often communicate. However, as several participants pointed out, funding for these types of endeavors is very limited and desperately needed.

GERMLINE AND HERITABLE GENOME EDITING

On the third day of the summit, Amander Clark (University of California, Los Angeles) began a discussion of germline and heritable genome editing by reviewing the work of the International Commission on the Clinical Use of Human Germline Genome Editing. In its 2020 report Heritable Human Genome Editing, the commission observed that no country has yet decided that it would be appropriate to move forward with clinical applications of heritable human genome editing.⁵ The commission described the societal and ethical issues that would need to be debated before arriving at such a conclusion, but it did not make a judgment about whether a safe and efficacious methodology of heritable human genome editing should be permitted. Instead, it laid out a rigorous set of preclinical and clinical criteria that would need to be met before any such procedure could be deemed safe and effective. “These criteria have not been met and further research and review would be necessary to meet them,” the commission concluded.

Katsuhiko Hayashi (Kyushu University), Kyle Orwig (University of Pittsburgh), and Mitinori Saitou (Kyoto University) extended Clark’s discussion of the science and techniques for editing human sperm and eggs and their precursor cells. Genome editing of stem cells leading to both sperm and egg cells has been conducted in animal models and in human cell cultures and has led to important advances in the understanding of mammalian reproduction and development. It also has shed light on

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causes of human infertility, which affects many millions of people around the world. Genome editing of human sperm, eggs, and their precursor cells would be one way to make changes in the human genome that could be passed down from one generation to the next, but the implantation of genetically modified human embryos to produce a pregnancy is currently prohibited in many countries and is not explicitly permitted in any country.

Dieter Egli (Columbia University), Shoukhrat Mitalipov (Oregon Health & Science University), Kathy Niakan (Francis Crick Institute and University of Cambridge), and Dagan Wells (University of Oxford) provided an update on the science and techniques of editing embryos, including human embryos. Genome editing of human embryos has revealed valuable information about the biology of our species. Such editing also would have many advantages over the editing of somatic cells to treat disease in children or adults, where it can be difficult to deliver editing molecules to the large number of cells that would need to be altered. However, editing of embryos would create genetic changes that can be passed from one generation to the next and, as such, poses tremendous technical and societal challenges. As an example of the former, the chromosomes in early-stage human embryos are unusually susceptible to chromosomal breakage, said Wells, which provides a warning against the therapeutic use of genome editing methods that create double-stranded DNA breaks. At the societal level, many nations forbid genome editing of human embryos, and others require that all such embryos be destroyed within 14 days of fertilization.

RESPONSES TO HERITABLE HUMAN GENOME EDITING

Tina Rulli (University of California, Davis) made the argument that heritable human genome editing will not save lives, cure diseases, or have therapeutic value. Heritable human genome editing does not consist of curing a baby who would otherwise be sick from a disease, she said. Rather, it is part of a reproductive decision to create a baby free of a disease. Since heritable genome editing fails to alleviate an otherwise inevitable disease state, it fails to have the morally urgent basis and value of medical therapies. Prospective parents who wish to create a child have an array of other options, including preimplantation genetic diagnosis, gamete donation for the affected sperm or egg, or adoption. Heritable human genome editing’s lack of social value renders clinical research on the procedure unethical, said Rulli. Furthermore, heritable human genome editing raises serious medical and societal concerns, including the safety of the technology, the risk of dangerous genomic modifications being introduced into the human gene pool, the use of the technology to create babies with particular traits or enhancements, unethical eugenic uses of the technology, and unfair access to a technology that would only advantage the wealthy. These arguments far outweigh the comparatively low value of heritable human genome editing, Rulli said.

César Palacios-González (University of Oxford) countered that some heritable human genome editing interventions can be therapeutic in nature. The clinical decision to employ genome editing can be made after the creation of the embryo that will be subject to the intervention. In some cases, heritable human genome editing may be the only way to for a child to be healthy once an embryo has been created.

Ephrat Levy-Lahad (Shaare Zedek Medical Center) proposed a thought experiment: If safe heritable human genome editing is achieved, will more permissive public opinions and policies on heritable human germline interventions follow? Even while adhering to frameworks of accepted ethical principles, the social and cultural context of countries is likely to have an effect on such decisions. Countries that place a premium on the ability to create a family by bearing children could see applications that overcome infertility or enable biological parenthood as promoting human well-being. In those circumstances, countries could have compelling reasons for adapting or changing their laws on heritable human genome editing.

OVERSIGHT OF HUMAN GENOME EDITING

Katherine Littler (World Health Organization) reviewed the recommendations for governance and oversight of human genome editing laid out in the 2021 report of

a WHO expert advisory committee.⁶ By applying good practices in the governance of emerging technologies specifically to human genome editing, the framework seeks to help strengthen oversight measures at the institutional, national, regional, and international levels. The framework is not a panacea, said Littler, but it provides a mechanism for governance that incorporates considerations of equity and access.

Building on the work of the expert advisory committee, Piers Millett (International Biosecurity and Biosafety Initiative for Science) summarized the results of a survey of national and regional laws and regulations, research ethics guidelines, governance frameworks, key institutions, informal policies, non-governmental initiatives, and approaches and practices related to genome editing. Crosscutting findings were that most rules and ethical guidance were not focused on human genome editing but rather on such subjects as gene therapy, human subjects research, clinical trials, and medicine; some rules and guidance have been updated to address advanced biotechnology; some bans on embryonic research are in place; some rules and regulations are more closely aligned to human genome editing; and most rules and guidelines do not make much distinction between somatic and heritable editing and between research and treatment. New rules and regulations are being developed, Millett reported, though most respondents felt that somatic human genome editing was regulated in their countries. Challenges and potential shortcomings included a need for key definitions, insufficient public consultation, and a lack of monitoring to detect illegal activities.

Kaushik Sunder Rajan (University of Chicago) emphasized that the central issue is not the regulation of human genome editing but its governance, which extends far beyond regulations. Any governance framework for human genome editing must consider not just questions of equity and public welfare but the long histories of structural injustice and the redistributive, restorative, and reparative actions required to address those histories, Rajan said. This will require thinking about the translational pathways of innovation in more participatory and democratic ways and frame-shifting the ways in which governance questions are addressed.

RESPONSES TO UNETHICAL HERITABLE HUMAN GENOME EDITING

At the second summit in 2018, news broke that a Chinese scientist had conducted genome editing on human embryos implanted in utero to produce a pregnancy that resulted in the birth of twin girls. This action was swiftly condemned, at the summit and elsewhere, as a serious violation of scientific norms. The scientist responsible was imprisoned and assessed fines, and no known instances of heritable human genome editing have occurred since.

In an analysis of how Chinese stakeholders responded to news of the genetically engineered girls, Ping Yan (Dalian University of Technology) and her associates found that the Chinese government, scientific community, medical community, and ethicists all condemned the experiment and acted to strengthen laws, regulations, and ethics reviews involving genomic research and its applications. The reactions of the news media and public were more mixed, with many agreeing with the need for regulation and adherence to strong ethical principles while also expressing the hope that the advancement of technology could benefit humanity. The growing field of responsible research and innovation (RRI) calls for taking stakeholders’ needs and values into account in the stewardship of science, Yan added, which also emphasizes the need for good governance of science and technology at the local to global levels.

Yaojin Peng (Chinese Academy of Sciences and Beijing Institute for Stem Cell and Regenerative Medicine) also pointed out that China took steps to improve its legislation and regulations regarding life sciences, including human genome editing, after 2018. In China, gene therapy is regulated as a drug, human germline genome editing for reproductive purposes has been banned by criminal law, and basic research is subject to strict requirements, including ethics review and informed consent. “China’s legislation regarding human

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genome editing is basically in line with international standards,” said Peng. Beyond regulation, the Chinese Academy of Sciences has established an Ethics Committee of Science and Technology and has launched a series of discussions regarding the life sciences. In addition, the Guidelines to Strengthen the Governance over Ethics in Science and Technology emphasize making science and technology ethics education a vital part of undergraduate and graduate education. Peng called for open discussions among scholars from a variety of fields to assess controversies surrounding emerging technologies and to strengthen collaboration with colleagues inside and outside of China.

Joy Zhang (University of Kent) agreed that China’s ethical review has been substantially upgraded but also observed that it is still confined to traditional medical, scientific, and educational establishments. As a result, the new measures fail to directly address how privately funded research and other social ventures will be monitored, opening the door, as in other countries, to market-led research and medical tourism that is subject to less oversight.

Leigh Turner (University of California, Irvine) called attention to the risks posed by clinics selling unproven interventions based on genome editing, just as clinics selling unproven stem cell-based interventions operate today in countries around the world and attract people who come to those countries specifically to access them. Harms that can occur when powerful biotechnologies are prematurely marketed as therapies include fatal outcomes and serious injuries, the undermining of patient decision-making, the exploitation of vulnerable persons, deception and fraud, damage to credible scientific research, and public confusion and uncertainty. National variations in laws, regulatory vacuums, gray areas in legislation, and under-resourced regulatory bodies create environments in which genome editing hype could fuel premature commercialization of purported therapies. To prevent this outcome, ethical principles need to inform and be connected to regulatory frameworks, Turner said. Regulatory bodies also need to have the capacity, in both financing and personnel, to uphold legal standards.

Even if countries do not have specific policies or norms toward human genome editing, universal norms based on human rights exist and can be enforced by regional systems, said María de Jesús MedinaArellano (National Autonomous University of Mexico). The challenge for effective regulation and oversight is accountability, including appropriate enforcement and compliance. Furthermore, accountability is an issue for all countries, not just those in the Global South. Ethical oversight, coordination of regulation, accountability, and enforcement are therefore needed at the international level. This international oversight—combined with national oversight and coordination, guidelines from civil society or academic societies, mechanisms to guarantee compliance, and transparency—help build knowledge and trust so that people who are seeking services know where to go and can have confidence in the services they receive.

At the end of the summit, the organizing committee released a statement that summarized their views of the discussions and looked to the future.

STATEMENT FROM THE ORGANISING COMMITTEE OF THE THIRD INTERNATIONAL SUMMIT ON HUMAN GENOME EDITING

The Third International Summit on Human Genome Editing, convened by the UK Royal Society, UK Academy of Medical Sciences, U.S. National Academies of Sciences and Medicine, and The World Academy of Sciences, was held to discuss progress, promise, and challenges in research, regulation, and equitable development of human genome editing technologies and therapies.

After listening to three days of thoughtful and inclusive discussion, the members of the Organising Committee offer the following conclusions:

Remarkable progress has been made in somatic human genome editing, demonstrating it can cure once incurable diseases. To realise its full therapeutic potential, research is needed to expand the range of diseases it can treat, and to better understand risks and unintended effects. The extremely high costs of current somatic gene therapies are unsustainable. A global commitment to affordable, equitable access to these treatments is urgently needed.

Heritable human genome editing remains unacceptable at this time. Public discussions and policy debates continue and are important for resolving whether this technology should be used. Governance frameworks and ethical principles for the responsible use of heritable human genome editing are not in place. Necessary safety and efficacy standards have not been met.

Governance mechanisms for human genome editing need to protect ongoing, legitimate research, while preventing clinics or individuals from offering unproven interventions in the guise of therapies or ways to avoid disease.

Somatic Human Genome Editing⁷

Numerous clinical trials using somatic human genome editing are in progress or soon to be initiated, with preliminary but encouraging results that point to future therapies. The dramatic improvement following CRISPR-based research interventions for sickle cell disease offers hope for patients. Many techniques, including base, prime, and epigenetic editing, may also prove to be useful interventions for a broad range of both genetic and acquired diseases and disorders. However, as with other gene therapies, extended long-term follow-up is essential to fully understand the consequences of an edit and to identify any unanticipated effects, should they occur.

Improved techniques have enhanced the efficiency, precision, and accuracy of the editing process, yet effective delivery and editing remains difficult for many tissues of the body. Further research to diversify and increase the efficiency, specificity, and safety of editing-delivery systems is essential for improving potential treatment options and promoting equitable access.

Equitable Access for Somatic Human Genome Editing

As interventions based on somatic genome editing become more widespread, a commitment to equitable, financially sustainable, and accessible treatments becomes more urgent. In many cases, costs and infrastructure needs of current gene therapy treatments are not manageable for either patients or healthcare systems. Correcting this will require appropriate planning from the earliest stages of the research and development for each potential application. Ensuring research includes more genetically diverse populations and expanding the range of those who conceive and conduct the research, play a vital role in achieving equitable outcomes.

With sickle cell disease (as well as other genetic diseases), a large percentage of patients live in underserved countries and communities or in settings without adequate infrastructure. Moving from ex-vivo to “one and done” in-vivo somatic human genome editing can partially address this problem. But knowledge transfer between nations, improved clinics and research facilities, and strong oversight are also needed to establish sustainable access to safe interventions for research participants and patients.

Health care systems and the global health community should prepare to provide patients with cost effective, affordable, proven therapies. Therapies based on somatic genome editing that could help meet these needs should be a priority for research investment.

Human Germline Genome Editing for Research (Not for Reproduction)⁸

Basic research using genome editing in human embryos has continued, with the aim of either understanding aspects of early human development or exploring how the methods might be used to correct gene variants leading to genetic disorders. There has also been significant progress in basic research on deriving functional gametes from stem cells. Basic research in this field should continue.

Heritable Human Genome Editing

Preclinical evidence for the safety and efficacy of heritable human genome editing has not been established, nor has societal discussion and policy debate been concluded. (In some cases, preimplantation genetic testing is among the alternatives.) Heritable human genome editing should not be used unless, at a minimum, it meets reasonable standards for safety and efficacy, is legally sanctioned, and has been developed and tested under a system of rigorous oversight that is

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subject to responsible governance. At this time, these conditions have not been met.

Ongoing International Collaboration and Discussions

The Organising Committee calls for on-going dialogue and continued international collaboration on innovative approaches to governance and regulation of human genome editing technologies, the state of the science, and innovation in the treatment of genetic diseases.

DISCLAIMER This Proceedings of a Workshop—in Brief has been prepared by Steve Olson as a factual summary of what occurred at the workshop. The organizing committee’s role was limited to planning the event. The statements made are those of the individual workshop participants and do not necessarily represent the views of all participants, the project sponsors, the organizing committee, or the sponsoring Academies.

ORGANIZING COMMITTEE Robin Lovell-Badge (Chair), The Francis Crick Institute; David Baltimore, The California Institute of Technology; Françoise Baylis, Dalhousie University; Ewan Birney, The European Bioinformatics Institute; Alta Charo, University of Wisconsin-Madison, George Daley, Harvard Medical School; Javier Guzman, Center for Global Development; Daria Julkowska, Thematic Institute of Genetics & European Joint Programme on Rare Disease; Julie Makani, Muhimbili University of Health and Allied Sciences; Chris McCabe, Institute of Health Economics; Luigi Naldini, San Raffaele University School of Medicine; Cor Oosterwijk, VSOP (Association of Cooperating Parent and Patient Organisations); Lily Paemka, University of Ghana; Michèle Ramsay, University of the Witwatersrand; Elisa Reis, Federal University of Rio de Janeiro; Haoyi Wang, Chinese Academy of Sciences; Mayana Zatz, University of São Paulo.

REVIEWERS To ensure that it meets institutional standards for quality and objectivity, this Proceedings of a Workshop—in Brief was reviewed by Henry T. Greely, Stanford University; Richard Hynes, Massachusetts Institute of Technology; and Jennifer Merchant, Paris-Panthéon-Assas University II. Marilyn Baker, National Academies of Sciences, Engineering, and Medicine, served as review coordinator.

U.S. NATIONAL ACADEMIES’ STAFF Anne-Marie Mazza, Project Director and Senior Director; Katie Bowman, Senior Program Officer; Steven Kendall, Senior Program Officer.

ROYAL SOCIETY STAFF Connie Burdge, Policy Adviser; Jonny Hazell, Senior Policy Adviser.

SPONSORS This project has been funded in whole or in part by the Annenberg Foundation Trust at Sunnylands; National Academy of Sciences Cicerone Endowment; National Academy of Sciences W.K. Kellogg Foundation Fund; National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN263201800029I; and Wellcome Trust under Grant Number 218375/Z/19/Z.

SUGGESTED CITATION National Academies of Sciences, Engineering, and Medicine. 2023. Third International Summit on Human Genome Editing: Expanding Capabilities, Participation, and Access: Proceedings of a Workshop—in Brief. Washington, DC: The National Academies Press. https://doi.org/10.17226/27066.

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