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The Promise and Pitfalls of CRISPR Gene Editing for Human Health

Dr Hama lays out the potential benefits and cautions surrounding CRISPR gene editing, noting the challenges it still faces for use in fighting human diseases.

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CRISPR
Digital illustration DNA CRISPR structure in colour background. (© University of Chicago via Wikimedia Commons ID 150725585)

The Sankei Shimbun and JAPAN Forward recently published articles on the development by academic scientists in Japan of improved methods of gene editing. Building on previous efforts centered on "clustered regularly interspaced short palindromic repeats," or CRISPR gene editing, Kyushu University Professor Masaki Kawamata and his colleagues reported their findings in the April 2023 edition of Nature Biomedical Engineering, an international journal of science. 

The press offices of Nagoya University School of Medicine, where co-author Dr Hiroshi Suzuki is based, and Kyushu University released brief explanations of the team's findings. These may be more accessible than the scientific paper to lay readers. 

genome editing

Need to Carefully Assess Risks

There is a potential risk with currently available CRISPR gene editing methods. That is errors after targeted changes of disease-related genes or insertion of therapeutic genes. These errors could lead to unintended and markedly altered cell and tissue function. 

In this regard, Dr Kawamata and his colleagues pointed out that currently used methods to check the accuracy of gene editing are not very sensitive to post-processing mistakes. Thus, the new methods described by Dr Kawamata and his colleagues could lead to more effective gene therapy with greatly diminished risk of side effects. 

Before testing in patients, there needs to be independent verification of the published results by those who are versant in CRISPR gene editing. Also, testing in animal models to confirm safety and efficacy is both scientifically and morally necessary. For groundbreaking biomedical treatments, scientists owe it to themselves to confirm their findings and not be caught chasing shadows. 

Dr Yoshizumi Ishino (Kyushu University)
Professor Yoshizumi Ishino, PhD, first discovered the repeated sequence of DNA that forms the basis for CRISPR technology more than thirty years ago. (© Kyushu University)

Potential Windfall.

Should this particular method of gene editing turn out to be safe and highly effective, there will be a huge financial windfall and prestige. In fact, an intense, protracted battle has raged over who should rightfully receive the patent for CRISPR technology. The US Patent and Trademark Office (and US Court of Appeals) eventually awarded the patent to Dr Feng Zhang of the Board Institute, a nonprofit genetics research institute based in Cambridge, MA, and the Massachusetts Institute of Technology, rather than Drs. Jennifer Doudna and Emmanuelle Charpentier, who shared the Nobel Prize in Chemistry in 2020 for their work on CRISPR technology. 

As a point of interest, the 2020 Nobel Laureates did not in fact discover CRISPR — this honor goes to Dr Francisco Mojica, Universidad de Alicante, Spain and Dr Yoshizumi Ishino, at the time at Osaka University. 

Developing new therapies can be resource intense and expensive. One will note in Dr Kawamata and colleagues' paper the numerous organizations that funded the group's work. They included local and national government agencies, private organizations and pharmaceutical companies. 

If There's A Breakthrough

A breakthrough treatment could bring the inventors enough cash for the development of the next breakthroughs. For one treatment of Swiss-based CRISPR Therapeutics' for hereditary blood disorders, patients will face an estimated cost of $1.9 million USD. CRISPR Therapeutics currently has a market capitalization of about $4 billion USD. However, this could go much higher if their treatment succeeds in larger clinical studies and wins regulatory approval.

In fact, Dr Kawamata stated that, "The group is now working on a start-up business plan to spread the new genome editing platform." He also explained that "…we believe that this technology can make a significant contribution to the medical field… especially for rare diseases for which no treatment methods have yet been established."

Beyond Japan, many other groups have either already started testing in patients or are planning to start such tests, so Dr Kawamata and colleagues will need to move quickly. 

A medical researcher studies sickle cell anemia at the National Heart, Lung and Blood Institute. (Via Wikimedia Commons images No.39235727535)

Early Human Tests of CRISPER Gene Editing

CRISPR Therapeutics, in conjunction with Boston-based biopharmaceutical company Vertex Pharmaceuticals, began small-scale clinical trials in 2019 using their CRISPR technology for the treatment of sickle cell anemia. 

Red blood cells contain hemoglobin, the protein that carries oxygen needed by tissues. In sickle cell anemia, a mutation of one DNA nucleotide leads to deformed hemoglobin, which in turn leads to deformed red blood cells and decreased oxygen carrying. 

Humans have two copies of the hemoglobin gene, one from each parent. A mutation in just one copy does not lead to sickle cell anemia but is actually protective against malaria. People with one mutated hemoglobin gene and one normal gene live in places where malaria is endemic, such as the Mediterranean, the Middle East, India and sub-Saharan Africa. Most sickle cell anemia patients in the US are African Americans. 

The consequences of having both mutant genes include anemia, potential for a stroke and intense, persistent pain. As sickle cell anemia is a genetic disorder, there is currently no cure. There is only management of symptoms with blood transfusions and powerful painkillers such as opioids. 

What's Involved in Treatment

CRISPR Therapeutics' treatment involves collecting some of the patient's bone marrow cells, which make red blood cells, changing its genes with CRISPR gene editing to the fetal hemoglobin gene and returning the cells back to the patient. The goal is that the new, gene-edited cells will produce normal hemoglobin and over time replace the cells with the defective hemoglobin gene. 

Preliminary reports indicate that after one-time treatment, sickle cell anemia patients have not had the need for blood transfusions or opioid treatments for pain. 

Aside from using one's own cells, there are a number of strategies to deliver edited genes. For example, encapsulating CRISPR in nanoparticles or non-harmful viruses and injecting them systemically or into specific areas of the body. Changing adult dividing cells through CRISPR gene editing is a promising method of treating genetic disorders without affecting healthy cells, as current treatments can through such as chemotherapeutics.

Far Into the Future.

While the genetic cause of sickle cell anemia is relatively straightforward, there are hopes that CRISPR can be used to treat more complex genetic disorders. There are formidable barriers, however, such as the sheer number of genes that need to be edited. 

For example, the debilitating and difficult to manage mental illness schizophrenia is believed to be mediated by hundreds of genes. Furthermore, many of the genes associated with schizophrenia have roles beyond brain functioning ("pleiotropic"), and changing these genes may change the functioning of other organs

Some have proposed using gene editing to boost heritable traits like intelligence by manipulating genes in embryos. As with schizophrenia, many of the genes associated with intelligence — over 1,000 have been identified ー serve functions in other organs. 

For example, increasing intelligence could change the shape of the eye. Even changing apparently benign traits, such as eye color, could lead to global changes such as changes in skin and hair color. 

Currently, the state of knowledge of the genetics of physical and mental traits is limited. Moreover, there is a potential for editing errors following CRISPR gene editing and few suitable nonhuman animal disease models. For these reasons, gene editing, especially during the embryonic stage, for complex human diseases and traits is probably far off in the future. 

Chinese biomedical researcher Dr. Jiankui He (Image via Wikimedia Commons)

Ethical Questions.

Before that day arrives, both lay people and scientists wonder whether gene editing should be allowed at all. The current debate moves well away from technical challenges to vaguely defined values (e.g., human dignity, genetic identity), the right of a state to impose its values over the values of individuals, and the right of individuals to make choices based on personal values. Psychological factors ("cognitive biases") that underlie decision making in general also appear to have a significant role in the debate. 

Debate becomes even more intense over the question of gene editing of reproductive cells (sperm and egg) and embryos. Changes to genes in these cells are heritable. That is, if adults arising from these edited cells and embryos have children, then the edited genes will be passed on to their children and to their children. 

Manipulating mutant genes in reproductive cells or embryos would be the logical step in preventing genetic diseases. Studies have been performed with human embryo using CRISPR gene editing. And most gene-edited embryos are destroyed at the completion of the studies, without implantation into a womb. 

However, in 2018 at an international conference on human genome editing, Dr He Jiankui reported his work on human embryos that underwent both gene editing and implantation. Two apparently healthy girls were the result. 

The Case of Dr He Jiankui

Despite growing up in poverty, Dr He was a bright and enthusiastic student. Following graduation with a degree in physics from a highly selective technical college in Hefei, Dr He earned a doctorate in biophysics at Rice University in Houston. 

While a post-doctoral researcher at Stanford University, Dr He responded to an ad placed by the city of Shenzhen offering generous financial incentives, including lab and business start-up funds, if he moved back to China. Dr He took a position at a technical university in Shenzhen in 2012. Then in 2017, Dr He was inducted into the prestigious Thousand Talents Program. Subsequently, in conjunction with the opening of the 19th Chinese Communist Party National Congress, he was recognized by state media for his accomplishments.

Following his announcement at the international conference on human genome editing, the People's Daily, the official newspaper of the Central Committee of the Chinese Communist Party, praised Dr He's work, "the world's first genome-edited babies … born in China". 

Following near universal condemnation of Dr He for potential ethical lapses and lack of transparency, the "laudatory" People's Daily article quickly vanished. Furthermore, the Chinese Communist Party branded Dr He a non-person and sentenced him to three years of prison for "illegal medical practice". In 2023, a "group of [Chinese] scholars" roundly denounced Dr He by name, and called for more restrictions of work involving genetic editing. 

Institutional Duplicity Undermining the Science 

Dr He was called an "amoral mastermind." And Dr He's university and the hospital in which the embryo study was performed claimed that absolutely no one knew what he was up to and that documents necessary to conduct clinical studies were forged. 

More likely, though, given Dr He's extensive vetting by the government and the presence of the Chinese Communist Party "at every school" and "every hospital," everyone, including the government, knew exactly what he was up to. And they possibly facilitated his experiment so as to boost China's international standing and to cement China's place in genetic history. 

In addition to possibly lacking in integrity, some accused Dr He of being motivated by pure self-interest rather than scientific curiosity and a genuine desire to help people. 

The "He episode" left an extremely bad impression of genetic editing. It is possible that governments, including that of Japan, may restrict all human genetic editing clinical projects.

This episode has left a negative impression of science in general as well, that scientists are self-interested and more than willing to break rules to come out on top. Perhaps because the process of developing new treatments is so costly, a few are willing to cut corners and cross ethical boundaries. Scientists should reflect on the current incentives they face, in addition to the ethics of gene editing.

animal research
A rat used in animal research (© Stanford University via Wikimedia Commons)

Animals in the Loop.

As noted earlier, testing in laboratory animals will be essential in establishing safety and efficacy of CRISPR gene editing. Mice have been the go-to species for testing gene editing as they have a short gestation period, large number of offspring and rapid maturity. For example, Dr Kawamata and colleagues used mice to confirm that their method was an improvement compared to what is currently available. 

Mice as model species have drawbacks, however. Those include having a genome significantly different from that of humans, small organs which may lead to overestimation of treatment efficacy, and species specific embryonic development. 

Nonhuman primates have a higher degree of biological similarity to humans compared to mice. A study using monkey embryos that underwent routine CRISPR gene editing demonstrated the occurrence of numerous genetic errors. Given that monkey biology is close to that of humans, this finding suggests that current gene editing technology is not ready for use in human embryos. 

It should be noted that the gene targeted in the monkey study was the same gene that Dr He targeted in his human embryos. (Whether the girls from Dr He's experiment are in fact healthy is unknown. There has yet to be independent verification.) 

Rather than jumping on the latest, flashiest scientific bandwagon, careful evaluation and verification of scientific claims, and thorough reflection of long-term safety and efficacy data are preferred. This is the very least that scientists can do for patients. And the least they should do for a public that has grown suspicious of public health measures, such as vaccination, during the Wuhan coronavirus pandemic. 

Slow and steady will win the race.

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Author: Dr Aldric Hama

Find other reports and analysis by Dr Hama here, on JAPAN Forward.