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Human Genome-Edited Babies: First Responder with Concerns Regarding Possible Neurological Deficits! Abdul Mannan Baig
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Department of Biological and Biomedical Sciences, Aga Khan University, Karachi 74800 Pakistan ABSTRACT: The ultimate outcome in genome-editing research stepped into unknown territories last month when two babies were brought into the world with clustered regularly interspaced short palindromic repeats (CRISPR)−CRISPR-associated protein 9 (Cas9) facilitated knockdown of chemokine receptor 5 (CCR5). An immediate outcry by the public and the scientific community followed, which is still ongoing with much apprehensions and criticism of the ethical and scientific aspects of the procedure and its effects on the future of genome editing needed in other stubborn inheritable diseases for which there is no cure at present. With the debate on the consequences of this particular receptor knockdown still going on and the after-shocks in the form of queries expected to continue for some time in the future, we enter the arena of this particular genome editing as first responders with concerns regarding the neurological aftermath of CCR5 knockout in the babies born. KEYWORDS: CRISPR-Cas9, chemokine receptor 5, human genome, human genome-editing, HIV, germ cells
A. BABIES BORN VIA HUMAN GENOME EDITING IN THIS STUDY The ethical considerations, formal approval, rationale, and procedural details of CCR5 knockdown by clustered regularly interspaced short palindromic repeats (CRISPR)−CRISPRassociated protein 9 (Cas9) (Figure 1) in the recently reported human genome-editing has received outcry and criticism by the public and scientists worldwide.1,2
the risk of the acquisition of HIV without the knockdown of CCR5 by CRISPR−Cas9 genome-editing. Many critics question the objective of the study and provide existing alternative methods to genome-editing as evidence that could have enabled the couple to have babies without the risk of transmitting HIV.1,2
C. RISKS OF CCR5 KNOCKOUT BY GENOME EDITING IN HUMAN BABIES With the knowledge of the role of CCR5 in HIV uptake into human cells,3 it should not be presumed that deleting CCR5gene by CRISPR−Cas9 (Figure 1) or other gene-editing techniques would not have a wide range of effects on organ and tissues where CCR5 might be playing vital roles, some of which are being investigated and others are yet to be determined. Not taking into consideration the diverse effects of CCR5 in tissue growth and knocking it down to prevent HIV infection clearly appears to be a negligence rather than an honest error in planning and execution in research of this magnitude. It is now clear that as the babies born with this genome-editing continue to grow into childhood, teenage years, and possibly adulthood, the effects of the inability to express CCR5 on different organs and tissues will become evident in the future.
B. PROBLEMS WITH THE RATIONALE The lead researcher who declared the birth of the twin baby girls has detailed1 the objective and rationale of his study, which was to enable a couple, with the male being HIV positive, to have a healthy offspring, which would have been at
D. KNOWN STRUCTURE, TISSUE DISTRIBUTION, AND NON-NEURONAL FUNCTIONS OF CCR5 CCR5 is a G-protein-coupled receptor (Figure 2A) that is known to interact with a diverse group of downstream signaling adapter proteins. Several organs like bone marrow, lymphoid tissue, and organs where T-lymphocytes and macrophages play roles in host-defense mechanisms are known to express high density of CCR5. The normal
Figure 1. Schematic diagram showing the human genome-editing using CRISPR−Cas9 reported recently,1 which involves removal of both the copies of the CCR5 gene in spermatozoa and ovum before in vitro fertilization. This genome editing was done to prevent acquisition of HIV infection from an HIV positive father. © XXXX American Chemical Society
Received: December 1, 2018 Accepted: December 3, 2018
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DOI: 10.1021/acschemneuro.8b00668 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience
Figure 2. (A) Structure PDB 5UIW showing structural details of CCR5 GPCR. This protein is linked to several downstream adapter proteins of which PLC−IP3 and IP3R-mediated calcium (Ca) signaling and its effects are shown. (B) Expression of CCR5 in brain cells like microglia, astrocytes (pink), and neurons (blue). Inflammation particularly caused by viruses enhances CCR5 mediated recruitment of inflammatory cells across the blood−brain barrier. CCR5 on neurons that bind β-chemokines (red spots) plays a neuroprotective role. Babies with CCR5 knockout by genome-editing would be unable to use the inflammatory and neuroprotective functions of CCR5.
microglia (Figure 2B). The binding of CCR5 to β-chemokine has a neuroprotective role,3 a function that would be lost in CCR5 genome-edited babies. CCR5 binds to chemokines and is known to prevent host cell damage particularly in non-HIV infections. It is important to note that inflammatory diseases of the brain are known to increase the expression of CCR5 in diverse types of infections involving brain like in Japanese encephalitis, where CCR5 expression enhances lymphocyte activation (Figure 2B) and thereby promotes host cell survival. Also, CCR5 is known to be essential for T cell recruitment for several encephalitic viruses such as West Nile virus (WNV), murine hepatitis virus (MHV), and herpes simplex virus (HSV),4 a list of possible infections against which the genomeedited babies would be helpless. A study has shown that in mixed neuronal/glial cultures both CCR5 and CXCR4 facilitate HIV neurotoxicity, but paradoxically, this study also found evidence for a CCR5-mediated neuroprotective pathway3 (Figure 2B). Other studies have reported the CCR5-gene knockout to be associated with improved cognitive functions in animal models. The latter also brings into question the real intentions behind the reported study,1 which might be an effort to observe and replicate similar effects in humans.
expression of CCR5 in various tissues including the brain (Figure 2) reflects its significance in normal physiological processes. Functionally, CCR5 is known to play a dynamic role in the human inflammatory response by directing inflammatory cells to sites of inflammation. CCR5 is also a substrate for protein kinase C (PKC), a downstream adapter protein of the receptor. There are reports of functional cross-talk between CXCR4 and CCR5 that execute precise biological functions and modulate the T lymphocyte responses. It has emerged to play role in bone as blockade of CCR5 using specific antibodies has been shown to impair human osteoclast function. CCR5 is a critical molecule for regulatory T-cellmediated blood−brain barrier protection as well. Expression of CCR5 gene was also reported in a promyeloblastic cell lines, suggesting that this protein may play a role in granulocyte lineage proliferation and differentiation.
E. ANTICIPATED EFFECTS OF CCR5 GENE KNOCKOUT ON BRAIN FUNCTIONS Here, I attempt to debate the possible future neurological deficits that are expected in the genome-edited babies based on the known biological roles of CCR5 in neurological tissues. As our understanding of the functional role of CCR5 in brain and glial tissue is limited and needs to be researched in detail, neurological effects of the knockdown of CCR5 gene cannot be predicted with any degree of certainty. The expression of CCR5 is known in brain cells like neurons, astrocytes, and B
DOI: 10.1021/acschemneuro.8b00668 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience
F. EDITING THE GENES IN GERM-LINES: A WALK INTO UNCHARTED WATERS OF THE HUMAN GENOME Procedures that use germ cells for somatic cell nuclear transfer (SCNT) in vitro for obtaining embryonic stem cells (ESCs) from blastocysts and their use in somatic and neuronal cell regeneration have been proposed in the past.5 Unlike genome editing, the SCNT procedures use germ cells but the human genome is not edited in the process. The recent birth of the first genome-edited human babies1,2 seems like a déjà vu of the discovery of the potential of ESCs and the research that followed it in the past decade. Like then, here again we attempted to run before learning to walk. Taking a genomeedited germ cells to form an embryo and subsequently fullterm babies born out of it needs to have been meticulously planned and perfectly executed after procurement of all the possibilities of its risks and benefits. In the present case,1,2 few if not most of these considerations were missed or rushed. Above all, the off-target effects of CCR5 gene knockout by CRISPR−Cas9 were clearly overlooked. Knocking out a particular gene, like CCR5 in this case, can have remote effects on other genes and therefore the cellular function. Failure of the cross-talks of CCR5 with other chemokine receptors could have deleterious effects that we do not completely know at present. Performing a major human genome-editing of this scale should not be rushed to win a competition in becoming the first ever to do so. Unless the effects of a particular deletion or addition to the human genome is fully calculated, executing the results by advancing the experiments into a stage of bringing babies to life is more sloppy than a scientific breakthrough.1,2
legitimate research on more genome-editing deserving diseases as Huntington’s chorea, sickle cell disease, and cystic fibrosis, to name a few of them. The governments, legislative bodies, and ethical review regulators may now push for greater restrictions, which can hamper and slow down the genome editing benefits for the diseases mentioned above. Tighter regulations should be implemented, but this example should not slow down the research on those inherited diseases that have no cure other than genome-editing. Most alarming is the thought that the edited genome in these baby girls can be passed on to their offspring, which has the potential to alter the original evolutionary genetic code, not enforced by nature.
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AUTHOR INFORMATION
ORCID
Abdul Mannan Baig: 0000-0003-0626-216X Notes
The author declares no competing financial interest.
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ACKNOWLEDGMENTS Author would like to thank Miss Preet Katyara for her critical review of this Viewpoint. This project is partly funded by Aga Khan University.
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REFERENCES
(1) Cyranoski, D., and Ledford, H. (2018) How the genome-edited babies’ revelation will affect research. Nature, DOI: 10.1038/d41586018-07559-8. (2) Cyranoski, D. (2018) CRISPR-baby scientist fails to satisfy critics. Nature 564, 13. (3) Kaul, M., Ma, Q., Medders, K. E., Desai, M. K., and Lipton, S. A. (2007) HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection. Cell Death Differ. 14 (2), 296−305. (4) Dawes, B. E., Gao, J., Atkins, C., Nelson, J. T., Johnson, K., Wu, P., and Freiberg, A. N. (2018) Human neural stem cell-derived neuron/astrocyte co-cultures respond to La Crosse virus infection with proinflammatory cytokines and chemokines. J. Neuroinflammation 15 (1), 315. (5) Baig, A. M. (2014) Designer’s Microglia with Novel delivery system in Neurodegenerative Diseases. Med. Hypotheses 83, 510.
G. THE FUTURE HARDSHIPS THE GENOME-EDITED BABIES COULD FACE Unlike cell lines experimented upon or lab mice that are euthanized at the end of the experimental work, this experiment has brought to life two individual humans who were destined for their birth because of a human designed research plan. The babies, with one having a single copy of CCR5-gene and the other with complete deletion of this gene, would be possibly growing to childhood, teenage years, and adulthood with the threat of premeditated diseases looming over their heads. There are so many questions that come upfront while thinking of them as human beings and the adversities that they might face while they grow. Even the lead researcher had no answer to the question of how he thought the society will treat the genome-edited babies. Considerations such as their identities needing to be kept in secret and regular serological tests being required appear to transform their lives into anything but normal. In the baby born with both the copies of CCR5-gene been knocked out future blood transfusion and organ transplantation, if needed, is expected to elicit an immunological response, to CCR5 for obvious reasons, which can be life threatening. H. CONCLUSION AND FUTURE DIRECTIONS This Viewpoint has focused on the possible neurological deficits in the genome-edited babies reported recently.1,2 The ripples from this incidence could have a domino effect in other organs and tissues where the functions of CCR5 are yet unknown. Additionally, controversial human genome-editing like this one is expected to have an alarming effect on C
DOI: 10.1021/acschemneuro.8b00668 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
