Science Policy For All

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Update on Genetic Engineering using CRISPR/Cas-9 Technology and Human Embryos

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By: April Killikelly, PhD

A previous post on this blog featured the genetic engineering system CRISPR/Cas-9 and posed questions about the ethical and safety concerns raised by this technology. Specific concerns about the regulation and monitoring of CRISPR/Cas-9 technology were also raised by the author. Subsequently, it was revealed in the online journal Protein and Cell that a Chinese research group lead by Junjiu Huang at the Sun Yat-sen University in Guangzhou had used the CRISPR/Cas-9 system to genetically manipulate 86 non-viable embryos, of which 28 were successfully transformed. The authors claim both Science and Nature rejected their paper in part, due to ethical concerns. This was not the first test of this technology, but it was the first use in human embryos. There was also evidence that the CRISPR/Cas-9 system acted to create off-target mutations in parts of the genome where the researchers had not intended. It should be noted that this result is significantly different from a previous result where the success rate was higher and the rate of off-target effects was smaller. The authors state that the decreased efficacy and increased rate of error could be attributed to the nature of non-viable embryos.

The revelation of this international study redirects the conversation surrounding CRISPR/Cas-9 technology from questioning the development of this technology to its implementation. There are three significant considerations:

Controlling human genetic engineering

The first and easiest measure of control could be a complete ban on all manipulations of the human genome. Would this be ethical? If there are tools and technologies available to prevent illness and suffering, do we have an obligation to use them? Dr. Francis S. Collins, director of the National Institutes of Health (NIH), has already issued a statement saying that the NIH “will not fund any use of gene-editing technologies in human embryos.” Banning the use of technologies in the United States will do little to prevent other countries from using them. The US would then have minimal influence on the future development of genetic engineering technologies, such as the CRISPR/Cas-9 system. However, a ban in the US may also create a two-tiered system in which those who can afford to access this technology would travel abroad to receive it, whereas those without financial means would do without.

Regulation of the technology by identifying candidate mutations

Attempting to regulate this technology would not be simple either. We must carefully define candidate genetic mutations that would warrant the need for genetic editing. Huang et al. aimed to modify the gene that causes β-thalassaemia with the clear intention of trying to prevent a potentially fatal human illness. But other cases aren’t so clean-cut, even from a biological standpoint. A mutation in the beta chain of the hemoglobin gene causes sickle cell anemia, if inherited from both parents (homozygous). However, when the mutation is inherited from only one parent (carrier or heterozygous) it has a protective effect against malaria. If we have the technology to remove all of the sickle-causing mutations, we would be leaving whole populations vulnerable to malaria. Is this ethical? The presence of a known mutation does not always guarantee that a disease will manifest, depending on the penetrance of that mutation. Even when diseases are caused by a single gene mutation, the nature of disease is complex and sometimes cannot be remedied by “fixing” individual genetic mutations. However, many disease states aren’t caused by a single mutation but rather by a summed effect of many genes that in themselves are only responsible for a small portion of predisposition or risk of disease. Therefore, when trying to identify candidate mutations, it’s important to consider the biological context in a broad scale. Widening the focus to include other perspectives on disease increases the complexity of the issues. The polarization of the deaf community in response to cochlear implant technology illustrates this challenge. Not only is a mutation difficult to define, but so is the definition of illness.

Somatic vs. Germline Mutations

Despite the huge promise and potential posed by technologies that modify genetic material, an important distinction must be made between somatic and germline mutations. Somatic cells are those terminally differentiated cells that live and die within the lifetime of the organism. Classic examples are the somatic skin cells we shed daily. Germline cells, however, only reside within gonads and ovaries and undergo a specific genetic process called meiosis. The genetic material within germline cells is passed on to all future generations. In the context of the CRISPR/Cas-9 debate, modification of the genetic material of an embryo will modify both the somatic and the germline genetic material.

Before CRISPR technology was developed, Sangamo Biosciences in Richmond, CA was the forerunner in the field of genetic modification technology, and was promoting the use of their zinc finger nucleases for somatic gene therapy. The effects of modifying the genetic material solely within somatic cells (both good and bad) only last for the lifetime of the somatic cell. This limits the impact of any off-target genetic changes or side effects, and makes the application of this technology more similar to conventional medications. This similarity also ensures that this technology is easier to regulate by agencies such as the Food and Drug Administration (FDA). As such, Sangamo are currently testing the use of their technology in Phase I clinical trials through modifying white blood cells to be used in the treatment of HIV/AIDS.

The recent use of CRISPR/Cas-9 technology reported by Huang et al. resulted in genetic changes to all 8 cells in the human embryos, thus altering both the somatic and the germline cells. Therefore, the induced genetic changes would persist not only for the lifetime of the embryos, but for all future generations that resulted. Mutations within the germline DNA leave little room for error. Despite the non-viability of the embryos studied, many scientists believe that Huang et al. pushed the science too far. Edward Lanphier, President of Sangamo, draws a clear line in the sand: “We believe there is a fundamental ethical issue in crossing the boundary to modify the human germline.”

However, this is not the consensus in the scientific community. Some scientists would argue that for research purposes, alterations of germline cells should not be instantly written off. Nobel Laureate Craig Mello of the University of Massachusetts cites cancer, diabetes, and age-related illness as “good reason to experiment with discarded embryo and embryonic stem cells for research purposes.” Dr. Mello is not alone. Geneticist George Church of Harvard University agrees that genome editing could greatly increase the efficiency of generating healthy embryos for IVF.

Most scientists do agree on the growing need for a conversation about the unique challenges, benefits, and threats associated with gene editing technologies. Without the discourse of knowledgeable and insightful people, the information vacuum is likely to be filled by less nuanced and more media savvy sources. To that end, the NIH hosted a “CRISPR Roundtable Discussion” with a panel of intramural and extramural scientists on Monday May 4th. This meeting by no means constitutes a definitive ending to the discussion, but hopefully it represents a beginning.

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Written by sciencepolicyforall

May 7, 2015 at 9:00 am

5 Responses

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  1. Nature Biotechnology asked various experts in the field the following question: “With the current pace of advances in the use of gene editing technology, IVF and germ stem cell research, to what extent do you think germline engineering is inevitable?”
    Here are their answers: http://www.nature.com/nbt/journal/v33/n5/full/nbt.3227.html

    meltersd

    May 18, 2015 at 10:12 am

  2. Not surprising, the National Academy of Sciences and National Academy of Medicine will launch a major initiative to develop international guidelines for rapidly advancing technology to modify human embryos and germ cells.

    http://www.nature.com/news/us-science-academies-take-on-human-genome-editing-1.17581

    meltersd

    May 18, 2015 at 4:59 pm

  3. […] stunned the international community back in April when they published the results of applying the CRISPR/Cas9 genome editing technology to modify human embryos. Many considered such work had crossed an ethical ‘red line’. Yet China’s National Medical […]

  4. […] changes in the Chinese study were minimal and were not used for reproductive purposes, the work ignited debate and criticism among scientists and bioethicists. Members of the consortium met earlier this week and issued the following statement: “We believe […]

  5. […] said ‘very sorry.’” Others think that the recent advances in gene-editing technology (such as CRISPR), to correct genetic errors, will diminish the need to clone. Additionally, the thought of cloning […]


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