My Letter to Lulu and Nana, the world’s First CRISPR Gene Edited Babies
Dear Lulu and Nana,
Welcome to the world, very special girls!!!
You are very special, not because of your DNA, but simply because you are human. While you will (likely) hold the distinction of being the world’s first CRISPR gene edited children, it is your humanity that makes your arrival worthy of praise, love, dignity, and celebration. There is nothing particularly special or unchangeable about our human DNA. We share thousands of base pairs of sequence with the oldest known bacteria. Your genome has by now been shuffled around countless times; that little CRISPR’d piece is an insignificant drop in a bucket of genetic change that started with the homologous recombination in your parent’s egg and sperm, to the mutations that you acquired as you grew in your mother’s womb due to her diet and her environmental exposure, to the viruses that have you have already encountered, and the vaccines you have probably received.
You may know by the time you can read these letters, that your arrival caused waves of concern all across the world. Were your parents lied to? Were they consented properly for the treatment? Will the scientists who helped create you be punished? How will that knowledge (that you were potentially conceived in deceit and someone “disappeared”) affect you when you are a teenager? Will you grow up as normal girls, or will there be negative, and unforeseen consequences to your gene surgery…but probably more likely from your un-asked-for celebrity?
Humans have been tinkering with the genetics of crops, animals, and yes, even human babies (so called 3 person IVF, or mitochondrial replacement) for many years- albeit never with the precision and targeting of the bespoke CRISPR/Cas(n) systems.
Human assisted reproduction is a consumer driven process. It is not standard in the industry to wait for clinical trials to prove the safety and efficacy of treatments; for example, ICSI, ooplasm transfusion, embryo biopsy followed by pre-implantation genetic testing, and sperm selection (to name just a few) were essentially translated directly from the research laboratory to clinical practice without undergoing randomized clinical trials (RCT), the gold standard of medicine. “Gene surgery” may not be viewed as another IVF procedure now, but undoubtedly it will be in the future.
The flaws in this work have been enumerated: inadequate medical indication, a poorly designed study protocol, a failure to meet ethical standards for protecting the welfare of research subjects, and a lack of transparency in the development, review, and conduct of the clinical procedures. These may be flaws, but certainly many other reproductive techniques escaped this level of scrutiny by simply skipping the clinical trial step altogether.
Many lines of evidence suggest that children conceived through assisted reproduction suffer from a variety of poor perinatal outcomes, birth defects, cardiovascular effects, and epigenetic disorders and cancers. We have barely scratched the surface of our knowledge of the epigenome, and yet, we forge ahead. We allow the use of ART by anyone who can afford it for any reason at all; including, such eyebrow raising reasons as “family balancing” — i.e. gender selection. Surely, the prevention of the transmission of HIV is as worthwhile a cause?
The public seems to be demanding that every single thing be “known” about CRISPR science and the genome before proceeding with treatments. This is a standard that is not applied to other medical specialties.
The genome is so complex that we won’t be able to fully understand it for hundreds of years. We can’t wait that long to use technology that can save tens of millions of lives, and provide dramatically better quality of life to hundreds of millions.
Another point of contention with the work that lead to you, Lulu and Nana, is the remote possibility of unknown off-target effects. However, a very elegant approach demonstrating no off-target effects has already been developed in human embryos. There is no evidence for off-target caused pathogenic outcomes from any CRISPR study, including in mice and pigs with large numbers (up to 40) of CRISPR sites. I am positive that Dr. He screened all of the CRISPRd embryos for large off-target effects before replacing them. The hysteria and hand wringing about off-target effects is absurd. We know now more about CRISPR (as evidenced by the sheer volume of publications) then many other treatments. There are billions of off-target effect “possibilities,” but it may not even be possible to understand the genome fully, ever. It is time to start outlining an actual pathway for clinical translation of CRISPR/Cas9 and stop with the histrionics.
Is FDA has said that CRISPR is safe enough to start clinical trials with, the FDA HAS approved several CRISPR clinical trails and even a recent IND. It makes sense that CRISPR systems should be safe: they come from bacteria that humans are exposed to all day everyday and that we make antibodies against, with no detrimental effects. The CRISPR components are at work inside both you AND ME, right now.
Editas is expected to enroll 10 to 20 patients with the IVS26 mutation in a Phase I/II open-label, dose escalation study to evaluate the safety, tolerability, and efficacy of EDIT-101.
CRISPR Therapeutics and Vertex Pharmaceuticals say they plan to start a Phase 1/2 study in the U.S. and Europe by the end of 2018 for sickle cell anemia.
Many are critiquing the choice of CCR5, claiming that HIV transmission is “easily” prevented during pregnancy and delivery (there is still a 1% risk of transmission with treatment when the MOTHER is infected) and delivery, and HIV+ mothers cannot breastfeed. Aside from that there will be hundreds and hundreds of times over your lifetime that you may come into contact with your parent’s blood, saliva, tears… no one has the right to tell you or your parents that the choice to treat you by modifying CCR5 was not good enough. That was a personal decision made between your parents their physician and Dr. He, to try to give you the best life possible, so your father does not have to shy away from interaction with you that other parents take for granted.
CCR5 has been studied for decades, and many people who have this naturally occurring mutation that protects them from HIV transmission. The Dean of Harvard Medical School, Dr. George Daley, includes CCR5 on his list of acceptable genes to edit. HIV costs society many billions of dollars each year. It is a worthwhile target to be sure.
Did your doctor’s negligently expose you the the HIV virus? Not if well established protocols for processing HIV+ sperm were followed.
Dr. He says that he did follow the protocols, and on that point I do not doubt him. HIV and most viral particles “live” in the semen, which is washed away from the sperm cells until no viral load can be detected, routinely, for IVF labs all around the world. The embryos created with HIV+ sperm are transplanted with no issues into surrogate uterus hundreds of thousands of times with no issues.
-In 2016, a comprehensive international review of all published reports of double washed sperm used for assisted reproduction found no cases of HIV transmission in over 11,000 cycles of either intrauterine insemination or IVF/ICSI.
Some people are citing the POTENTIAL increase in susceptibility to flaviviruses, such as West Nile virus, due to the loss of a functional CCR5 protein as a flaw in this work, but is it?
Typically, a single citation is provided from Lim et al, who looked at 4 populations in the USA (only). This study features such eye brow raising remarks, such as;
“Clinical-outcome data were available only for the California cohort.” You only had clinical outcome data for ONE population in your study?
Closer examination reveal that of 125 “race-unstratified” patients from California, 76 (60.8%) presented with fever, 38 (30.4%) with neurological disease, and 6 (4.8%) died.” The sum of the clinical data is based on 125 individuals??!?!?!?!?!?!
So there are glaring limitations to the study most commonly cited, including the association between CCR5Δ32 homozygosity and disease outcome- only 19 individuals in the study were CCR5Δ32 homozygotes with defined disease outcomes.
Follow up work by the same people concluded that “CCR5 Deficiency is a Risk Factor for Early Clinical Manifestations of West Nile Virus Infection, but not for Infection per se.” So, the mutation is not associated with infection at all, and “may” be associated with worse outcomes, although, the outcome data were self reported via questionnaire, NOT independently measured.
So lets put the risk of WNV into perspective- and maybe some of you would like to compare that to the incidence and risks for HIV/AIDS.
It has been estimated that 1 million people have been infected with the WNV in the US, with a seroprevalence rate of less than 3%. 80% of individuals infected with West Nile show NO symptoms at all.
1 in 150 persons infected with the West Nile virus will develop a more severe form of disease. In 2016, the CDC reported that there were 1,310 “neuroinvasive” disease cases of WNV (ie. Severe). (Overall, the incidence of neuroinvasive WNV disease in the United States was 0.41 per 100,000 people.) Among patients with neuroinvasive disease, 1,250 (95%) were hospitalized and 105 (8%) died. A percentage of a percentage of a percentage. A very small percent.
The increase in POTENTIAL involvement of CCR5 with flaviviruses has been sketchily (at best) quantified. The work by Lim et al. characterized CCR5Δ32 homozygosity with a “more aggressive clinical presentation” compared to carriers of a normal allele, defined aggressive presentation as: painful eyes (P=0.003), swollen glands (P=0.018), generalized weakness (P=0.013), vomiting/diarrhea (P=0.035), and abdominal pain (P=0.032).
Additionally, mouse CCR5 antagonist models displayed reduced disease severity after dengue infection!!! CCR5 deficiency or pharmacological blockade in vivo reduced DENV-2 load in tissues and prevented disease development. The role of CCR5 in dengue indicates clear differences in how flaviviruses exploit the chemokine system during infection. Also in direct contrast, some studies have suggested protection against chronic hepatitis B infection and rheumatoid arthritis or prolonged survival of renal transplant individuals.
Indeed, there are ample data to suggest that CCR5 is involved IN BOTH POSITIVE AND NEGATIVE regulation of immune functions that relate to the regulation of leukocyte trafficking during infectious and post-infectious diseases. Here are three citations to get you started.
Fischereder M, Luckow B, Hocher B, et al. CC chemokine receptor 5 and renal-tranplant survival. Lancet. 2001;357:1758–1761.
Prahalad S. Negative association between the chemokine receptor CCR5-[Delta]32 polymorphism and rheumatoid arthritis: a meta-analysis. Genes Immun. 2006;7:264–268.
Thio CL, Astemborski J, Bashirova A, et al. Genetic protection against hepatitis B virus conferred by CCR5Delta32: evidence that CCR5 contributes to viral persistence. J Virol. 2007;81:441–445.
Lastly, CCR5 Antagonists (drugs that block the receptor and therefore the action of CCR5) are widely used to treat HIV. The post market- follow up data for this class of drugs does not indicate unusual deaths associated with Flavivirus exposures (at least not that I could find…).
I have seen some people compare your gene surgery to the Tuskegee Experiment. Choosing your parents as serodiscordant couple, ie. an uninfected female parter with an infected male partner virtually ensured that this is nothing like Tuskegee- the victims of the study, all African American, included numerous men who died of syphilis, 40 wives who contracted the disease, and 19 children born with congenital syphilis.
-Additionally, studies of HIV transmission through unprotected intercourse in serodiscordant couples (one HIV positive and one HIV negative) when the positive partner has an undetectable viral found no cases of HIV of HIV transmission between the couple after over 77,000 acts of unprotected intercourse.
You have many, many people cheering for you and the scientific pioneers that helped create you, even though they have clearly taken some mis-steps on the way to your arrival in terms of transparency, possibly informed consent, certainly to their Institution. I hope they quickly find their way back to the good graces of the scientific community. I am looking to the future, with all of the possibility and promise this technology brings.
Cheers to you, Lulu and Nana. May we meet one day!
“Here’s to the crazy ones, the misfits, the rebels, the troublemakers, the round pegs in the square holes … the ones who see things differently — they’re not fond of rules, and they have no respect for the status quo. … You can quote them, disagree with them, glorify or vilify them, but the only thing you can’t do is ignore them because they change things. … They push the human race forward, and while some may see them as the crazy ones, we see genius, because the people who are crazy enough to think that they can change the world, are the ones who do.”
Read about my top favorite applications of CRISPR to the molecular biology tool kit, my experience debating Human Gene Editing at Oxford University, my piece for CRISPR Journal, Pomp and Circumstance: Making the Case for CRISPR; A Scientist, A Scientist, a Bioethicist, and an Author Walk Into a Bar: Debating Human Genetic Engineering with one of CRISPRs’ Discoverers at Oxford University, the video of the debate on YouTube, a Dash of Science podcast; Gene Editing Tool Doesn’t Just Make Your Lettuce CRISPR; A Science Enthusiast Podcast and Video interview “Whatever the Hell CRISPR is” Sci-Gasm podcast: Solving world hunger and flying monkeys, the future of bio-tech and CRISPR/Cas9; Who’s Afraid of Genetically Engineering Humans with CRISPR/Cas9?
Dr. Carol Lynn Curchoe, Founder ART Compass
At ART Compass we support IVF professionals with lab information management and those #TTC. Find out more at www.artcompass.io