Nick received his B.S. in Biology from the University of Notre Dame and currently studies the spread of drug-resistant malaria.
While sci-fi depictions of genome editing portray parents custom-designing their children, biomedical scientists are excited about a much more pressing application: treating and preventing genetic diseases. Here’s how infectious diseases may be impacted.
Scientists have been intentionally manipulating animal genomes ever since Hermann Muller discovered that x-rays cause mutations in fruit flies back in 1926. Human-directed selection of domesticated plants and livestock goes back further by several thousand years. However, the advent of modern genetic engineering using programmable nucleases has opened the door to precise modification of human genes.
This is standard practice in laboratories all around the world that culture immortalized cell lines derived from humans. Genes in these cells are deliberately mutated so that scientists can determine how specific changes affect the cells’ phenotype: for example, how the cells respond to certain drugs or pathogens. What’s new is that scientists have recently succeeded in precisely editing the genomes of human embryos. While still extremely difficult and tightly regulated, this research raises ethical concerns about which genes should be open to modification, if any.
Nevertheless, genome editing research will proceed, however slowly, and at first will likely focus on human genes associated with severe diseases. If scientists tried to engineer the healthiest possible human, what would it look like? Heritable conditions caused by mutations in just one gene (cystic fibrosis, for example) are ideal first targets in editing people’s genomes due to the simplicity of their genetic cause. In addition, there are genes that come to mind when considering the effect human genome editing might have on infectious disease transmission. The two highlighted here are involved with protection against HIV and malaria, respectively.
Burden: 1.1 million deaths, 2.1 million new infections in 2015 (AIDS by the Numbers)
Target for editing: CCR5 gene
In 2008, Timothy Ray Brown, also known as the Berlin patient, was cured of HIV when he received a transplant of hematopoietic stem cells (HSCs) from a donor with something called the CCR5-Δ32 mutation. This means Brown’s donor had a congenitally inherited deletion of 32 nucleotides in the gene that codes for C-C chemokine receptor type 5 (CCR5), a protein normally displayed on the surface of immune cells derived from HSCs. It also means that, due to the deletion, Brown’s new immune cells had defective CCR5 proteins. Because the majority of HIV viruses worldwide, including Brown’s HIV-1 type, recognize CCR5 on human immune cells and use it to invade their host, people with defective CCR5 have increased protection from HIV infection. After the injection of new HSCs, the HIV in Brown’s body could no longer recognize cells that it could invade and replicate in, and he was cured.
Because protection is conferred by a simple 32 base pair deletion in one gene (for reference, the human genome contains approximately 3 billion base pairs), it is theoretically an easy target for editing. In April, scientists did just that. The team introduced the CCR5-Δ32 allele into non-viable human embryos using the CRISPR–Cas9 gene editing system. The embryos used in this experiment, known as 3PN, would otherwise normally be discarded, as they were the result of abnormal fertilizations of two sperm cells joining with a single egg which precludes proper development in vivo. However, the editing only worked in 4 of 26 attempts, and even then the embryos were mosaics, meaning some cells in the embryos retained normal unedited copies of CCR5 rather than exclusively incorporating the new version. But if improvements to the gene editing process are made and it becomes widespread in the future, scientists may again turn to CCR5 as a target for gene editing, which could prevent or cure millions of HIV infections. Additionally, CRISPR may be used to cure HIV patients by removing virus DNA that has integrated into the host genome.
Disease: Malaria (Plasmodium vivax)
Burden: 1,400 to 14,900 deaths (estimated), 13.8 million cases in 2015 (World Malaria Report 2015)
Target for editing: Duffy blood group antigen gene (DARC)
The characteristic alternating fever and chills of malaria are caused by Plasmodium parasites that infect our red blood cells (RBCs). Although the vast majority of malaria deaths are caused by the species Plasmodium falciparum, another species, P. vivax, causes a huge amount of morbidity from the Americas to Southeast Asia. Interestingly though, P. vivax malaria is conspicuously absent from most of sub-Saharan Africa, an otherwise malaria-rich region.
The people that live here show a high degree of resistance to P. vivax infection because they contain a genetic mutation that prevents a protein called the Duffy blood group antigen from being expressed on the surface of their RBCs. These people are dubbed Duffy negative. Normally, P. vivax parasites recognize the Duffy antigen as a receptor for infecting RBCs (similar to how the HIV-1 virus uses CCR5), so without that protein, Duffy-negative individuals are protected from infection. The Duffy negative phenotype can be conferred with a single point mutation in the DARC gene, a theoretically simple change to engineer.
However, there are compelling reasons to think twice before attempting to edit the DARC gene. For one, reports of P. vivax infection in spite of Duffy negativity are on the rise across the world, suggesting parasite evolution. Additionally, the Duffy negative phenotype has been associated with increased risk for prostate cancer and HIV susceptibility, among other drawbacks.
As with most new therapies, therapeutic human genome editing is likely to be very expensive for the consumer. Unfortunately, the overwhelming burden of the two diseases above is on the very poorest of people across the world. These people may not even have access to proper drugs, much less the advanced and tailored theoretical treatment with genome editing.
The good news is that human genome editing is probably not the best current solution to combat HIV and malaria anyway. Continued development of drugs and vaccines and increasing health and urban infrastructure in low-income countries is a much more attainable goal. Preventive measures like increased deployment of bednets for malaria and condoms for HIV will also go a long way to combatting these diseases. Interestingly, in the case of malaria, it appears that releasing genetically modified mosquitoes that are unable to transmit disease is much closer on the horizon than human editing. If the sci-fi “designer baby” scenario of the future does come to actualization, then perhaps someday there will be large-scale editing of the human CCR5 and DARC genes. For now, though, human genome editing remains just a controversial but exciting area of research.
Prospects and challenges in therapeutic genome editing (Open Access): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492683/
A very readable guide to genome engineering with programmable nucleases, including ZFNs, TALENs, and RGENs:
Search for genes related to disease outcome: http://www.omim.org/