The Consultation

In 2017, He Jiankui a credentialed scientist with a PhD in Biophysics and no medical licence or ethics training recruited eight couples through an AIDS advocacy group in China, to take part in a medical study.  He was expressly looking for couples who had suffered from the stigma of having HIV, and who wanted to spare their children that same fate.  He encouraged them to take part in an experiment that he framed as an “AIDs vaccine research program” but what it really was, was a genetic engineering experiment on human embryos.  The couples who were desperate to have healthy children, thought He Jiankui’s offer was in their best interests and most signed up to the clinical trial.

He Jiankui’s plan was radical.  He wanted to be the first person in the world to bring genetically engineered human embryos to term.  The techniques to alter the genetic material of living cells via genetic engineering have been around since the 1970s, but human applications had remained limited due to concerns about safety and efficacy.  It is important to note, that scientists first used CRISPR (a genome editing tool) to genetically engineer human embryos in April 2015, when Junjiu Huang's team at Sun Yat-Sen University in Guangzhou edited non-viable embryos in a lab dish.

He Jiankui was planning to go further.  First he wanted to use IVF (in Vitro Fertilisation) to fertilise an egg with a sperm cell in the laboratory.  Then he planned to introduce CRISPR Cas9 (think of this as molecular scissors) to make a cut in part of the zygote’s DNA.  Specifically, he was aiming to cut the CCR5 gene and disable it, so it could no longer code for the CCR5 protein.  This is a protein best known for being a receptor on white blood cells (HIV uses it to enter cells), but the CCR5 protein is also expressed across a range of non-immune tissues, like the brain. The scientist wanted to knock out this protein in the immune cells, so the HIV virus could no longer infect these cells.  But to edit at the zygote stage would mean every cell in the baby would be affected once cell division starts. You can think of it like this; every cell in your body traces back to a single fertilised egg (the zygote), and each time that cell divides via mitosis, it first replicates its entire DNA and passes an identical copy to each new "daughter" cell. This process repeats through every division as the embryo grows into a baby and beyond, meaning the DNA you have as an adult is essentially the same set of instructions present in that very first cell.

Even though the CCR5 protein would then be missing from the white blood cells which the scientist wanted to target, the protein would also be missing in the brain where it is also important and serves a different function.  This is one of the key risks He Jiankui did not disclose to the parents — disabling CCR5 is not a targeted intervention that only affects HIV entry. It has potential consequences for brain development, immune surveillance against other pathogens (West Nile virus, influenza), vascular inflammation, and pain processing, because the protein is active in all of these tissues too. He then planned to implant the 5-6 day old embryo post fertilisation back into the mother at the blastocyst stage —when the embryo was a ball of about 100-200 cells.  The baby would then grow naturally in the mother’s womb till it was time to be born.

Rather than inform the participants adequately of the risks and alternatives, He Jiankui deliberately withheld information so that the couples would agree to be part of his research.  He did not tell them that they could have conceived naturally without any risk of passing on the virus (All the men in the study were already on antiretroviral medication which would have suppressed their viral load).  He did not tell them that knocking out the CCR5 gene might lead to partially functional or altered CCR5 protein with unpredictable effects.  He did not tell them that the CCR5 gene is not simply an HIV doorway; the protein is involved in immune function, brain development, and inflammatory responses, and disabling it carries known risks.  He only told them in simple terms that the editing could produce off target affects in other parts of the DNA, but he did not mention potential consequences like cancer or other serious diseases later in life. Of the eight couples recruited, seven ended up signing consents and participating.  Five embryos were implanted, two couples became pregnant, both came to term, resulting in a total of three gene edited babies eventually being born.

The following year in November 2018, the scientist announced to the world, that he had genetically engineered twin girls with HIV immunity.  Up until the announcement, the clinical project had been conducted secretly - He concealed it from his university, from regulators, and from the public.  His experiment did not have ethics approval.  Instead, He gave himself his own green light, by forging formal documents from an ethics review panel, complete with fake signatures and stamps, so that it looked like his clinical trial had been vetted and authorised.  He used the forged paperwork to assure prospective couples and local medical practitioners that the experiment was sanctioned by major institutions, including the Shenzhen Harubino Hospital—which later vigorously denied ever holding an ethics committee meeting for his project.

While the gene editing — the microinjection of CRISPR-Cas9 and guide RNA into newly fertilised eggs — was done by He's own team members, He Jiankui needed to secure the help of doctors and embryologists to perform the embryo implantations.  He did not tell these people that the human embryos had undergone CRISPR-Cas9 genome editing, so the clinical staff believed they were performing normal, unedited fertility treatments.  He also used healthy stand ins to take mandatory blood tests prior to IVF to fool the doctors and clear the couples for IVF.  This was because Chinese regulations explicitly banned couples with an HIV-positive partner from receiving assisted reproductive technologies (IVF).

When He Jiankui made his experiment public in November 2018, by posting videos on YouTube telling the world that two genetically engineered girls had been born with HIV immunity, other scientists demanded to see proof.  So He Jiankui presented slides and data at an international scientific summit in Hong Kong.  At this time, under close scrutiny more disturbing information came out.

He Jiankui had announced that ‘no gene was changed except the one to prevent HIV’. But when independent scientists reviewed his slides, they spotted an ‘off target’ mutation – meaning CRISPR had accidentally cut and altered DNA in a completely different part of the genome that he hadn’t intended to touch.  He Jiankui had also told the media that he had successfully ‘turned off’ the genetic doorway to HIV.  But the data showed only one of the twins had both copies of the CCR5 gene edited (and even then it was done incorrectly and unevenly).  The other twin only had one copy of the gene changed, meaning she had no biological immunity to HIV at all. 

Scientists also found out that the editing was not uniform — different cells had different edits — which is the hallmark of mosaicism.  This is because when CRISPR is injected into a one-cell zygote, the cut is not instantaneous. There is a delay between injection and the actual DNA cutting. CRISPR-Cas9 did not finish all its cutting before the zygote divided. The Cas9 enzyme remained active as the embryo went through its first, second, and possibly subsequent divisions, cutting DNA at different times in different cells. Each cut, repaired independently by the cell's NHEJ (repair) machinery, produced a different mutation. The result is that the twins are now genetic patchworks — different cells in their bodies carry different versions of the CCR5 gene, and some cells may carry no edit at all.

An official Chinese government investigation followed and He Jiankui was taken to court. 

The Chinese court ruled that He Jiankui's intricate network of lies constituted the illegal practice of medicine. By using forged papers and switched blood samples, he tricked medical personnel into committing what they thought were legal procedures, crossing the line of scientific research and medical ethics. He was sentenced to three years in prison and was fined US$434,000.

The He Jiankui affair triggered a substantial overhaul of China’s legal framework for human gene editing, since at the time of his 2018 experiment there was no actual law directly banning germline editing.  That gap is why He was ultimately convicted only of “illegal medical practice” rather than a gene-editing-specific offence.

Closer to home, I spoke to Professor Jack Heinemann, a Professor of Genetics at the University of Canterbury, New Zealand, with decades of experience in genetic engineering and biosafety. I was curious to get his opinion on the technological advances in genetic engineering and overall safety.  Bearing in mind that human germline editing is illegal, but other forms of genetic engineering are continually progressing and becoming more efficient, why did Professor Heinemann still have safety concerns about the technology?

He noted that with each new genome editing tool, whether CRISPR Cas9 (which was used by He Jiankui and causes a double strand break in the DNA) or newer base editing systems (which chemically converts one DNA base into another without breaking the DNA backbone) the effect of how accurately they bind to just the target DNA, is not 100% precise. 

“Precision implies that the tool makes changes ONLY where you want it to. That is misleading. These tools have no inherent self-discipline! The same features that make them good at making intended changes also make them pretty good at making unintended changes too. There is no way to prevent this from happening.”

As I found out to my great surprise, Genome editing tools are never 100% precise, and the root cause is that they operate through analog biochemical processes governed by thermodynamics and probability. No genome editing tool — CRISPR-Cas9, base editors, ZFNs, TALENs, or prime editors — achieves zero off-target effects.

So why is "analog" the right word to describe this system?

In a digital system, a match is binary — either identical or not. A computer comparing two strings of 20 characters returns a simple yes or no. But CRISPR-Cas9 doesn't "read" DNA like a computer. It binds to DNA, and binding is a thermodynamic process — it depends on the free energy of the interaction between the guide RNA (gRNA) and the DNA target. This energy exists on a continuous (analog) spectrum, not a binary one.

The key insight is that the binding energy that holds the gRNA-DNA complex together doesn't require a perfect 20-out-of-20 match. A partial match — say 17 out of 20 bases complementary — still generates enough binding energy for the complex to stay together long enough for Cas9 to cut.

Professor Heinemann acknowledged, “As much as genetic engineering is still controversial today; 25, 50 years ago, it was even more controversial. So it's become less so.”  This is because genetic modification of bacteria, plants and animals has become routine in modern laboratories. CRISPR-Cas9, since its adaptation for genome editing in 2012-2013, has become what the scientific literature describes as "the most widely used genome editing technology in molecular biology laboratories all around the world".

By genetically modifying bacteria scientists can develop new drugs, biofuels, bioplastics, and agricultural products. Synthetic biology — which involves designing entirely new genetic circuits and metabolic pathways in bacteria and yeast — is now a well-established field with companies, academic departments, and standardised toolkits. CRISPR is used routinely to knock out genes, insert new pathways, and optimise microbial production of everything from medicines to industrial enzymes.

CRISPR gene editing in plants has become standard practice in agricultural research worldwide. CRISPR-Cas9 has been applied to major crops including rice, soybean, oilseed rape, wheat, and maize. The technology is used to enhance disease resistance, improve yield, increase nutritional content, and create climate-resilient crop varieties.

Genetic modification of animals is routine in research laboratories, particularly for creating disease models and studying gene function. While not "animals" in the traditional sense, genetic modification of human cells has also become routine in the laboratory.  As of 2023, CRISPR-based therapies have entered human clinical trials, including ex vivo editing of T-cells for cancer immunotherapy and treatments for sickle cell disease and beta-thalassemia. (Ex vivo editing of T-cells means taking a patient's T cells out of their body, changing their genes in a lab using tools like CRISPR growing millions of them, and putting them back into the patient to fight diseases like cancer).

What remains controversial and heavily regulated is the commercial release of genetically modified organisms into the environment (particularly crops and livestock), and the modification of human embryos — which, as the He Jiankui case demonstrated, was widely condemned.

Professor Heinemann spoke about how there is a misconception that genetic engineering is ‘just like nature, but faster.’  I found this interesting and asked him, why genetic engineering is ‘not just like nature.’  He replied, “This technology is not the same thing as nature, even if the mutations have an analog in nature…  What makes gene editing unnatural is that people can make certain outcomes arise at frequencies that would be impossible even if the Earth were 20 billion years old. This allows combinations of changes and the production of a biologically relevant population of “clones” that do not happen in nature, and harms that almost would never arise in nature.”

In the context of He Jiankui, he was not accelerating nature, he was:

·      Using a bacterial immune enzyme to cut human embryo DNA (a mechanism that doesn't occur in nature).

·      Trying to reproduce a natural mutation (CCR5-delta32) but producing novel, previously unstudied mutations instead.

·      Bypassing thousands of years of natural selection that would have filtered the mutation in a real population. In nature, any mutation must "prove itself" against changing environments, competing pathogens, famines, migrations, and countless other variables across hundreds or thousands of years. This doesn't happen when you genetically engineer a change.

·      Introducing the edit into a genetic background (Chinese) that had no co-evolutionary history with CCR5 disruption.

·      Creating off-target mutations that are artefacts of the technology, not natural variation.

·      Producing mosaicism that is a technological artefact, not a natural phenomenon.

·      Making changes that will be heritable across all future generations without any environmental testing.

When we talked about the He Jiankui scandal of 2018, Professor Heinemann commented, “We are fundamentally still a species frozen in the concept of genetic determinism.  The problem with (genetic engineering) is that it will start with trying to fix those who can't be fixed any other way, and it will use the most vulnerable minority groups first.  Those who have congenital conditions for which we have been intolerant to make other kinds of changes as a society. We will look to change them through their genes.  And then, it will grow to being, if you're poor, it's the fault of your genes. If you can't do well at university, that's the fault of your genes. And it's not the fault of us not being able to adjust and teach appropriately for an evolving human cultural society. It's not our fault for not being able to build wheelchair ramps. It's your fault for needing these things.”

After He Jiankui announced he had delivered genetically engineered babies to the world in 2018, the question arises what has happened to these babies.  Are the children growing up well and are they safe?  Scientists can only speculate.  Some of the risks facing the children could include; they may have increased susceptibility to other infections like the West Nile virus and influenza (without the CCR5 protein the immune response is impaired), they have off-target mutations which could cause the development of cancer later in life, the mosaicism the children have might lead to unpredictable organ system failures, they might have neurological effects (since CCR5 is expressed on neurons, astrocytes and other brain cells – not just immune cells, a lack of this protein could affect learning), and beyond all the medical risks, the children face unique psychological burdens - knowing they are being watched for signs of something going wrong — could impose significant psychological stress as they grow up and eventually learn the full story of what was done to them.

The children have been placed under a long term medical monitoring protocol, however because of the immense global scrutiny and the illegal nature of the experiment, their specific health data has become a tightly guarded state secret. The only available information regarding their health comes from two conflicting sources; the claims of the researcher and the scientific community. Following his release from prison, the researcher, He Jiankui, stated in interviews that the three children are "perfectly healthy and have no problems with their growth". He claimed that his team sequenced their entire genomes and found no unintended modifications outside of his original medical objective. Independent scientists and international bioethicists heavily distrust these claims.  Ultimately, while the public is told the children are developing normally, the true status of their health remains completely unknown to the international scientific community

Trying to improve the genetic quality of a human population, typically by encouraging reproduction among people with traits deemed desirable and discouraging or preventing reproduction among those with traits deemed undesirable, is what we know as ‘Eugenics.’ Professor Heinemann spoke to me about the history of eugenics and how it was born in the UK.  I was surprised by this because I thought it had started in Germany under Hitler.  But Professor Heinemann pointed out, “The practitioners of eugenics were the UK, Canada, and the United States. Who then, through their laws and their research in eugenics fuelled the German campaign, which became hugely radicalised under what was later to become the National Socialists, the Nazis. Hitler relied on U.S. research to justify his campaigns to purify the race.  The U.S even into the 1970s, had sterilization laws that were based on the eugenic era; that there are some people who shouldn't breed.  The term eugenics was coined by Sir Francis Galton (Charles Darwin's cousin), who in the late 19th century was a statistician.  He coined the term and thought that he could use a statistical approach to improve the human breeding stock. That was ultimately picked up and turned into legislation in the various Western countries and became a type of white supremacist approach.”

“The kinds of traits that were most desirable were blue eyes and blonde hair. But you have really famous Supreme Court decisions where, they were starting to sterilise immigrants, mainly from Eastern Europe, because Eastern Europe was full of ‘undesirable genetic types’ that led them to sexual deviation, they were less intelligent, and they were criminals. The simplification of human phenotypes of that nature to some kind of gene, we know as geneticists, is absurd. But, nevertheless, you now have political movements and real harm done to people based on who gets to choose what traits are desirable. That is still happening today. You have IVF. You have pre-implantation embryo screening. And depending on where you live you can screen for all sorts of things, including things like eye colour and height.”

Human gene-editing trials are growing rapidly in number in today's climate, and a genuine strategic competition between the US and China has emerged. To be clear, this is in terms of treating disease via therapeutic (somatic) gene editing, not germline editing which is off-limits since the 2018 He Jiankui scandal.  This race can lead to casualties if safety monitoring is lax, and trial designs are vetted too easily. 

Sadly, just days after I talked to Professor Heinemann, RNZ News reported on the death of a girl in a Chinese gene editing trial.  The report mentioned the death had been kept secret until recently.  The girl had “died a week after receiving a spinal infusion of trillions of viruses last March designed to penetrate the brain and fix a rare genetic condition that caused her mild cognitive impairment. But her parents, who paid more than $800,000 to fund the experiment, were not adequately informed about the risks…  The trial was led by neuroscientist Zilong Qiu, one of several researchers globally racing to turn base editors – a more precise form of the CRISPR gene editor – into custom treatments for children with rare genetic conditions.”  The report also mentioned that, “With the girl’s treatment, Qiu was aiming for the world's first ever gene-editing therapy directed at the brain, rewriting the mutated gene in her neurons so she could make a vital protein.  Instead, she died a week later from a severe immune reaction.  Seven experts who reviewed the details said Qiu and his team downplayed the trial's risks and went ahead despite low odds of success.”

Professor Heinemann summed up the problem well when he said, “We have a culture of science and that culture has the same kind of demographics as any other aspect of society. It has powerful, corrupt, conflicted, and selfless people. And sometimes all of those are in the same person expressed under different circumstances. So, my point is that science isn't scientists. Scientists are people.  And they're flawed. And the science system that scientists make is just as flawed as any other political, social system. All we can do, though, is hope that we promote such tools like academic freedom to allow people to disagree, to say sometimes that they think that's wrong, and to do so with some kind of authority to say that it's wrong, so that those who are conflicted or corrupt don't just have the microphone all the time.”

See you in the next post!