The CRISPR Advent of Lulu and Nana

This was an article published in Theology in Science, reproduced with permission.

If you could protect your children from getting HIV, would you do it? The parents of Lulu and Nana in China did exactly just that with the help of Dr. He Jiankui (hereby abbreviated HJ), a scientist from the Southern University of Science and Technology. HJ reportedly modified a gene called CCR5, which encodes for a receptor in white blood cells that common strains of HIV use to infect us. HJ did this modification in human embryos using a novel gene- editing technique called CRISPR. The question arises if Lulu and Nana are the last of their kind, or the firstborns among many to come.

What is CRISPR?

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene-editing system is one of the few scientific breakthroughs that receive a lot of media attention. The CRISPR/Cas system is actually an adaptive immune response in bacteria against viral infection. ¹R. Sorek, C.M. Lawrence and B. Wiedenheft, Annual Review of Biochemistry 82 (2013), 237–266; M.P. Terns and R.M. Terns, Current Opinion in Microbiology 14 (2011), 321–327; T.R. Sampson, S.D. Saroj, A.C. Llewellyn, Y.L. Tzeng and D.S. Weiss Nature 497 (2013), 254–257; T.R. Sampson and D.S. Weiss, Biochemical Society Transactions 41 (2013), 1407–1411.

But scientists developed this adaptive immune system to delete and edit genes of interest. This system consists of the Cas protein and guide RNA (sgRNA),²M. Jinek, K. Chylinski, I. Fonfara, M. Hauer, J.A. Doudna and E. Charpentier, Science 337 (2012), 816–821.  which with the Cas protein, delete the gene that is indicated by the sgRNA. In other words, scientists are then able to design sgRNA against any genes of interest and the CRISPR/Cas system of the target cell will eliminate those genes.

When did CRISPR begin?

In December 1987, researchers found CRISPR sequences in Escherichia Coli, but did not characterize their function.³Y. Ishino, H. Shinagawa, K. Makino, M. Amemura and A. Nakata, Journal of Bacteriology 169 (1987), 5429–5433. It was not until two decades later that this information was picked up by scientists at Danisco, a food company. They determined that the CRISPR is part of a bacterial innate immune system against viruses.⁴R. Barrangou, C. Fremaux, H. Deveau, M. Richards, P. Boyaval, S. Moineau, D.A. Romero and P. Horvath, Science 315 (2007), 1709–1712; H. Deveau, R. Barrangou, J.E. Garneau, J. Labonte, C. Fremaux, P. Boyaval, D.A. Romero, P. Horvath and S. Moineau, Journal of Bacteriology 190 (2008), 1390–1400; P. Horvath, D.A. Romero, A.C. Coute-Monvoisin, M. Richards, H. Deveau, S. Moineau, P. Boyaval, C. Fremaux and R. Barrangou, Journal of Bacteriology 190 (2008), 1401–1412.

Then finally in June 2012, Jennifer Doudna from UC Berkeley reported that CRISPR can be used for genome editing. ⁵M. Jinek, K. Chylinski, I. Fonfara, M. Hauer, J.A. Doudna and E. Charpentier, Science 337 (2012), 816–821.

What about CRISPR & HIV?

CRISPR in theory can be used as a genetic therapy option for dealing with HIV. In 2015, Khalili’s group from Temple University was able to take HIV+ patient cells and use CRISPR to cut out the HIV gene while leaving the patient’s DNA intact,⁶M.K. White, W. Hu and K. Khalili, Discovery Medicine 19 (2015), 255–262; H.S. Wollebo, A. Bellizzi, R. Kaminski, W. Hu, M.K. White and K. Khalili, PLoS One 10 (2015), e0136046; Y. Zhang, C. Yin, T. Zhang, F. Li, W. Yang, R. Kaminski, P.R. Fagan, R. Putatunda, W.B. Young, K. Khalili and W. Hu, Scientific Reports 5 (2015), 16277.  performed in vitro. Then they proceeded with an in vivo experiment, creating a mouse model that expresses the HIV gene in its DNA. They then were able to use CRISPR to cut out the HIV gene in these mice, showing the possibility of using CRISPR in vivo as a therapeutic agent.⁷R. Kaminski, Y. Chen, T. Fischer, E. Tedaldi, A. Napoli, Y. Zhang, J. Karn, W. Hu and K. Khalili, Scientific Reports 6 (2016), 28213; R. Kaminski, Y. Chen, T. Fischer, E. Tedaldi, A. Napoli, Y. Zhang, J. Karn, W. Hu and K. Khalili, Scientific Reports 6 (2016), 22555; M.K. White and K. Khalili, Oncotarget 7 (2016), 12305–12317.  In November 2018, HJ announced the birth of Lulu and Nana, babies with modifications against HIV infection.

But why HIV? HIV is a complex disease, involving the immune system. Given that CRISPR is a genetic tool, why not attempt to cure a genetic disease? There are approximately 3000 single-gene, monogenic, heritable disease traits,⁸J.S. Alper, BMJ 312 (1996), 196–197; A. Velazquez, World Review of Nutrition and Dietetics 80 (1997), 145–164.  which means CRISPR can be used to potentially cure at least these 3000 monogenic diseases.⁹D.J. Weatherall, BMJ 321 (2000), 1117–1120. Following that line of reasoning, the first clinical trial using ex vivo CRISPR therapy was launched in September 2018 on a monogenic blood disorder, beta-thalassemia.

CRISPR Risks

That all sounds great, so what’s the problem? There are many concerns, but here I will raise only three scientific concerns:

1. Off-target effects: The key to the CRISPR targeting system is the sgRNA, which is used to determine which gene(s) get deleted or edited. Given that our DNA is 3 billion base pairs long, it is of course a major concern to edit the correct gene out of the myriad of base pairs in the genome.

2. On-target effects: Even if we got the CRISPR system to have 0% off-target effects, we do not know all the possible effects of an on-target CRISPR modification. One often cited example is the elimination of sickle-cell anemia leading to an increased risk of contracting malaria.¹⁰K.S. Bosley, M. Botchan, A.L. Bredenoord, D. Carroll, R.A. Charo, E. Charpentier, R. Cohen, J. Corn, J. Doudna, G. Feng, H.T. Greely, R. Isasi, W. Ji, J.S. Kim, B. Knoppers, E. Lanphier, J. Li, R. Lovell-Badge, G.S. Martin, J. Moreno, L. Naldini, M. Pera, A.C. Perry, J.C. Venter, F. Zhang and Q. Zhou, Nature Biotechnology 33 (2015), 478–486. With regards to CCR5, studies have shown that CCR5 knockout mice are more susceptible to genital herpes simplex virus infection, because CCR5 is required for the innate immunity to function.¹¹M. Thapa, W.A. Kuziel and D.J. Carr, Journal of Virology 81 (2007), 3704–3713. We need to see how Lulu and Nana react to challenges to their immune response to ascertain the effects of the absence of CCR5. In general, on-target effects cannot always be known beforehand and will accumulate over time as more modifications are performed.

3. Chimerism: It is not trivial to get every single cell in an embryo to be transfected by CRISPR. Thus it is possible that the resulting fetus would turn out to contain a much smaller proportion of edited cells, ¹²M. Sancho and T.A. Rodriguez, Cell Cycle 13 (2014), 9–10. rendering the CRISPR operation useless. HJ already reported that while the one baby has both CCR5 alleles edited, the other baby only has one allele edited. This means the second baby is a CCR5 chimera who might still be susceptible to HIV infection.

Questions from a Christian scientist

We still need to validate HJ’s claims about this experiment and assess exactly what he did. But let’s take a few steps back away from the experimental details. As a scientist, I find the puzzles involved in any CRISPR application fascinating. However, as a student of theology, I can’t help but to raise questions that I hope we can work together to address.

What are scientists? We are a group of people who have decided to spend years practicing to generate hypotheses, design experiments, and interpret the results with the hope of discovering something new. This reiterative process involves a myriad of minutiae ranging from which virus strain to use to which scientific paradigm we wish to defend or challenge. Yet we are not trained to think of our underlying worldviews in generating these hypotheses and applying our findings. Has God given us CRISPR to have dominion over creation? Scientists have created a more efficient fuel-producing CRISPR-edited algae.¹³P.B. Otoupal and A. Chatterjee, Frontiers in Bioengineering and Biotechnology 6 (2018), 122. CRISPR can be used to combat climate change by creating bacteria that can help modulate levels of greenhouse gases¹⁴M. Abdelrahman, A.M. Al-Sadi, A. Pour-Aboughadareh, D.J. Burritt and L.P. Tran, Plant Physiology and Biochemistry 131 (2018), 31–36; H. Huang, C. Chai, N. Li, P. Rowe, N.P. Minton, S. Yang, W. Jiang and Y. Gu, ACS Synthetic Biology 5 (2016), 1355–1361.. Al Gore would approve. The list is endless. But at what point do we keep changing nature before we change our actions? Most would disagree with the dominion language and prefer the term “steward” and “co-creators” ala Phil Hefner. Even so, CRISPR gives a new meaning to “co-creator” because of its potential for human modification.

Who are these parents? All news reports have narrated the birth of Lulu and Nana in terms of HJ’s work, but what about the parents who decided to allow HJ to perform this “genetic surgery” as he calls it? HJ defends himself by saying that the parents have consented. We can only wonder the millions of thoughts that cross their minds as they consent to HJ’s proposal. Their thoughts may range from despair to hope. They might see themselves as caretakers and stewards of their kids. What should a pastor say to their congregation members on this? But perhaps congregation members no longer go to their pastors with these questions. Have they turned to scientists for hope? Have scientists become the modern-day priests and prophets in guiding us how to become better caretakers and stewards of our children and this world?

What are these babies? Emily Whitehead was the first CAR-T cell therapy patient who got cured of leukemia. Like Emily, Lulu and Nana will conjure the innate curiosities of scientists. Did Lulu and Nana consent to this? They will be subjected to monitoring, testing, if not further experimentation. Perhaps they should get to know each other to share their experiences. Have they been reduced to experimental subjects or have they ascended to be the first transhumans on our planet?

Last but not least, what makes us human? Or to put it more bluntly, how are we different from animals? The thought of animal experimentation is more acceptable than human experimentation in any circumstances. We, Christians, presume a unique place for ourselves in creation for having been created in the image of God. But what constitutes that image of God? Theologians have shied away from Augustine’s substantialist and von Rad’s functional notions of the image of God when faced with similarities of genetic materials and behaviors found in primates. Barth, for example, resorted to a more relational notion of the image of God to keep us unique. More contemporary theologians, like Moritz, construct a combination of both functional and relational notions of the image of God where humans are elected by God (relational) to be stewards of nature (functional). ¹⁵J. Moritz, “Natures, Human Nature, Genes and Souls,” Dialog: A Journal of Theology 46:3 (Fall 2007); J. Moritz, “Evolution, the End of Human Uniqueness, and the Election of the Imago Dei,” Theology and Science (August 2011); J. Moritz, “Made as Mirrors: Biblical and Neuroscientific Reflections on Imaging God,” Ex Auditu 32 (2016). In so doing, there is nothing special about our DNA, thus why does it matter if our CRISPR DNA turn us into a crisper image of God, healthier than Jesus himself?

“Let us make man in Our image,” said God in the book of Genesis. “Let us CRISPR man in our image,” ponder scientists in their academic journals. It is time for theologians to cry out and prepare the way for what is to come.