Risk, rewards, and regulations for gene editing

...the paucity of scientific information about the Chinese twins, known by the pseudonyms Lulu and Nana, has created an atmosphere of suspicion and mistrust.

Professor Robin Lovell-Badge, Head of the Division of Stem Cell Biology and Developmental Genetics at the Francis Crick Institute

Professor Robin Lovell-Badge, Head of the Division of Stem Cell Biology and Developmental Genetics at the Francis Crick Institute, told Laboratory News that the paucity of scientific information about the Chinese twins, known by the pseudonyms Lulu and Nana, has created an atmosphere of suspicion and mistrust.

It is three years since biophysicist, Dr He Jiankui, was jailed for his role using CRISPR (clustered regularly short palindromic repeats) gene editing to manipulate embryos. The lives and development of the twins remain shrouded in secrecy. The Chinese authorities carried out an investigation of the science and completed an assessment of the now notorious episode, but those findings have not been published.

“I suspect the Chinese Government wants to avoid further scrutiny, and probable criticism, from the West,” said Professor Lovell-Badge, who is also a member of the WHO committee for Oversight of Human Genome Editing (COHGE).

Regulatory oversight of human genome editing

The COHGE was formed after the announcement of the experiment in which human embryos were manipulated using the CRISPR gene editing technique. The committee has been addressing the issues and has produced nine recommendations for future public use of human genome editing. The WHO committee has issued three reports on human genome editing: a position paper, recommendations, and a framework for governance. Its report [1], which provides a new governance framework delivering concrete tools and recommendations for the management of specific practical challenges and illustrative scenarios, got little publicity. Perhaps because the world’s focus was on the pandemic at the time. The committee, of which Professor Lovell-Badge is a member, urged the WHO to work with the international scientific community to develop a registry for basic and preclinical research and to “develop an assessment mechanism to identify clinical trials using human genome editing technologies that may be of concern”.

He Jiankui’s gene editing experiment

He Jiankui justified his experiment editing the twins’ genes as a valid exploration of the possibility of conferring a resistance to HIV infection. When he unveiled his work, Dr He said IVF was used to produce the embryos and editing was carried out to genetically alter them by disabling the C-C motif chemokine receptor 5 (CCR5) gene. This gene has been identified as producing a receptor which allows HIV to enter and infect cells during the single-cell stage.

Initially, the Chinese trumpeted He Jiankui’s achievement but with the immediate international backlash they backtracked, condemning the work, and closing the laboratory. Following a closed trial in Nanshan District People’s Court, Dr He was sentenced to three years in jail and fined for ‘illegal medical practice’, along with two members of his team.

Aside from the serious questions around ethics, the scientific dilemma moving forward is how to determine how changes to the twins’ genomes may translate to actual benefits or risks throughout the rest of their lives. It is this problem which is now on the minds of geneticists and psychologists.

Professor Lovell-Badge, renowned for his work on the Y chromosome’s SRY gene as the determinant of sex in mammals, says the issues will remain unresolved until the Chinese are more forthcoming.

Safety concerns and health risks

...the scientific dilemma moving forward is how to determine how changes to the twins’ genomes may translate to actual benefits or risks throughout the rest of their lives

Professor Robin Lovell-Badge, Head of the Division of Stem Cell Biology and Developmental Genetics at the Francis Crick Institute

Prof Kiran Musunuru, geneticist and cardiologist at the University of Pennsylvania is critical of He’s work. Having examined his manuscript and identified several problems, he believes it is important the global science community understands the outcomes of this research. Writing in the MIT Technology Review [3] Prof Musunuru noted that there was evidence of mosaicism in both twins. This means the edits to the gene were not displayed uniformly throughout the twins’ bodies. Some of their cells may contain the edits He made, while others may contain no edits at all, leaving the twins as vulnerable to HIV as they would have been naturally. Worse still, some might incorporate unintended ‘off target’ edits that could create health problems of their own, either within the twins themselves or their offspring.

According to Sean Ryder, a Biochemist from the University of Massachusetts Medical School, even those genes that He intended to edit were not selected correctly. Intending to delete a section of CCR5 that mimicked the so called ‘delta 32’ mutation, He assumed that editing the same region of the genome would lead to the same outcome. An “outrageous assumption” according to Ryder. As a result, there will be no way of predicting the consequences without monitoring the twins throughout their entire lives.[4]

Confidentiality before collaboration

In China, geneticists and psychologists will be discretely monitoring the twin girls. In an echo of the Truman Show movie, their lives will be under the microscope - probably permanently. However, the global scientific community is excluded from this work.

In his book ‘The Mutant Project’ [2], Professor Eben Kirksey suggests that some Chinese government officials were somehow complicit in the experiment. But Professor Lovell-Badge is encouraged by the fact that one member of the Human Genome Committee is Chinese and was involved in the proposed reforms introduced into the ethics review process.

“What He did has been widely condemned by scientists, and ethicists, at a time when China is trying to become the scientific superpower – It could have been a big step backwards for them, one that the Government would like to be forgotten,” said Prof Lovell-Badge. “The relevant laws in China have been tightened up and a review process established to try to prevent something similar happening again. Our committee, which has been addressing governance of human genome editing, were reassured by this. In my view, openness would be the best way to put it all behind them, but perhaps this is not the way things are done there.

“With respect to the genome edited children, it is of utmost importance to protect their identity. Therefore, while we are all very keen to learn about what has happened with them, and whether the editing has affected them in any way, we have to respect this need for confidentiality. Moreover, it may never be possible to know whether the editing had any significant consequences for the children – each may carry different mutations. Every child born carries a few de novo mutations not present in their parents.”

Will outcomes ultimately reward China?

"The concern is not about authorities in the West or elsewhere, but about potential ‘rogue’ scientists. There may be clinics which might want to profit financially ...[]... offering heritable edits as part of IVF.”

Professor Robin Lovell-Badge, Head of the Division of Stem Cell Biology and Developmental Genetics at the Francis Crick Institute

Some may fear that the knowledge the Chinese will gain as Lulu and Nina grow up might prove advantageous. Asked if the ethical values Western authorities currently wish to uphold might slowly erode as research attempts to stay abreast of possible insights gained from this experiment, Prof Lovell-Badge was sanguine.

“It is highly unlikely that the Chinese will gain any advantage. It will be very difficult for scientists in China to pursue research on heritable human genome editing. The concern is not about authorities in the West or elsewhere, but about potential ‘rogue’ scientists. There may be clinics which might want to profit financially from spinning the story, suggesting that no harm was done, and offering heritable edits as part of IVF.”

For those interested in exploring these ethical and regulatory challenges further, in addition to outlining special challenges around postnatal, prenatal, and heritable human genome editing, one of the WHO scenarios covered in its new framework discusses ‘Heritable human genome editing: unscrupulous entrepreneurs and clinics expanding assisted reproduction' [1, p52], among others.

Author: Dermot Martin is a freelance science writer

References

1. Human Genome Editing: A Framework for Governance and Recommendations, World Health Organisation, July 14, 2021
2. Kirksey, E., The Mutant Project, Bristol University Press, 3 March 2021
3. Musunuru, K., Opinion: We need to know what happened to CRISPR twins Lulu and Nana, MIT Technology Review, 3 December 2019
4. Science | AAAS. 2020. Chinese Scientist Who Produced Genetically Altered Babies Sentenced To 3 Years In Jail. [online] [Accessed 22 September 2020].

Editor's note: an earlier version of this article named the twins as 'Lulu and Nina'. The editor apologises to the author who submitted the correct names in his submission. This error crept in during a later edit.