Berggruen Seminar Series: Heritable Human Genome Editing - Concepts and Scientific Issues

The 14th Berggruen Seminar organized by the Berggruen Institute China Center was live-streamed on Bilibili on January 21, 2021. Dr. Wang Haoyi, principal investigator and head of the genetic engineering research group at the Institute of Zoology, Chinese Academy of Sciences, was invited to discuss “Heritable Human Genome Editing: Concepts and Scientific Issues.” Hosted by 2019-2020 Berggruen Fellow Dr. Wang Yangming, principal investigator at the Institute of Molecular Medicine, Peking University, the event explored four topics: what genes and genome editing are, the applications of genome editing, heritable and non-heritable human genome editing, and scientific issues concerning heritable human genome editing.

What are genes and genome editing techniques?
The human body is composed of cells; in a large number of varieties, cells make up all tissues and organs of the human body. According to their functions, cells can be divided into two categories: somatic cells and gametes. Somatic cells, while capable of performing various functions and forming all kinds of tissues and organs, are not heritable, meaning they are not passed down to offspring. Gametes, however, comprised of eggs (female gamete) and sperm (male gamete), do carry genetic information in their nuclei to the next generation. That genetic information is stored in the form of chromosomes.

If a chromosome is like a ball of yarn, untangling the yarn and breaking it down into fibers is the process of uncoiling chromosomes into DNA molecules. Each chromosome is made up of a very long and tightly coiled double-helix of DNA, composed of two parallel molecular chains with a deoxyribose skeleton. Four bases–with acronyms of A, C, G, T–can be found inside the deoxyribose skeleton and form what are called base pairs. Reading one chain of DNA in a certain direction produces a sequence of bases whose complementary properties give rise to another sequence. The gene is a section of information on a double-stranded macromolecule of DNA. If the sequence of four bases on the double-stranded molecule has a specific biological function, such as encoding a protein or a functional molecule, it is considered a gene. These DNA base sequences are transcribed into RNA sequences, which will eventually be translated into proteins, the biologically-active machines that play a critical role in cells. They affect the properties of cells and therefore the properties of species. This principle applies to all creatures throughout nature, from humans and fish to insects and bacteria.

At fertilization, when life begins, an egg and a sperm, each carrying 23 chromosomes, come together to become a 46-chromosome zygote. The zygote then divides and forms a blastocyst, which develops into a fetus in the mother’s uterus. During the fetus’s development, its 46 chromosomes are duplicated whenever its cells divide and multiply. The information in all 46 chromosomes of an individual human is like a one-of-a-kind book, with each of the chromosomes acting as a chapter made up of different paragraphs. The human genome is thus a three-billion-letter book of life.

Genome editing can be likened to a pair of scissors for double-stranded DNA, a pair of tweezers for precise gene editing, or an eraser for removing a gene. Genome editing can also integrate new genes and add new information at specific sites in the genome. CRISPR-Cas9 is becoming a widely applied technology in genome editing because it is highly efficient and easy to use. The two scientists who developed it won the 2020 Nobel Prize in Chemistry. The technique allows researchers to deliver human-designed protein and RNA complexes into the nucleus and bind them to specific sites on the chromosome for precise DNA sequence modifications.

What are the potential applications of genome editing?
Dr. Wang Haoyi says that genome editing techniques could theoretically change the genetic information of any creature on Earth because they all share basically the same genetic logic. The prospects for genome editing applications are huge. For example, genome editing can be used to modify industrial microorganisms for better fermentation and bioenergy or be applied to crops and livestock to produce grains and food more efficiently. Transforming animal cells is also an effective way of supporting pharmaceutical development. Making slight changes to pigs’ genes could significantly accelerate their growth, which could improve breeding practices. Modification of enzymes related to cell walls could lead to sweeter tomatoes with longer shelf lives.

Human genome editing, which receives the most attention, can be divided into two types: non-heritable (somatic cell) and heritable (gamete and early embryo).

Non-heritable human genome editing techniques can be used to treat diseases but will not affect the genes of offspring. There are two kinds of therapeutic approaches to this type of genome editing. One is in vivo gene editing, in which proteins for gene-editing are injected into human muscle, blood, or tissue such as the eye with a viral or non-viral vector to modify the cells in the tissues and treat certain diseases. Another approach is in vitro gene editing, in which target cells are taken from the body to culture in vitro, edited, and then transplanted back into the body, such as stem cells from the blood system, or immune cells. Somatic cell gene therapy has been around for decades, so there is already a large amount of existing experience in regulation and research. Gene editing is a technical subcategory under gene therapy, so in the study of ethics and science, it is less controversial.

The heritable genetic manipulation of human gametes or early embryos, however, is entirely novel and has never been seen before in human history. This is the first time that humanity possesses the technology to actively influence natural evolution, so there exist not only scientific and technological challenges but also many ethical and social concerns. Genetic editing of an early human embryo changes the fetus’s cells and the sperms or eggs it will produce, invariably affecting the genes of its offspring.

Heritable Human Genome Editing report and regulations on heritable human genome editing
The 2018 case of genome-edited human infants had a major impact on the scientific community and society around the world. The International Commission on the Clinical Use of Human Germline Genome Editing was established in response, and scientists around the world, including Dr. Wang Haoyi, came together to develop a framework targeting clinical research on and responsible application of heritable human genome editing (HHGE), primarily considering technical, scientific, medical, and regulatory requirements. This organization was created not to support HHGE, but to establish clear regulations based on the understanding that some instances have already occurred and some may still occur.

Within a year and a half, the Commission completed a report entitled “Heritable Human Genome Editing” (HHGE) with three key messages. First, no clinical use of HHGE should be considered unless it is possible to efficiently and reliably make precise genomic changes without affecting other genes. Sufficient preclinical evidence must be obtained from cells, animal models, and human embryos that demonstrates either the reliability and accuracy of on-target changes without any off-target–changes other than on-target modifications that carry other risks–or mosaicism, a situation in which genetic editing modifies only parts of cells and leaves others unmodified. This aim, however, has not been reached with currently available technology, and further research is therefore necessary. Second, before any country decides to approve the use of HHGE, there should be national and international mechanisms to ensure that the preclinical requirements above have been met for initial responsible use. Third, if technological advances have been made and there are well-established international mechanisms, any clinical use of HHGE should proceed cautiously with initial uses restricted to a limited set of circumstances under which the highest-return and lowest-risk treatment can be delivered.

Even when preclinical data meet these criteria, rigorous clinical evaluation programs are needed to assess each clinical diagnostic and operational process. Strict rules and regulations must be put forward including informed consent and long-term follow-up. Additionally, initial use of HHGE must be restricted to circumstances that meet all of the following criteria: treating a serious monogenic disease; applying a modification known to cure the disease; not subjecting normal embryos to accidental modifications; and no other option available for the parent to give birth to a healthy child. “Heritable Human Genome Editing” classifies possible applications for HHGE by the following categories: Category A–serious monogenic (single-gene) diseases in which all children of a parent would inherit a disease that could lead to major morbidity or early death; Category B–serious monogenic diseases in which some children of a parent would inherit a disease; Category C–monogenic conditions with less serious impacts; Category D–polygenic (multi-gene) diseases; and Category E– applications not related to heritable diseases which are ethically challenging and which make changes to normal genes.

Dr. Wang Haoyi points out that strict scientific and technical regulation is needed for the application of HHGE, as well as in-depth discussion and supervision from the international scientific community. In all processes including technology development, decision making, and clinical evaluation, an international scientific body needs to be established to provide advice and evaluate data reliability, quality, and progress. Technology is a double-edged sword. In-depth discussions about technology must be carried out and analyses on the application of specific technologies in specific conditions must be analyzed. The evaluations of technical difficulties, risks, and benefits for each specific disease are different; “cure-all” technologies don’t exist. Now is the time to conduct research, gain understanding, and make independent judgments as information becomes more readily available in the Internet Age.


Drafted by: Cai Xinyi (intern) from University of Chicago, USA
Edited by: Lan Tianmeng (intern) from Renmin University of China