CRISPRed babies in China: a growing scandal

On November 26th 2018, the world was hit by huge news from China: first gene-edited human babies were born, two twin girls. Chinese physicist turned genetic engineer Jiankui He, associate professor at the South University of Science and Technology of China claimed to have used CRISPR gene editing technology on human embryos for seven couples during fertility treatments, in a registered clinical trial. In the process a gene for a cell membrane protein CCR5 was deleted, which is known to be largely (but not exclusively) responsible for HIV infection. One of these 7 interventions led to a successful pregnancy with twins, to a Chinese woman named Grace. Her two newborn girls, called Lulu and Nana are now, according to He, resistant to HIV and AIDS.

Internationally, it was AP who broke the news, in this article. Predictably, the identity of the family is secret, as He made clear, they cannot be contacted. The day of announcement was chosen strategically because on November 27th, Second International Summit on Human Genome Editing starts, incidentally in China, organised by US national academies of sciences, engineering and medicine. While He already fantasised of receiving a Nobel Prize in MIT Technology Review, the conference organisers, He’s own university, the funder of his clinical trial and his Chinese peers quickly distanced themselves from He and his human experimenting with public statements. Even his ethics approval is being disputed.

The guest post by pseudonymous TigerBB8 below will give you a lay-down on what happened in this human CRISPR affair in China so far.

Jiankui He studied physics in China, but he was trained in USA where he received his PhD at Rice University and did postdoc at Stanford, as his CV shows (now for some reason removed, but here is a backup). Just 3 days before He broke the news on CRISPR human babies, the gene engineer published an opinion piece titled “Draft Ethical Principles for Therapeutic Assisted Reproductive Technologies“, in the newly founded The CRISPR Journal.  Of course it contains not a word of what he allegedly already did. He also declared there that “no competing financial interests exist”, though he runs a company Direct Genomics where the CRISPR magic allegedly has happened, while he was officially on unpaid leave to focus on his business. He’s South University allegedly admitted online to own a part of this company.

CRISPR-CAS9 gene editing technology is highly specific and efficient, but not considered safe for human use, most definitely not for embryo editing. It has off-target effects, which means mutations, and could under circumstances promote cancerous transformation of gene-edited cells. But He remained unconcerned and went ahead. If He actually did what he says he did, that is.

My personal suspicion is that no babies were CRISPR in the production of this show. He’s statement that the family cannot be contacted is one give-away. But also, it makes perfect sense for someone keen to create such a shock wave without having to prove much to claim to have made the two human newborns resistant to HIV and AIDS, rather then curing some deadly hereditary disease. For the latter namely, He would be asked to prove success in one form or another, even if by simply proving the children are alive and well. An alleged HIV resistance is something no sane person will ask a proof for, neither in a child or a grown up many years later. Even if the babies Lulu and Nana do exist, there is no way of even knowing if they have even been CRISPRed as embryos. We all might have been served some fake news. We might even never find out, and the story will be quietly forgotten in a couple of months.

But even then, the damage is done. George Church, the big man of Broad Institute in Harvard, found what He did was “justifiable”. Church, whose plans include resurrection of woolly mammoths and engineering of humans to become resistant to all diseases and to live for ages, all with the help of CRISPR technology, might be now tempted to try and put his visions into practice. There are certainty many others with ideas for interesting CRISPR experiments on humans. Following He’s alleged success story, they might be tempted to go to China, or elsewhere, where ethics can be bought and patients won’t sue. It’s called Ethics Dumping.

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Gene-edited babies in China, breakthrough or fake news? Either way, it is Chinese way.

By TigerBB8

Monday, the 26^th of November, a scientist in China, Jianhui He, a PhD trained in Rice and Stanford in USA, announced that he has helped an HIV positive man and his HIV negative wife to successfully have their own twins born a couple of weeks ago. These two girls were the first genetically edited human babies in the world, as He claimed.

Dr. He posted a video on his university faculty page to explain this procedure and the reason he chose to perform it to produce HIV-resistant babies.

Some people online reminded the confused science world that this news just popped out right on the eve of the Second International Summit on Human Genome Editing that was to start on Nov 27^th in Hong Kong, China.

In a couple of hours, the Organizing Committee of the Summit issued a statement, through Molly Galvin at the Office of News and Public Information of US NAS, confirming that Dr. He has been scheduled to speak at the Summit on Wednesday. Their statement implied that they were not aware of the birth of the gene-edited twins and they hope that “the dialogue at our summit further advances the world’s understanding of the issues surrounding human genome editing”

Chinese pro-government news agencies such as people.com.cn Shenzhen branch, in its first news report on Nov 26, presented it as a great historical breakthrough that Chinese scientists lead the world on using gene editing for disease prevention. However, after seeing quite some criticism from all over the world online, this news piece has since been deleted from its website, though still available on others who reposted it like the one shown in the screenshot of Chinanews.com.

The majority of the Chinese public was super excited about what they believe as the milestone achievement made by Dr. He and was cheering on Weibo (Chinese version of Twitter) that Chinese scientists are way ahead of their Western peers. Quite many Weibo users wasted no time to dream about next Nobel prize for China.

At the same time, commentators on Twitter (which is not accessible from Mainland China) were mostly negative if not condemning of the bold and unethical actions of Dr. He. Some even suspected that this might be a Chinese version of STAP case.

As the human baby experiment started to receive some negative comments and even criticism on Chinese public platforms such as Weibo and WeChat, an ethical approval of the study by the ethic committee of Shenzhen HOME Women’s and Children’s Hospital was shared, showing that a protocol with a title of “CCR5 gene editing” had received approval on March 7^th, 2017, and the PI of the protocol was Dr. Jiankui He.

A prominent figure in Public Science in China (although he lives in US), Dr. Shi-min Fang, was among the first of Chinese scientists seriously opposing Dr. He’s study on editing genes of babies. In his tweet (his tweets are always re-posted almost immediately on Weibo by his followers in China), Dr. Fang commented that the attempt was unethical, and the gene editing was unjustified. He questions the floppy review and approval of this project and urges that projects like this should be banned and Dr. He should be punished.

At the same time, an open letter signed by more than 100 Chinese scientists, mostly in biomedical field inside and outside of China’s mainland, has emerged. The letter, calling Dr. He’s experiment an act of craziness, urges Chinese government to ban any future attempts on heritable human gene editing.

While the criticism has been pouring in from all over the world, the parties willingly or unwillingly involved in the reported birth experiment of gene-edited twin girls, started to extract themselves from the situation.

The first to leave the party were members of the ethic committee that supposedly granted the approval. Members whose signatures were on the approval letter all denied signing that document. However, no one alleged that his or her signature was forged.

Next was the university, Southern University of Science and Technology, where Dr. He is affiliated as an associated professor and was recruited through the country’s famous 1000 people program. The university issued a formal statement saying that Dr. He has been on an unpaid leave since February of this year and the gene-editing work he claimed to have accomplished had nothing to do with the University. In their statement, the University determined that He’s work “has seriously violated academic ethics and codes of conduct” and they will formally investigate the incident, relying on an independent committee of international experts.

Meanwhile, relevant government offices at every level, from the City of Shenzhen, the Province of Guangdong, and the National Health Commission of the country have all issued statements regarding this experiment. None was aware of the project happening until Dr. He released the news himself.

Interestingly, a search on Chinese Clinical Trial Registry (ChiCTR) returned a formal registration of He’s clinical trial on “Safety and validity evaluation of HIV immune gene CCR5 gene editing in human embryos” with a trial number ChiCTR1800019378. A close look at this registry, however, reveals that the trial was retrospectively registered on Nov 8, 2018, very likely the time after the successful birth of the twin girls. The clinical trial’s applicant is Qin Jinzhou, who has a PhD from a veterinarian school, with major in Animal Genetics, Breeding, and Reproduction.

The registry disclosed yet another piece of important information, the funding source. It was funded through a Free Exploration Project by Shenzhen Science and Technology Innovation Commission (SZSTI), a government office that oversees all science and technology development affairs in the city of Shenzhen. Well, again, in just a couple of hours, the SZSTI issued statement that it never funded He’s baby gene editing research.

As the story is continuously evolving, more and more interesting yet controversial facts are being shared hour by hour. Although it has already demonstrated poor management from the administration parties of biomedical research in China, another piece of the puzzle cannot be ignored, the possible issue of research misconduct. So far, there is not much evidence supporting this speculation, however, it will not be a surprise if it turns out to be this case. We’ll see.

Update 27.11.2018. Rice University now investigates he’s former PhD advisor and current business partner, Michael Deem. AP News previously wrote that “Deem also holds what he called “a small stake” in — and is on the scientific advisory boards of — He’s two companies.”

And in China, Southern University of Science and Technology (SUSTech) now locked up He’s office, as TigerBB8 notified me.

The note on the door says:

“Do not enter! If you do, do it on your own risk”

As reported by Bejing News on Weibo, the funding for He’s CRISPR experiments on humans came from the SUSTech. Each participating couple is promised RMB 280k (~USD 40k), each live born gene-edited baby is scheduled to be followed until age of 18. The screenshot below the news message is of He’s institutional website, where only research on “nonviable human embryos” is mentioned

TigerBB8 also found the Informed Consent Form, on He’s institutional website, here is a backup. The remuneration offer of RMB 280k is explicitly stated there, participants also received a “Ping An Group’s Anxingbao insurance for babies born”. We learn this preamble:

“The theoretical basis of the experiment: Based on the human assisted reproductive technology, with the core of the CRISPR / Cas9 gene editing technology, gene editing of the CCR5 gene in the embryo would knock out the CCR5 gene. It would help these CCR5 gene editing babies to obtain the genotype of the Northern European to naturally immunize against HIV-1 virus;

Method:
Based on the human assisted reproductive technology, early embryos were injected
with trace amounts of Cas9 RNP after intracytoplasmic sperm injection (ICSI) during normal IVF treatment. Cas9 RNP (Cas9 protein and optimized optical sgRNA) can act on the CCR5 gene, so as to prevent the newborn from the AIDS by editing the CCR5 gene and hindering the HIV-1 virus from invading the (CD4+) T cell. With the help of  Preimplantation Genetic Screening or preimplantation genetic diagnosis (PGS / PGD), high-throughput whole genome sequencing, early pregnancy screening and other rigorous techniques could reduce the probability of birth defects, deformed children, etc., and decrease the risk of off-target issues and other risks. This technique
may be able to produce IVF baby naturally immunized against AIDS (Referred to as baby) [SeeAnnex I: Technical Procedure Flow Chart]

2. Technical Objectives: The main objective of this project is to produce infants who have the ability to immunize against HIV-1 virus.

The document contains this section on “Possible risks and precautions” for the participants:

1. With the existing knowledge, the additional operations proposed in this project will not put the mother at risk of contracting HIV and other infectious diseases. In case of any disputes over rights and obligations during the project period between you and the medical institution, the contract signed shall prevail, and the project team is not responsible for this.
2. In order to ensure normal embryo development, in vitro fertilization and incubation phase injection of trace substancesis at the trace amount (pg level, that is 10(-10) – 10(-12) g). It does not guarantee that gene editing will play its role. It is normal if the infants do not have the capacity of natural Immunity to AIDS. The project team does not assume legal responsibility in this situation.
3. The primary risk of gene editing (DNA-targeted CRISPR-Cas9 endonuclease) is the off-
target effect of generating extra DNA mutations at sites other than the intended target.
This is due to that the technique can cause nonspecific cleavage, resulting in mutations in non-targeted genomic sites. PGD, whole genome -wide sequencing, amniocentesis
and peripheral blood test of mothers in different stages of pregnancy after transplantation will minimize the possibility of substantial injury. Therefore, this project team is not responsible for the risk of off-target which is beyondthe risk consequences of the existing medical science and technology.
4. Since the male volunteer in this project are infectious patients, even though the use of IVF as a means of pregnancy has the least possibility of transmission of the virus to the
mother or the baby , it cannot completely remove the risk of infection. The risk is Not caused by this project, and this project team will not take responsibility.

It is now even more peculiar that He hides Grace and her newborn twins Lulu and Nana, because he actually should have all the rights to parade their photos and data on YouTube or international TV:

Rights of the project team
1. After birth, the project team or the medical institution should preserve the umbilical cord blood for later use. After the baby is born, it needs to cooperate with the project team or the medical institution to conduct a series of routine tests. For details, see Appendix 5: Post-natal Maternal and Infant Test Project
2. Baby’s photo on the day of birth will be kept by the project team. The project team has the portrait right of the infant and can make it open to the public. [See Attachment VI: Portrait License for Use]
3. The baby’s blood samples need to be disclosed to the public. If parents are willing to disclose their portrait and name, their wishes prevail.
4. Regarding the project results, only the project team has the right of final explanation and announcement to the public. The volunteers have no right to explain, publish, or announce project related information without permission.

Update 28.11.2018. A transcript of He’s talk and the following discussion from yesterday at Human Genome Editing Summit was published by Bryan Bishop.

We also learn that another senior figure at Harvard, the Dean of Harvard Medical School George Q Daley is very enthusiastic about human embryo editing.

At the conference, He doubled down and announced there is another CRISPRed baby on the way.

It seems however he won’t be giving another talk at the Hong Kong Summit and was commandeered to return to Shenzhen

Update 30.11.2018

Chinese news CCTV announced in Jiankui He’s case: “suspension of related personnel science and technology activities“:

“The Ministry of Science and Technology has requested the relevant units to suspend the scientific and technological activities of the relevant personnel. The next step of the Ministry of Science and Technology will, on the basis of comprehensive and objective investigations, be investigated and dealt with in accordance with the law”.

Update 4.12.2018

Chinese media report (backup here) how Jiankui He recruited his participants: he either never mentioned any risks, or promised to “get rid of” any defects the baby might be born with. This is the experience of one participant who chose to opt out:

“32-year-old Zheng (a pseudonym) chose to opt out before signing the consent form. […] But the doctor did not tell him specifically what the experimental method was about, he also recently learned that a technique was known as “gene-editing.”

Zheng said he remembered asking Dr. Zeng Wen, will the experiment not be risky? Can you help him to a healthy baby? The doctor told him that the baby is unlikely to be unhealthy, the probability is very low. He told Zheng, technology was tested on animals, with a high success rate; laboratory can also run a series of tests to ensure the baby’s health, at the fertilized egg stage and embryo selection period, “you can select the best baby”, and they will continue with physical examination of the woman, will buy insurance for their children after birth, provide a long follow-up observation. Zheng did kept asking: “What if do you do if unhealthy babies are born?” The doctor said: “Do not worry, if there is a problem with bad health, we’ll help you get rid of it”

It is not clear how that was meant.

 

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