Bowdoin Science Journal

Bioethics

Unpacking the Ethical Implications of Human Germline Editing

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On December 30th, 2019, biophysicist Dr. He Jiankui was sentenced to three years in prison for forging ethical review documents and misleading doctors into unknowingly implanting gene-edited embryos into two women in China (Normile 2019). One of these women had a set of twins and the other had a single child. These children are now the first genetically modified humans in history to be resistant to HIV. They can pass this modification to the next generation, and their whereabouts are still unknown (Greely 2019). Jiankui used CRISPR/Cas9, a gene editing tool, to modify their germlines and edit the CCR5 gene, a contributor to broad immune responses (his focus was its importance to HIV viruses).

Based on the National Natural Science Foundation of China, there has been a total of 3.7 billion yuan (roughly $576 million) government spending on embryonic stem cell research from 1997 to 2019 (Lou 2021). Germline gene editing research is allowed, but establishing a pregnancy with genetically modified embryos has been outlawed by multiple regulations (Xinqing 2014). Similarly to China, the National Institutes of Health within the US estimates that human embryonic stem cell research has received $1.48 billion in government funding since 2009. There are no current laws or regulations that ban germline gene editing conducted through private funding within the US, but it would have to be approved by the FDA for marketing and clinical studies. No proposals have been submitted (​​Genetic Literacy Project 2019). Dr. Jiankui has since been disgraced by the scientific community around the world for his actions. Some scientists believe that germline gene editing is not only an unethical practice but a potentially dangerous one that could lead to a new era of eugenics with irreversible harm (Genetic Literacy Project 2019). Little is known about the intricate details of Dr. Jiankui’s experiment, but what has been revealed poses several hard-hitting ethical questions. Should we manipulate the next generation of humans? What are the ethical dilemmas in the advancement of this technology? To create an informed opinion on the matter, it is helpful to first understand the intricacies of Dr. Jiankui’s experiment, and how exactly he made the first genetically modified children.

Dr. Jiankui conducted human germline genome editing, which refers to the technique of modifying not only the genetic information of a subject but also what can be passed down to the next generation (Normile 2019). Germ cells can create a new generation (ex. sperm and eggs). So germ cells, and cells that produce germ cells, are known as the germline. These are different from somatic cells, which are body cells that continuously divide throughout a person’s lifetime and play a minimal role in gene inheritance (Greely 2019). Certain alleles or alterations to CCR5 within the human genome can provide resistance to HIV. Thus, Jiankui used CRISPR to alter CCR5 in HIV-susceptible patients to make them resistant to the disease.

CRISPR, which stands for clustered regularly interspaced short palindromic repeats, is a technique originally found in bacteria as a defense system to render inserted viral DNA ineffective. It also allows for the modification of DNA (Rapini 2023). The enzyme Cas-9 can cut pieces of DNA and is guided to its location based on an attached strand of RNA (called the guide RNA strand). By cutting a targeted sequence of DNA, it can render protein-coding genes inactive or disfunctional. After Cas-9 has cut the target DNA, researchers can choose to place a modified DNA sequence in the vacant space (Fig 1).

Figure 1. The editing technique of CRISPR involves the guide RNA strand, guide RNA sequence, Cas-9 enzyme, and target DNA (Roach 2015).

While little is known about Dr. Jiankui’s specific technique in using the CRISPR/Cas-9 system, we know that he modified the gene CCR5 (Greely 2019). CCR5 is a gene on chromosome 3 that encodes for a protein called C-C chemokine receptor type 5 (also shortened to CCR5) (Normile 2019). CCR5, along with another receptor called CD4, is utilized by the HIV virus to bind to bacteria-detecting/destruction cells called macrophages (white blood cells) and infect them. The HIV virus protein envelope binds to the primary receptor CD4 on the macrophage with the gp120 protein, which are exterior “protective” protein around the HIV cell. If the CCR5 coreceptor is present as well, it can successfully enter the macrophage, release viral RNA and enzymes, and infect the macrophage. This infection alters the function of the macrophage, causing it to assemble and release viruses. Eventually, the gene that codes for the gp120 receptor is altered by a mutation and can now bind to a different co-receptor called CXCR4 which is found on the CD4 plus T-cells. (Prakash 2019). The same process of virus construction occurs within T-cells, but as the viruses leave the T-cell it ruptures the plasma membrane. This kills the T-cells, causing a weakened immune response and eventually resulting in the onset of AIDS.

Figure 2. The mechanism by which the HIV viral envelope infects the macrophage creates mutated viral cells with different gp120 receptors and destroys T-cells. (Prakash 2019) 

It is believed that Dr. Jiankui used the CRISPR/Cas-9 system to delete 32 base pairs of the CCR5 gene, therefore making it produce non-functional copies of the CCR5 protein. This was done in the hope that HIV would be unable to infect the white blood cells of the babies born from the embryos (Normile 2019). If Jiankui only modified somatic cells using this technique, the children may or may not have gained protection against HIV and could not pass it down to the next generation.

In 2015 (before He’s experiment was released) Jennifer Doudna, one of two researchers who published their findings on CRISPR, convened with the U.C Berkeley’s Institute for Genome Innovation, which was composed of Nobel laureates and esteemed professors of bioethics. They concluded that conducting germline editing would be irresponsible until matters such as balancing the potential risks and benefits have been concluded and that there is a broad societal consensus about the appropriate use of proposed applications of this technology (Cohan, 2018). Jennifer Doudna and Emmanuelle Charpentier created this technology to find ways to edit out faulty genes and cure diseases at the source—within our genetic code (Doudna 2019). However, after the release of He’s experiment, Doudna publicly stated her evolving concerns relating to this application of her discovery. During her national press tour in 2019, she shared a frightening dream she had in which a colleague of her’s asked about CRISPR but later turned out to be Hitler (Than 2019). This likely stems from the horrifying history of Nazis and the eugenics movement, which stemmed from the idea of improving the genetic quality of humans and sterilizing and or eliminating those with unfavorable traits. She also voiced that her opinion on germline genome editing has been evolving from an outright ban to warranting it in certain circumstances. However, her underlying opinion remains that it would have to be under transparent and safe circumstances and concern a medical need that was unmet by any technology. In addition to Doudna, countless other scientists have come out in disagreement with He Jianku’s work including researchers from Stanford University, Harvard Medical School, and the NIH (Cohen 2018). Specifically, a journalist from Science magazine states that representatives from eight countries who attended the International Summit on Human Genome Editing in Hong Kong came to a consensus that his actions were irresponsible, violated international norms, lacked transparency, and did not have sufficient medical justification (Cohen 2018).

Jennifer Doudna stated that her goal was to edit out faulty genes, but that definition leaves a lot to interpretation. How can we as a society come together to define the parameters of a faulty gene? From treating HIV to Down Syndrome, these conditions hold more than just health implications, but social ones as well. If the scientific community deems it accessible to prevent Down syndrome using human germline genome editing, are they stating that humans that currently possess this condition are “wrong” and have “faulty genes” in need of correction? Whoever holds the power to manipulate this technology essentially has the power to decide what the next generation of humans will be capable of and what genes are deemed “faulty” within our society. Jianku’s reckless use of technology was majorly deemed wrong for its lack of transparency, safety, and following set regulations upheld by currency bioethical standards. However, in situations like parents wanting their children to be healthy, it is completely understandable that human germline editing sounds like an intriguing way to protect their children. For these reasons, it is imperative to familiarize ourselves with the development of this technology, and its continued push for regulations across the world to maintain ethical standards. Further, it is also important to ask ourselves hard-hitting questions such as: should one person, scientist, or government have the power to determine what the next generation will possess, look like, or become? We as members of society must continue to stay informed in a world with the capacity to genetically modify human beings.

References:

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    Join David Ignatius. “Walter Isaacson & Jennifer Doudna join Washington Post Live to discuss CRISPR.” Washington Post. March 2021. https://www.youtube.com/ watch?v=cKHuuALENZk
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