Tutankhamun is believed to have died of sickle cell disease.1 Sickle cell disease (SCD) is one of the first targets for gene editing therapy. We have known there was a genetic variation for at least 50 years. Studies in Cameroon and Tanzania all show the genetic variation and now there is at least one proof of concept to edit the genetic anomaly. There are three targets, specifically involving hemoglobin.
Interestingly there is more genetic variation in Africa than any other continent, due mainly to the long history of humans in Africa. Variation is also a superior survival characteristic for populations. But it makes it more difficult to find genetic targets that can be targeted for SCD.
A young woman, Victoria, appeared at the WHO conference in London this week, to talk about her experience of being the first person cured of SCD. She tearfully explained the pain she experienced, her fear of discussing her condition in a class discussion about blood disorders, and her frequent hospital stays. She still managed to graduate from high school, become a mother, and was working toward becoming a nurse but then she became almost completely disabled and unable to walk. Dana Delaski her hemotologist found a researcher in Nashville for a bone marrow transplant, and her brother agreed to be her donor (and was a match). But while in Nashville she had a devastating episode which landed her in the hospital instead of the bone marrow transplant.
Dr. Frangoul presented the option of gene therapy.2 They had to collect stem cells from her bone marrow, and used those cells to edit the sickle cell disease targets from them. This took about a year, but upon her return for treatment, within minutes of injecting the new cells she said that she felt her life changed instantly. She said she felt reborn. Her immune system had been suppressed with chemotherapy, so she was isolated for 30 days. After three months she was able to return to her family. She was also faced with opioid withdrawal which she had been given for her life long pain, but she succeeded.
She was able to be active with her children, attend their games and her children no longer believe she is about to die as they told their teachers, Victoria started planning for the future again. 3
It was noted that 110 other patients with SCD have been cured using gene therapy.
Gene Thereapy Opportunities in Native Populations
Meanwhile in the United States, in a population that predates the United States, fairly isolated and not as genetically diverse as Africa, are the Navajo Nation people. One in 2,000 Navajo babies are born with a genetic mutation in the ARTEMIS-SCID gene4 producing the most severe form of immune deficiency also know ad the Bubble Boy Disease (girls also get it).
HT was born April 7, 2018 at the Tuba City Regional Hospital in the Navajo Nation. It was soon discovered that he had SCID and was sent to UCSF where ultimately gene therapy clinical trial was his best option. Using his own cells, instead of donor bone marrow transplants, they were edited and inserted into his body to develop into T-cells. Tracking this development, three of them were identified after three months. After an incredible number of setbacks, HT was eventually found to be ready for the outside world and returned to the Navajo Nation for a normal life.5
So what are we waiting for to treat all of the Navajo babies? The cost is $3 million dollars for each person,6 and federal support is needed to realize the benefit from this incredible cure.
The Ethics of Human Gene Editing
It is hard to argue with the results in the first trial for gene editing in sickle cell disease for Victoria. In fact, we should celebrate a human victory over the struggle to survive and conquer this terrible killer.
In 2015, the Organizing Committee for the International Summit on Human Gene Editing met in Washington, D.C. at the National Academies. I was there in the discussion group that day where the room was filled to capacity. The committee was being organized globally, under the United Nations, UNESCO but is led by the national academies representatives from several countries including the U.S., U.K, Hong Kong, and China. The Committee met again to assign work projects in 2016 in preparation for he Second International Summit on Human Genome Editing. The second summit was to be held in China, but China quietly withdrew7 and the summit was held at the University of Hong Kong in November 2018. Speculation about why China withdrew usually leads to their global embarassment involving Dr. Jiankui. This week, the Third International Summitt on Human Gene Editing was sponsored by the British Royal Society in London. Fortunately, I was able to attend online by reserving tickets months in advance. Victoria spoke about her story at this session.
The International Commission on the Clinical Use of Human Germline Genome Editing, organized by the U.S. National Academies is charged with creating guidelines for clinical use of gene editing.
There are two types of cells that can be edited. Somatic cells which are cells the human body creates everyday differentiated into different cells of the body. Germ line cells are those that carry the chromosomes with genes that are inherited by our children and editing those cells would mean the change would carry on to the succeeding generations of humanity. There is a third area called epigenetics which we understand less than any of the other two cell types. Epigenetics is the ability for genes to learn and take their changes to the next generation, like a mother who has suffered trauma can pass along the genetic tendency for anxiety to her children. Changing Germline cells is a much more difficult ethical question than editing somatic cells or even epigenetics effects. Is it ever ethical to change the course of human development?
Many think of Victoria’s sickle cell disease and how she recovered her life. Changing her germline cells to prevent her children from the same fate should be an obvious “yes”. Her gene therapy was somatic cell therapy so it will not be heritable, but maybe it should also be made heritable by editing the germline? In the National Academies Commission report of 2020 on germline gene editing, they found that not one country has yet permitted the gene editing of germline cells in humans.
When He Jiankui, the biophysicist in China, chose to experiment on humans to prevent them from being susceptible to HIV-AIDS, there were no approvals of his clinical trials which were required as part of human research in China. The scientist was sentenced to three years in prison along with two of his collaborators in 2019. He was also consulting with scientists in the U.S. which have been documented as encouraging him to proceed with his experimentation.8 He has been released and has set up an office in Beijing where he intends to continue his experimentation9 in the private sector (which is really government controlled, because there is no true private sector as we know it in the U.S., in China. Which also means if he is continuing to work, he is doing so with the approval of the Chinese Communist Party).
The National Academies in the U.S.
In a report a couple of years ago, the National Academies committee on human gene editing completed a report with recommendations on whether it was ethical to have clinical trials with gene editing of humans. The conclusion was that clincial trials are acceptable ethically if it is to cure disease or infirmities, but not for enhancement or creating super characteristics of humans.10 (I can say that I heard a Russian scientist in Geneva say quite openly that his country was working on gene editing to create super human athletes, shocking at the time, but perhaps taken with some skepticism.)
Ultimately, we will likely settle on a regulatory framework like we did when genetically modified crops were experimental in open fields, and many protocols and safety mechanisms were used to prevent unintended consequences from the experiments. Eventually, when no biodisasters occurred the experimental precautions were relaxed, many other agencies were allowed to engage in supporting experimentation and now more than 90% of the crops grown in the U.S. are genetically modified,11 and the rest of the world is rapidly increasing its share. Human gene editing could follow that same pattern.
Global governance of the ethics of human gene editing requires good faith adherence of all the nation-states in the world. As I wrote last week, agreeing to more treaties with more infringements on sovereignty will not change China’s behavior in the area of research with dangerous pathogens.12 Will global governance ensure China will not repeat its rogue experimentation on humans?
Let’s hope so. Because without severe sanctions for one of the world’s super powers (who is increasingly seeking alliance with a second world super power, Russia) they have little to deter their unprincipled ambition.
During the summit, discussions of CHina’s new regulations for gene editing were raised. Piers Millet, former U.N. Biological Weapons Convention Director, now thinktank director in Washington, D.C., commented to BBC that China was ahead of the world with regard to their regulations in this area.13 Countries that are weak on the rule of law, often have strongly worded laws and regulations but poor enforcement consistency or fairness. The fact that it applies to the government sector and not the private sector is a gaping hole in the safety net; but it is not unlike the U.S. where similar restrictive regulations apply only to federally funded projects, not private sector work.
Emerging technologies like human gene editing often need more room to grow and experiment because we do not know what wonderful improvements of human life they might bring, or what horrific results we should guard or regulate against. So China may be our proving ground for this new and emerging technology whether we want it or not.
But any movement toward consensus with ethical experimentation is better than having none. There is no stopping this technology. There should be no stopping of a global dialogue about it. But when the Committee was asked whether there would be a Fourth Summit, there was no answer.
[Caveat about the caption graphic: I really dislike using the Frankenstein trope when discussing genetic modification because it has negative connotations about GMOs and human gene editing. Yet, it is something everyone understands in a glance — unintended consequences can happen with experimentation, even when well-meaning.)
This article is read by award-winning narrator, Naysan Adlparvar, and sound engineering was provided by Summer Sutton.
Hawass Z, Gad YZ, Ismail S, et al. Ancestry and Pathology in King Tutankhamun's Family. JAMA. 2010;303(7):638–647. doi:10.1001/jama.2010.121 at https://jamanetwork.com/journals/jama/fullarticle/185393
Dr. Haydar Frangoul & Victoria Discuss Gene-Editing Therapy
Victoria Gray, personal story presentation, Third Summitt (March 5, 2023).
Fydor Urmov, Director Technology & Tanslation Professor, Innovative Genomics Institute presentation, Third Summit (March 7, 2023).
https://www.ucsf.edu/news/2022/12/424486/how-gene-therapy-saved-child-bubble-boy-disease
Fydor Urmov, Director Technology & Tanslation Professor, Innovative Genomics Institute presentation, Third Summit (March 7, 2023).
https://www.statnews.com/2018/11/26/human-genome-editing-summit-china/
https://www.statnews.com/2019/01/31/crispr-babies-michael-deem-rice-he-jiankui/
https://english.elpais.com/science-tech/2023-01-11/the-man-behind-the-first-genetically-modified-human-babies-wants-to-resume-experimenting.html
https://nap.nationalacademies.org/catalog/24623/human-genome-editing-science-ethics-and-governance
It is closer to 90% in the U.S. see https://www.nationalacademies.org/our-work/international-commission-on-the-clinical-use-of-human-germline-genome-editing.
https://www.bbc.com/news/science-environment-64857311