What Was He Jiankui, the Brain Behind CRISPR Babies, Thinking?

On the eve of the Second International Summit on Human Genome Editing in Hong Kong last week, researchers were stunned to learn from a carefully orchestrated media campaign that He Jiankui, PhD, had performed genetic germ cell editing on a human embryo, which was artificially inserted into a woman and allowed to come to full term. A set of twins was born, one of which was born with a genetically engineered mutation of the CCR5 gene, known to facilitate HIV virus to enter white blood cells. By inactivating the gene, HIV infection could be prevented.

He Jiankui’s Rationale

At least 2 trials in adults are in progress looking at the same mutation, but these mutations are being induced in somatic cells of adults infected with HIV, with no ability to pass along the mutation to potential offspring. This was the first experiment where an embryo in the early stages was altered in a way that will affect sperm and eggs, thus allowing the altered genetic code to be passed to all future generations with unknown consequences. It was obviously a huge step forward in technology—one that is fraught with controversy.While presenting his data in limited form at the conference, He Jiankui defended his work.

In the 15-minute presentation, he outlined the rationale for performing the procedure, stating that the mutation induced in the CCR5 gene would prevent children born with the mutation from getting HIV infection. In this case, the father was known to be HIV positive and the mother HIV negative. He acknowledged the likelihood that children born to an HIV-negative mother and HIV-positive father will be infected is actually very low, but said he was hoping to prevent any future HIV infections, citing the ongoing trials in humans that have shown some success in preventing infection. He also noted that HIV therapy, while highly effective, is not available to a large segment of the population.

He reported altering the fetuses in 6 couples, but only one pregnancy has been brought to full term. Such work is banned by law in the United States, but the legality in China is uncertain. Nonetheless, many ethical questions were raised by the scientific community.

In response, Anthony Fauci, MD, NIAID director and an HIV researcher, said, “There are so many ways to definitively protect yourself against HIV that the thought of editing the genes of an embryo to get an effect that you could easily do in other ways in my mind is unethical.”

How Did We Get Here?

Moreover, Pablo Tebas, MD, a researcher from University of Pennsylvania who conducted a set of experiments that crippled CCR5 in HIV-infected humans, claimed that “the experiment is not medically justified, since mutations in CCR5 make people much more susceptible to serious consequences from West Nile infections.”He Jiankui used CRISPR—Cas9 technology—to genetically alter human germ cells, which were later artificially implanted and were carried to full term. A set of twins named Nana and Lulu are apparently healthy and show no signs of any ill effects, according to He.

He shared data of mice where a CCR5 knockout mutation was performed and demonstrated a very high success rate and a limited number of off-target mutations. He bred the mice for 3 generations and showed that tissue samples taken from the mice showed completely normal anatomy.

CRISPR-Cas9 is an exciting gene-editing technology that was developed by scientists at Berkeley and MIT in 2012 that has been used extensively in animals and nonviable human fetuses to alter the genetic code in an effort to prevent diseases like cystic fibrosis, muscular dystrophy, and sickle cell anemia. CRISPR and CRISPR-Cas9 genes were discovered first in E Coli, and then streptococcal bacteria, which used them to render their immunity to viral infection.

Scientists used the bacterial model to develop CRISPR-Cas9 systems in the laboratory to perform gene editing. The system has 2 key components to perform targeted genetic mutations. Cas9 is an enzyme that promotes the cutting of double stranded DNA to allow insertions or deletions of short DNA segments. The second component is a specific predesigned RNA sequence that serves as a guide to insure the cas9 cuts the DNA strand at the precise place to allow the DNA insertion.

The organism recognizes that its DNA is damaged and attempts to repair it. At this stage, DNA segments can be inserted to permanently alter the genome of the host. In the case of bacteria, the genetic alteration confers permanent immunity to future viral infection. This genetic mutation can be copied and passed to the next generation. The technology has been extensively studied and applied to animal cells in an effort to protect them from unwanted DNA mutations.

Scientific Backlash

If applied to germ cells, the altered genetic code is passed along to future generations of animals born to the animal whose genome was altered. He was able to demonstrate a minimum of off-target mutations and none that were considered significant. No one previously had ever attempted to do this type of work in viable human fetuses.There is consensus among genetic scientists that this work should not be done, for ethical reasons, until more is known about the outcomes. He Jiankui self-funded his experiment, keeping it secret from the university he worked for and from the scientific community at large. He claims to have recruited patients who wanted to be protected against AIDS and stated that he was quite clear in disclosing what the experiment could and could not do. He states that he went to great pains to develop a consent document that he said was peer-reviewed by 4 other scientists. He went on to state that the parents were informed, highly educated, and understood completely what they were consenting to.

There was a great deal of discussion and questions during the conference, much of it directed toward He’s assertion that he had a sound consent agreement that was completely understood by the patients. There were some discrepancies: He stated that his work was sanctioned by his university, when in fact, it wasn’t. He also told the parents that he was working on an AIDS vaccine, and not a genetic mutation to prevent acquiring HIV infection. There are several other questions about his research that could not be answered because his presentation was brief and lacked detail. He stated that a more detailed version of his study will be or has been submitted to a peer-reviewed journal, but this remains to be seen.

He Jiankui considers himself a pioneer and says his work was a great scientific advancement. He stated he intends to follow the twins throughout their lifetimes and would be responsible for any untoward effects that occur as result of his experiments. Despite those statements, He was widely rebuked by the scientific community for proceeding with this experiment in a nontransparent fashion, without proper discussion, without other scientists, and with complete disregard to the consensus statements of all the major genetic engineering communities.

Not Without Precedent

On the other hand, some scientists were not completely negative about the use of this technology. Harvard Medical School Dean George Daley took a more measured approach, stating that this misstep should not deter future developments in genetic engineering. Most scientists, including Jennifer Douda of the University of California Berkeley and one of the founders CRISPR therapy, was quite adamant in stating that this type of work reinforces the urgent need to confine the use of gene editing and human embryos to settings where a clear unmet medical need exists and where no other medical approach is a viable option, as recommended by the National Academy of Science.Throughout history many scientists have taken a less than ethical approach to achieving knowledge in the name of science. In 1918, famed Canadian-American neurosurgeon Wilder Penfield, MD, pioneered an operation that removed the tops of skulls of patients without anesthesia, in an effort to study epilepsy. In so doing, he was able to map out the architecture of the brain. Today, using prisoners—willing or otherwise—who were kept awake while the tops of their skulls were removed in order to probe the brain would, without question, be unethical.

William Beaumont is known by many as the father of gastric medicine, but he took an ethically damnable route to get there. In 1822, he performed operations on Alexis Saint Martin following a gunshot that left his stomach open. Over several years, Beaumont experimented with Saint Martin’s stomach, inserting and removing food into the hole in his abdomen and extracting samples of gastric acid for analysis. At one point, Saint Martin ran away and moved to Canada, but Beaumont made his way to Canada and continued to study Saint Martin over the course several more years. From these clearly unethical operations, he learned a great deal about how the stomach digests food.

Perhaps the most infamous example occurred during World War II, when German scientists performed operations on unwilling patients in an effort to learn more about the physiology and function of human beings. Breakthroughs in understanding of diseases occurred, but they came without consent and at the price of unimaginable human suffering.

Will history remember the work of He as being “reckless because of the terrible risk benefit ratio,” as stated by Hank Greely of Stanford University, or “monstrous,” “unconscionable,” and “premature,” as stated by a group of 122 Chinese genetic scientists? Or will history remember He as a great scientist who spurred meaningful advancements in science and medicine? He, for his part, stated “we believe ethics are on our side of history,” and concluded his remarks at the conference by stating that he had reflected deeply on how to help families facing genetic disease before he undertook his experiments.

He Jiankui has no regrets. Will we?

Simon Murray, MD, is an internist based in Princeton, NJ. The piece reflects his views, not necessarily those of the publication.Healthcare professionals and researchers interested in responding to this piece or contributing to MD Magazine® can reach the editorial staff here.