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The Issue of Inheritance in Epigenome Editing

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Tremendous strides have been made in genome editing – the application of sophisticated techniques and tools to edit the DNA of a cell. Earlier this month, the US Food and Drug Administration approved the first CRISPR-based gene therapy to treat patients with sickle cell disease.

DNA code provides the instructions for our cells’ molecular machinery to create proteins, but the master regulator of whether those genes are expressed – i.e., turned “on” or “off” – is the epigenome.

What is the epigenome?
The epigenome is a vast, complex array of chemical modifications that occur to DNA or DNA-associated proteins in a cell, regulating gene activity. Epigenetic changes can occur in response to internal or external factors, such as environmental stimuli, hormone and signaling pathways or disease and pathological states.

While epigenetic compounds “mark” the genome when they attach to DNA and modify its function, they do not alter the underlying DNA sequence. Therefore, an alternative approach to affect changes in gene function – beyond genome editing – is to edit the epigenome. Instead of taking a pair of scissors to the genome, epigenome editing is likened to applying a dimmer switch, which carries advantages such as reversibility and a reduced risk of off-target effects.

As epigenetics research has advanced over recent decades, so too has the suite of tools enabling precise modifications to be made to epigenetic marks. Now, a number of companies are developing epigenome editing-based therapeutics to target diseases such as muscular dystrophy, which causes progressive muscle weakness.

Given that epigenetic changes are reversible, epigenome editing has emerged as a tool that would likely pose fewer ethical issues compared to the permanence of genome editing. However, emerging research is demonstrating that epigenetic changes might be heritable, at least in some organisms. This phenomenon is known as transgenerational epigenetic inheritance, or TEI, and it’s a heavily debated subject within the scientific community.

Evidence suggesting TEI could happen in mammals is limited, but does exist.  

Technology Networks interviewed Dr. Tsutomu Sawai, associate professor in the graduate school of humanities and social sciences at Hiroshima University, and Dr. Mitsuru Sasaki-Honda, postdoctoral fellow in the Center for iPS Cell Research and Application at Kyoto University to discuss the question: If TEI occurs in humans, what ethical implications might this carry for epigenome editing-based therapies? Sawai and Sasaki-Honda are co-authors of a recent Stem Cell Reports forum piece on this subject. 

Molly Campbell (MC): Can you discuss your work in philosophy and bioethics, and why you have focused on epigenome editing?  

Tsutomu Sawai (TS): Science and technology are surging forward, unlocking new possibilities for the present and future. Yet, the boundaries of research and technological innovation remain unclear, including who should define them. This paper delves into epigenome editing – a cutting-edge research field poised to offer societal benefits.

With novel insights based on the latest science, we explore uncharted ethical territories in transgenerational inheritance, a hotbed of debate in human genome editing ethics and regulation. As medical applications of epigenome editing emerge, we are passionate about illuminating critical yet overlooked ethical considerations.

MC: Why might epigenome editing be advantageous over gene editing in some circumstances?

TS: Epigenome editing stands at the frontier of biotechnology, offering a tuneable approach to gene regulation without altering the DNA sequence itself. Its reversible nature positions it as a promising candidate for treating a spectrum of genetic and chronic conditions.

MC: Why did you choose to write this forum piece?

TS: Recent findings, published in February, reveal that even the seemingly advantageous epigenome editing could have far-reaching consequences for subsequent generations.

This potential to influence our progeny necessitates a broader ethical reflection, extending beyond the immediate safety and efficacy of its medical use. With this in mind, our discourse cautions against undue optimism regarding the ethical and regulatory landscape of epigenome editing, especially concerning its transgenerational inheritance.

MC: There are a number of tools and technologies adopted for epigenome editing. Can you discuss the most commonly used tools, and perhaps some of their applications?

Mitsuru Sasaki-Honda (MSH): CRISPR interference (CRISPRi) and CRISPR-mediated transcriptional activation are popular and straightforward tools for suppressing and activating genes, respectively. For example, a clinical trial is planned utilizing CRISPRi principles for suppressing a pathogenic gene in a form of muscular dystrophy. These are "on-site–only" tools that are designed to act without epigenetic memory and are less likely to touch a transgenerational issue for now.

MC: TEI has been demonstrated in several organisms, but whether it occurs in mammals is not yet clear. Why is this? Can you talk about why it is important when considering the future of therapies that utilize epigenome-editing tools?   

MSH: Compared to other species, it is still technically challenging to separate the pure epigenetic changes through several generations from direct environmental effects and genetic changes in animal investigations, and most epigenetic changes made in parents appear to be erased in germline and embryonic stages that all the cells pass through to grow into an offspring.

But Takahashi et al. successfully demonstrated that it could happen, even if the experiment design is tricky. This means that artificially induced epigenetic changes can be passed beyond generations as an intergenerational epigenetic memory.

Indeed, not all, but a certain type of epigenome editing aims to establish an epigenetic memory to achieve a persistent effect. So, theoretically, scientists are likely to discover how to execute inheritable epigenetic editing beyond generations. It means that you could epigenetically control your offspring's biological features, intentionally, before birth. This situation will create the same ethical issue as heritable genome editing.

MC: What are the key challenges when deciding how technologies such as epigenome editing are developed or authorized for human application?

TS: Our first step is to rigorously establish when and how epigenome editing may affect future generations. We must then weigh the significance of this heritability in human applications. Should the hereditary impact of these interventions be deemed ethically and regulatorily negligible, it could shake the foundations of the current opposition to human germline genome editing, which is tightly controlled for this very reason.

Consequently, we find ourselves at a crossroads, tasked with aligning the ethics and regulations of epigenome editing with those established for human genome editing, striving for consistency and foresight.

MC: In your opinion, what applications of epigenome editing might we see in the clinical space soon? Are there applications that are still being refined, that we will perhaps see in the future?

MSH: There are already plans for epigenome editing to be applied in humans. Advances are very rapid and new tools will become increasingly feasible to use. Currently, those cases are applying "on-site–only" tools that are designed to act without epigenetic memory and are less likely to touch a transgenerational issue, but we will see cases emerging with "memory-forming" tools that may touch it.

In terms of disease inheritance, transgenerational "block" might be appealing to some people, but we should take care of the possible outcomes carefully.

MC: Is there anything further to this conversation that you think is important to highlight?

MSH: We believe that science and technology can help us but sometimes they are simplified for convenience.

Ethical discussions need advanced understanding and scientific predictions to find any pitfalls in them. Issues around inheritability are especially sensitive. We need to consider how to apply these technologies, balanced with other technological and social methods, to truly benefit the people who need assistance without relying on a certain straightforward direction.

Dr. Tsutomu Sawai and Dr. Mitsuru Sasaki-Honda were speaking to Molly Campbell, Senior Science Writer for Technology Networks.