Thu. Jun 13th, 2024

The CRISPR-Cas “genetic scissors” enables genetic changes to be made faster than ever before. While the first patients are being treated with CRISPR therapies, germline interventions are still the subject of international debate. Their application carries a high technological and social risk.

Cover illustration: © JUN CEN (www.instagram.com/juncenart)

As heritable human genome editing is an international issue, we have compiled all the articles of the issue 268 of our German language journal GID as PDF and on our website as an English-language dossier. Please feel free to pass it on to potentially interested parties.

Dossier Human Heritable Genome Editing (February 2024)629.31 KB

Content

  1. Introduction – Lilly Presser and Dr. Isabelle Bartram
  2. Just do it? Current landscape of international debates on human genome editing – Dr. Daniel Papillon
  3. “The security debate is a red herring” A disability rights perspective on human genome editing – Interview with Prof. Dr. Gregor Wolbring
  4. Social Justice and Human Rights. Principles for Global Deliberations on Heritable Human Genome Editing – Dr. Katie Hasson
  5. Germline editing made in Germany? Calls for German embryo research – Dr. Isabelle Bartram

Introduction

By Lilly Presser, biology student and student assistant at GeN, and Dr. Isabelle Bartram, molecular biologist and Program director at GeN.

Genome editing describes new molecular biology technologies that can be used to precisely modify DNA. In particular, the discovery of the so-called “gene scissors” CRISPR-Cas9 has brought the topic to the attention of the media. This article is intended to provide an overview of the current state of development as a basis for this issue of GID, which focuses specifically on the debate on germline modification through genome editing.

CRISPR generates hope for the development of new therapies due to its more precise and efficient application compared to previous genetic engineering methods. In basic biomedical research, for example, the development of model organisms like knock-out mice, where certain genes are inactivated, has been significantly accelerated. However, the genome editing method gained publicity not only due to its simpler application. In 2018, the Chinese scientist He Jianku announced that he had created the first genetically modified babies using CRISPR technology – a scandal that added pressure on the international debate on genetic modifications in humans.

Scientists promise to be able to alter the human genome in a targeted and precise manner in order to treat and cure diseases. Such interventions can take place somatically or at the level of the germline. In somatic gene therapy, people with diseases caused by small gene variants can be treated. Either cells are removed, modified in the laboratory and reintroduced into the patient (ex vivo), or the genome editing complex is injected directly into the patient (in vivo) where it modifies the genome of cells. Another option is germline interventions – as put into practice by He Jiankui – in which germ cells or embryos are genetically modified. Unlike somatic approaches, these changes are passed on to the next generation and are hereditary. While germline interventions are illegal in most countries with corresponding legislation1 , the first CRISPR-based gene therapies are currently reaching clinics around ten years after their development began.

The first CRISPR therapy

Two genetic blood disorders – sickle cell anemia and beta-thalassemia – are now to be treated for the first time using CRISPR-Cas. These two diseases are caused by an aberrant variant in the gene for the blood pigment hemoglobin. In the case of sickle cell anemia, this means that red blood cells do not have their typical concave shape, but are partially sickle-shaped or curved, resulting in clumping. Oxygen transport in the blood is impaired, which can lead to severe physical pain, organ damage, and a greatly reduced life expectancy – on average around 40 years – for those affected. The first CRISPR therapy for sickle cell was approved in the UK in November 2023, followed by approval in the USA in December. It is called exa-cel (exagamglogenic autotemcel or Casgevy) and was developed by Vertex Pharmaceuticals and CRISPR developer Jennifer Doudna’s company, CRISPR Therapeutics. The European Medicines Agency (EMA) also recommends approval for exa-cel. The therapy consists of removing blood-forming stem cells from patients and modifying them using CRISPR-Cas. Instead of treating the defective hemoglobin gene itself, so-called fetal hemoglobin is reactivated. This form of hemoglobin is active at a specific embryonic stage and is silenced after birth. Using CRISPR-Cas, it is reactivated in blood stem cells from patients in the laboratory and transplanted back into their bodies. There, the cells will produce red blood cells and the fetal hemoglobin will compensate for the symptoms of the blood disorder.

As small as the intended genetic intervention by exa-cel may be, the treatment represents a massive intervention in the patient’s body. The therapy only works if the body’s own blood stem cells have been destroyed beforehand. The chemotherapy required for this is very physically demanding. One advantage of gene therapy over conventional stem cell transplantation is that the risk of the patient’s immune cells rejecting the modified stem cells is significantly lower than with donated cells.
The results from clinical studies with a total of around 100 patients have been promising so far, with almost one hundred percent of those treated reporting the disappearance of pain. However, the duration of the effect and potential long-term side effects are not yet known. Some scientists, including those within the FDA – the US Food and Drug Administration – are concerned about possible unwanted genetic changes caused by the Cas enzyme that remains active.2 There is also the question of who can afford such a therapy, as it costs around two million euros per person.

Problems and hope

Even though CRISPR-Cas is more efficient and precise than previous genetic engineering methods, new studies repeatedly show that the technology is far from being as flawless as presented by some media reports. One example of unwanted effects is He Jankui’s attempt to make “CRISPR twins” resistant to HIV by means of genetic modification at the embryonic stage. The CCR5 gene contains the information on building blocks for a protein that is a target for HIV on the surface of immune cells. He tried to induce a naturally occurring change in the gene that is known to cause HIV resistance. Affected individuals are missing 32 base pairs in both copies of the gene, the variant is therefore called CCR5-Δ32. Even if the germline intervention has worked as planned, it is difficult to predict how a change in the protein will manifest itself. Genes often have a pleiotropic effect, i.e. they are not only responsible for one function, but for several. CCR5, for example, also plays a role in brain function.3 Thus, enormous health consequences are at stake.

In addition to the problem that the consequences for the protein cascade are not directly apparent, the actual precision of the gene scissors is also called into question.4 This is because the term “scissors” is actually also very misleading. The nuclease that causes a double-strand break in the DNA is not nearly as precise as a pair of scissors. It is not a simple “cut” but chemical bonds that are broken. A double-strand break can therefore also occur imprecisely and cause unwanted mutations. The use of CRISPR-Cas can also lead to off-target effects, i.e. changes to genes that lie outside the target sequence. Depending on where these changes occur in the DNA, they can go unnoticed or have serious consequences – in the worst case, they can lead to cancer. Another risk is genetic mosaics. Here, the desired changes are not present in all cells in the embryo, but only in some, as in a mosaic. This can also lead to health problems.

Dispute over recognition and money

When weighing the technical benefits vs. risks of genome editing, the economic context is often ignored. As the price of the gene therapy exa-cel shows, there is a lot of money at stake. In 2020, Jennifer Doudna and Emmanuelle Charpentier were awarded the Nobel Prize in Chemistry for the discovery and development of CRISPR-Cas in 2012. However, a second research team led by Feng Zhang was also working with the technology at the same time. There has been a patent dispute between the teams since 2016 for millions in license fees and recognition in the scientific community for the technology as a whole. In February 2022, the US Patent Office decided that Zhang would receive the patent for the use of CRISPR-Cas in higher organisms, as he was the first to use the technology in mice and human cells. In the meantime, other research teams around the world have also filed patent applications for various applications of the technique.

A global debate is necessary

Great financial interest from many sides exist to present CRSIPR-Cas as precise and safe tool and to develop it for a variety of profitable applications – one of which is the fertility sector. As the data on egg transfer and surrogacy abroad shows, national legislation cannot prevent many intended parents from using ethically controversial reproductive technologies. The regulation of research into and use of heritable genome editing must therefore be an international issue. This dossier therefore addresses the international debate on germline interventions from a critical feminist and anti-eugenic perspective.

Dr. Daniel Papillon, spokesperson for the International Coalition to Stop Designer Babies, outlines the evolution of global debate since the development of CRISPR-Cas. An interview with Dr. Gregor Wolbring, Professor of Disability and Ability Studies, underlines the importance of the disability rights perspective. Wolbring criticizes the focus of the debate on the safety of the technology, which civil society actors sometimes also fall prey to. In order to move away from this limited perspective, an international alliance has developed principles of human rights and social justice in relation to heritable genome editing. Dr. Katie Hasson from the US Center for Genetics and Society presents these guidelines. In the last article of the dossier, Dr. Isabelle Bartram draws a line back to the German debate, in which the legal ban on embryo research is currently being discussed. Scientists are trying to overturn the Embryo Protection Act with the dubious promise of “germline therapy”. However, the debates taking place at the highest level are characterized by a striking lack of feminist and economically critical arguments. Once again, the focus is on purely scientific arguments and unrealistic promises, while social effects are ignored. A gap that this issue of GID aims to fill.