Last night I watched “Make People Better”, a documentary about He Jiankui’s gene-edited babies. It was a decent documentary (if a bit overdramatized, with lots of generic footage of labs and Chinese streets). Although it did a pretty good job summarizing the story for a non-technical audience, it didn’t present any significant information that wasn’t present in other sources. I would recommend watching it, but only if you’re not already familiar with the He Jiankui affair.
Basics of the story
He Jiankui (known as JK) was an associate professor at SUSTech, a university in Shenzhen, China. Working secretly, JK and his research collaborators in China used CRISPR/Cas9 to disable the CCR5 gene in human embryos. The embryos came from couples where the mother was HIV-negative and the father was HIV-positive, and the goal of disabling CCR5 was to make the children HIV-resistant. The embryos were implanted into at least one mother, who gave birth to gene-edited twins in October 2018.
JK wanted to publish the results in Nature, but Nature required that human experiments be registered as a clinical trial, which JK had not yet done. When JK registered his experiments in the Chinese clinical trial database, Antonio Regalado (a reporter at MIT Technology Review) saw this and broke the news before JK was ready to publicize it. This was shortly before Second International Summit on Human Genome Editing, a conference in Hong Kong at which JK gave a presentation describing his work.
At this conference, JK was denounced by the academic community, who criticized his experiments as rushed, sloppy, and without a strong medical justification. Before the conference, the Chinese government had briefly lauded his work as a “historic breakthrough” but switched to condemning him after criticism grew stronger. After JK gave his presentation, he was escorted out of the conference by security agents and placed under arrest. He was eventually sentenced to 3 years in prison for falsifying ethical review documents.
Notes from the movie
The movie draws an interesting parallel between this story, and the story of Patrick Steptoe and Robert Edwards, pioneers of IVF. In 1977 they acted unilaterally to do the first human IVF, which at the time had no regulatory oversight and was highly controversial. But in 2010, Edwards was awarded the Nobel Prize for their achievement. This story might have inspired JK to act similarly.
However, given that the movie was clearly intended for a non-technical audience, I wish they would have had more explanation of how CRISPR editing actually works, and why JK’s method (NHEJ-mediated knockout of CCR5) was sloppy and low-effort. In my opinion, this choice of method clearly shows that JK was just trying to be first, and didn’t care much about medical benefit. For protecting against HIV transmission, there are much better ways than gene editing.
The movie also compares JK’s story to the case of Jesse Gelsinger, a patient who died in 1999 after receiving a high dose of an adenoviral gene therapy vector. Gelsinger’s death set back the field of gene therapy by about 15 years due to the controversy it caused. JK’s actions are now causing a similar chilling effect on human germline editing.
The movie emphasizes that although JK was first to gene-edit humans, he had supporters in the academic community, and likely within the Chinese government. For example, the title of the movie, “Make People Better”, comes from James Watson’s response when JK asked him what germline editing should be used for. However, these people dropped their support once the negative public reaction became clear.
Given that JK is now out of prison, I wish they had more information on what he is currently doing. But I suspect that he is not allowed to talk about this.
My thoughts on the affair
Personally I believe that human germline editing can indeed “make people better”, and should be used for this purpose when it is proven safe and effective. JK believed this too, but his arrogance has ended up setting the field back by years.
There are two main lessons from this story:
People who support something in private may disown it publicly if it causes too much controversy.
Secret unilateral action to advance a controversial area of research can backfire due to negative public reaction. This is especially true if the action is rushed and sloppy. It might have been better for JK to not hide his project. Although it still would have caused a lot of controversy, the total amount would likely have been lower, and he wouldn’t have ended up in prison.
And weird sound effects for cells dividing, which had me breaking out in laughter.
I watched large parts of it on 2x speed, especially the interviews with George Church and Ryan Ferrell. Note: the documentary withholds Ryan’s full name but it’s present in other sources.
Steptoe had already died and was thus ineligible.
Basically, this method cut the DNA of the CCR5 gene, and left it up to the cell to put it back together. The cellular repair mechanism (non-homologous end joining) will randomly add or delete a few bases around the cut site, which has a good chance of disabling the gene. However, it doesn’t always work, and due to how early embryos develop, it can end up editing some of the cells but not others (this is what happened).
What JK should have done is as follows: first, pick a more medically useful target than CCR5 (perhaps PCSK9). Second, edit human stem cells to disable this gene. Editing stem cells would allow for verifying the edit before making an embryo with the edit. After the edit is confirmed, transfer the nucleus of an edited stem cell into a human egg cell, and then implant the resulting embryo.
However, nuclear transfer is more difficult than CRISPR microinjection, so JK chose the easier option.
I wouldn't be so quick to judge JK on his choice of method. Stem cell nuclear transfer is obviously superior, but parents want a child that results from their gametes (necessitating the use of embryonic stem cells for the modification), and the retention of correct imprinting in cultured ESCs wasn't solved until a few years later. How big of an issue that imprinting would be in humans isn't known, but I wouldn't want to be the one to find out. Not to mention that, if He went the adult stem cell route instead, the baby being a clone might've been even bigger news.
His choice to do it in the first place was misguided, certainly, due to the questionable gene target (given modern medicine), the risks of off-target and mosaic mutations inherent to CRISPR microinjection, and the amount of blowback it caused for the field.