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Gene Editing of Human Beings

In this article from the summer 2018 edition of Today's Christian Doctor, Dr. David Prentice discusses how genetic engineering has the potential for great benefit and great harm.

by David A. Prentice, PhD

“I mean, if we could make better human beings by knowing how to add genes, why shouldn’t we do it?”
—Nobel Laureate James Watson, 1998

“Soon it will be a sin for parents to have a child that carries the heavy burden of genetic disease. We are entering a world where we have to consider the quality of our children.” 
— Embryologist Robert Edwards, 1999

Gene editing (the current term of art for genetic engineering or genome manipulation) has potential for great benefit but also for great harm. Newer techniques for genetic engineering provide much better accuracy than was achievable in the past and bring targeted genetic changes within reach. The range of medically beneficial applications is broad, including treating individuals with genetic diseases, intractable cancers and various previously incurable diseases. There is also the potential for designing new drugs and truly personalized, genetically-tailored therapies. But this more refined genetic manipulation technology also could be used to design children, weaponize biological agents or even alter or dehumanize our concept of humanity. As with many cutting-edge biological technologies, much depends on the targets, attitudes and motivations of the innovators.

Genetic engineering has become a hot research topic of late, due primarily to the recent development of more accurate enzyme systems to target and cut DNA at specific sequences. These targeted nuclease systems provide sequence-targeting precision that was previously unavailable. Prior techniques for genetic engineering primarily utilized the addition of genes as DNA pieces that integrated randomly (in placement and in number of insertions) into the genome, or with insertion facilitated using various viruses as vehicles which gave partial targeting into some portions of the genome but still produced largely a shotgun effect of gene insertion. One of the earliest gene therapy clinical trials used this technique to successfully correct severe combined immunodeficiency (SCID; so-called “bubble boy syndrome”) in children, adding a correct gene to autologous hematopoietic stem cells in these children.1 However, the technique’s random insertion of the functional gene resulted in some instances where the added gene (containing a strong genetic promoter) inserted close to normal, growth-promoting genes and stimulated overproduction of the growth-promoting gene, resulting in leukemogenesis.

We should also be aware of other brute force genetic manipulation techniques, specifically cloning (somatic cell nuclear transfer) and construction of three-parent embryos (which is also a form of cloning.) These are actually extreme forms of genetic engineering. While cloning does not manipulate parts of the genome, nor insert or delete various genes, cloning as genetic engineering is indeed an attempt to create an individual with a specific genome, in a sense re-creating a genetic information bank already lived. Cloning also provides a mechanism to replicate a complete genome’s information, multiplying this effect many times over. Construction of three-parent embryos uses the same techniques but transfers the nucleus at the earliest stages of embryonic development. Further discussion of these cloning technologies requires its own article, but in brief we can note that these types of cloning techniques fall into the category of unethical; human beings are not treated therapeutically in these cases but instead new individuals are manufactured as experiments themselves.

For specific gene editing, the three current nuclease systems that are most promising are ZFNs (zinc finger nucleases), TALENs (transcription activator-like effector nucleases), and the CRISPR-Cas complexes (clustered regulatory interspaced short palindromic repeats-CRISPR associated system.)3 ZFNs are constructed from a class of transcription factors that bind to specific DNA sequences, normally acting to turn on specific genes in the cell. Upon binding to DNA, the enzyme makes a double-strand cut, which activates the cell’s normal DNA repair system to insert DNA at the cut site. TALENs are also constructed from transcription activator proteins. By constructing variations in the amino acid sequence, almost any DNA sequence can be targeted. Like a ZFN, once the TALEN binds to its specific DNA sequence the DNA is cut, activating the DNA-repair system of the cell, which inserts the added DNA as part of the repair of the cut. The CRISPR-Cas system also has a targeting portion associated with a nuclease (Cas), but the targeting uses a short guide RNA that base pairs with specific DNA sequences. Once the guide RNA binds to its specific target DNA sequence, the nuclease cuts double-stranded DNA at the binding site. Constructing different guide RNA sequences (easier than constructing different protein sequences) means any DNA sequence can be targeted for cutting. Safety is still a concern, particularly because these gene editing systems are not 100 percent accurate, leading to “off-target” cutting of DNA at sites throughout the genome other than the one desired site. Simple human genetic variation may be a barrier to successful therapeutic gene editing until accuracy can improve.4

Clinical trials have already begun in attempts to modify specific genes of people affected with genetic diseases or to treat cancer patients using genetically-altered immune cells. These projects are worthwhile pursuits, not least because they target alleviating the conditions of existing individuals. In one example, genetic correction of autologous epidermal stem cells has been used successfully to replace the diseased skin of a young boy in Germany suffering from a genetic condition called junctional epidermolysis bullosa (JEB).5 JEB is a severe and often lethal disease—more than 40 percent of patients die before adolescence—where a mutation in a laminin gene means skin cells cannot interconnect; instead, the skin blisters and falls off with the slightest touch, leaving wounds all over the body. There is no cure and little beyond palliative care for sufferers. An Italian team grew epidermal stem cells from biopsies of the boy’s skin, used a retroviral vector to add the full-length, normal laminin gene to the cells and then grew sheets of genetically-corrected skin which were transplanted onto the boy. The transplants replaced more than 80 percent of his skin, and within six months the boy was back in school sporting healthy, blister-free skin, and he has remained healthy and active.6

In a clinical trial recently begun, the first patient has received gene therapy for Hunter syndrome, a condition where an important sugar-metabolizing enzyme is mutated and non-functional. In this trial, the patient received an injection of the gene editing enzymes and new gene, which work to insert the new, functional gene into a specific site in the liver cells.7 The cells then function as a factory to create the needed enzyme.

Other trials are slated to begin soon in Europe and in the U.S. to use specific gene editing to treat patients with β-thalassemia and sickle cell anemia.8 The trials will target activating the gamma-globin gene to replace the mutated beta-globin.

Another promising gene editing technique is construction of chimeric antigen receptor-T cells (CAR-T). Genetic engineering combines antigen-detecting receptors and stimulatory proteins on a T lymphocyte with an antibody portion that targets the specific cancer or leukemia in the patient; the combination makes the cell able to specifically target and attack the individual’s cancer.9 Additional genetic modifications can also be added to equip the immune cells with other useful features in the treatment of the cancer. A version of this system was used to successfully treat two young leukemia patients.10,11

But despite the successes and promise of gene editing for treatment of patients, there have been ethically troubling attempts to alter the genomes of young human embryos. This “germline” gene editing is aimed at creating new individuals with altered DNA. And since the genetic modifications are incorporated into all of the cells so early in life, any genetic change will be passed on to future generations, with unknown consequences for the gene-manipulated individual as well as future generations. Chinese researchers previously published three reports on genetic manipulation of human embryos. More recently, scientists from the United Kingdom published their first experiment using CRISPR to disable different genes in human embryos simply to see how that would affect their early development.12 And finally, U.S. researcher Shoukhrat Mitalipov, PhD, reported a gene editing experiment on normal human embryos, including statements on his desire to gestate and birth some of these gene-edited children.13 Perhaps unsurprisingly, this researcher is also the one who created cloned human embryos, created three-parent human embryos using cloning techniques and advocated for gestation and birth of three-parent embryos. In their experiments to correct a mutation in the embryos’ genome, the researchers created 142 human embryos for the experiment; all were subsequently destroyed. The results reported by the team (100 percent effective with no off-target cuts) have been characterized as almost too good to be true and certainly much less than safe and effective. Other researchers have since published a paper that calls into question the conclusions of the Mitalipov gene editing paper, but whether or not the gene editing results are invalid in this experiment, there is a continued push by some scientists to do human embryo experiments. Dr. Mitalipov himself encouraged others to do gene editing experiments on human embryos, and he has stated his hope that U.S. lawmakers would loosen restrictions currently in place that prohibit funding of such experiments as well as clinical trials placing gene-edited embryos in the womb.

Those U.S. restrictions on clinical trials and gene editing experiments with human embryos were put in place by Congress, led by Alabama Rep. Robert Aderholt in 2015, and were a direct response to the attitude of some scientists and the National Academy of Sciences that creation, manipulation and destruction of human embryos in gene editing experiments is ethically permissible.14 The language suspends genetic experiments only with human embryos, but fully allows development and trials of genetic therapies for born individuals.

This highlights the real ethical line regarding application of genetic technologies: who will be genetically modified?15 Will we focus on born individuals and on gene editing that is truly therapeutic for human beings but not in the germline, or will be allow genetic experiments with human embryos and the manufacturing of new, better, genetically-designed human beings? Some researchers have foresworn any genetic experiments on human embryos, but there is still no final policy resolution. In the movie Gattaca, the main character struggles to overcome the stigma of not being genetically designed and enhanced (a “valid” birth), as well as to overcome the genetic caste system that gene editing of human embryos would create. Our human future, as well as our attitudes on how we treat “the least of these” among our fellow human beings, deserves full discussion.


BIBLIOGRAPHY

1 Marina Cavazzana-Calvo et al., “Gene Therapy of Human Severe Combined Immunodeficiency (SCID)-X1 Disease,” Science 288.5466 (28 April 2000): 669-672, doi: 10.1126/science.288.5466.669

2 Salima Hacein-Bey-Abina et al., “A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency,” NEJM 348.3 (January 16, 2003): 255-256, doi: 10.1056/NEJM200301163480314

3 For an overview, see Gaj T et al., ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering, Trends in Biotechnology 31, 397-405, July 2013

4 Samuel Lessard et al., Human genetic variation alters CRISPR-Cas9 on- and off-targeting specificity at therapeutically implicated loci, Proc. Natl. Acad. Sci. USA 114, E11257-E11266, Dec. 26, 2017, doi: 10.1073/pnas.1714640114

5 Tobias Hirsch et al., “Regeneration of the entire human epidermis using transgenic stem cells,” Nature 551.7680 (16 November 2017): 327–332, doi:10.1038/nature24487

6 David Prentice, “Adult Stem Cells and Gene Therapy Save a Young Boy,” Nov 16, 2017, accessed at: https://lozierinstitute.org/adult-stem-cells-and-gene-therapy-save-a-young-boy/

7 Jocelyn Kaiser, “A human has been injected with gene-editing tools to cure his disabling disease. Here’s what you need to know,” Science News, Nov 15, 2017, doi: 10.1126/science.aar5098

8 Ryan Cross, CRISPR is coming to the clinic this year, Chemical & Engineering News 96.2, 18-19, January 8, 2018; access at: https://cen.acs.org/articles/96/i2/CRISPR-coming-clinic-year.html

9 National Cancer Institute, “CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers,” Dec, 14, 2017; accessed at: https://www.cancer.gov/about-cancer/treatment/research/car-t-cells

10 Jennifer Couzin-Frankel, “Baby’s leukemia recedes after novel cell therapy,” Science 350, 731, November 15, 2015

11 Qasim W et al., “Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells,” Science Translational Medicine 9.374 (25 January 2017): eaaj2013, doi: 10.1126/scitranslmed.aaj2013

12 Heidi Ledford, “CRISPR used to peer into human embryos’ first days,” Nature News 20 Sept. 2017, doi: 10.1038/nature.2017.22646

13 Pam Belluck, “In Breakthrough, Scientists Edit a Dangerous Mutation From Genes in Human Embryos,” New York Times Aug 2, 2017; accessed at: https://www.nytimes.com/2017/08/02/science/gene-editing-human-embryos.html

14 David A. Prentice, “Modest but Meaningful Protection from Human Embryo Genetic Manipulation,” Townhall Dec 17, 2015; accessed at: https://townhall.com/columnists/davidaprentice/2015/12/17/modest-but-meaningful-protection-from-human-embryo-genetic-manipulation-n2094746

15 Michael Burgess and David Prentice, “Let Congress know to take it slow on human gene editing,” Dallas News December 28, 2016; accessed at: http://www.dallasnews.com/opinion/commentary/2016/12/28/let-congress-know-gene-editing-humans-bad-business

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