Genome editing can be risky. Meet the epigenome editors
The technology could tackle diseases such as atherosclerosis and hepatitis B
“WHEN IS A gene editor not a gene editor?” may sound like a scientific riddle with a groan-worthy punch line. But it is a question whose answer instead deserves many an appreciative intake of breath. That is because scientists keen to achieve more precise control over an organism’s genetics are experimenting with a surprising approach that leaves the genome itself unharmed.
The principle behind gene editing sounds simple. Molecules of DNA contain strings of chemicals called bases, sometimes referred to as the letters of the genetic alphabet. Alter this sequence of letters and genes can be turned on or off at will. It is a trendy idea already being applied in agriculture. But so far just one medical intervention has been approved: switching on a gene normally active only in infants to treat sickle-cell anaemia and beta-thalassaemia, two blood diseases, in adults.
The lack of medical deployment is, in part, because gene editing can go wrong. It requires cutting the DNA molecule and an off-target cut might, for example, disable an anticancer gene with possibly serious consequences. That provides an opening for an alternative. Epigenetic editing, as this alternative is called, employs similar biotechnology to gene editing but makes no cuts in the DNA. Instead it tinkers with the epigenome, a set of chemical markers attached to the genome that regulate genes’ activities. The tinkering is less intrusive than gene editing, and allows a gene’s output to be modulated, rather than simply switched on or off.
Epigenetic editing already shows promise for the treatment of certain metabolic problems, chronic viral infections and inherited genetic diseases. Over time that list should lengthen, as the role of the epigenome is better understood. And some visionaries hope for still more. They note that harbingers of old age, such as chronic inflammation and cellular senescence, have an epigenetic component, too. It is possible, they say, that epigenetic editing could one day be used not just to treat disease, but also to extend human lifespan.
The molecular machinery employed in conventional gene editing has two components. One is a guide that recognises where on the target genome the machinery needs to attach itself. The other is an enzyme that cuts the DNA at this point.
Epigenetic editing works in the same way, except that the enzyme which does the cutting is disabled and another enzyme is added. This additional enzyme adds or subtracts small groups of atoms either to or from the DNA itself, or from the histone proteins around which DNA molecules are wound to form chromosomes. The groups are methyl (a carbon and three hydrogens) and acetyl (two carbons, three hydrogens and an oxygen).
Methylation of DNA stops proteins that regulate gene activity, known as transcription factors, from binding to pertinent regions of the genetic material. Methylation and acetylation of histones affects how tightly those proteins bind to their DNA neighbour, and thus how easy it is for transcription factors to reach their targets. Manipulating these various effects can fine-tune what a gene can get up to in a cell.
Given the similarity of gene editing to its epigenetic cousin, it is little surprise that several of the firms involved in the latter were started by pioneers of the former. One such is Scribe Therapeutics of Alameda, California, which was co-founded by Jennifer Doudna. Dr Doudna shared a Nobel for her work on a gene-editing technique called CRISPR/Cas9, the guidance system of which is a DNA-like molecule called RNA that seeks out stretches of DNA with a complementary sequence of genetic letters. Cas9 is the editing enzyme.
Scribe’s own editing platform, ELXR, is a refinement of this arrangement that employs a smaller, nimbler enzyme called CasX. Benjamin Oakes, another of the firm’s founders, and its current boss, has a list of possible targets for ELXR, at the top of which is a gene called PCSK9. This encodes a liver protein that reduces the breakdown of cholesterol-rich packages called low-density lipoproteins (LDLs). These, if too abundant in the bloodstream, can lead to atherosclerosis, the main cause of heart attacks and strokes. And those, in turn, kill around 17m people a year.
Scribe’s proposed answer to this—which will, all being well, enter clinical trials in the summer—is an epigenetic edit that turns down the volume on PCSK9 and thus ups the destruction of LDLs. The cost of such a treatment would, admittedly, mean that only a small fraction of those affected by atherosclerosis could benefit. But, if it worked as intended, it would be much more convenient: a one-off dose rather than the daily round of pills currently prescribed to keep the condition at bay.
A different liver-related problem, hepatitis B, is in the sights of two other epigenetic-editing firms: Tune Therapeutics of Durham, North Carolina, and nChroma Bio of Boston. They have started trials of rival editors for the epigenome of the virus, HBV, which causes the illness. HBV hangs out in liver cells and often infects people for life. And hepatitis B, like atherosclerosis, is a big problem. It affects 250m people and kills more than 1m of them a year.
For now treatment is a daily dose of a drug that stops the virus reproducing—but only while it remains in the patient’s system. By disabling HBV genes, epigenetic editing offers the possibility of a cure.
Back in California, Epicrispr Biotechnologies has yet another target. Epic Bio, as it is known for short, was founded by Stanley Qi, a researcher at Stanford University who earned his PhD in Dr Doudna’s lab and who was the first to work out how to disable Cas9’s cutting mechanism. Dr Qi has his sights on facioscapulohumeral muscular dystrophy (FSHD), a currently incurable creeping paralysis caused by the activation in adulthood of a gene useful in embryonic development. Epic Bio’s editor, GEMS, is being deployed, in a trial currently involving eight patients, to deactivate this gene and thus effect a cure.
Those with other conditions might benefit from epigenetic editing, too. A review of the field published in January, by a group at the Chinese University of Hong Kong, lists a range of cancers; muscular dystrophies other than FSHD; several rare, inherited conditions such as Rett syndrome and Friedreich’s ataxia; retinitis pigmentosa (a form of blindness); chronic pain and even alopecia as possible targets.
Some of these conditions might also be tackled by other approaches. PCSK9 and HBV are both topics of conventional gene-editing projects and FSHD is under attack by a method that uses molecules called small interfering RNAs (siRNAs) to intercept the messenger molecules which carry the unwanted protein’s recipe to a cell’s protein factories. A real competition is thus going on between alternative candidate treatments.
Dr Qi waxes eloquent about epigenetic editing’s advantages—particularly over gene editing. His main point is that since much of the genome is not involved in regulating gene activity, off-target landings by an epigenetic editor will usually be in places where they can do little harm. Dr Qi is also among the visionaries who see epigenetic editing as a path to better and longer old age. But even in this highly speculative area, there are rival approaches. Other researchers, for example, seek to restore youthful vigour using a set of transcription factors that can perform epigenetic “factory resets” on cells.
It is not, of course, all plain sailing. In 2022 Feng Zhang, another gene-editing pioneer, started a firm called Moonwalk Biosciences that had epigenetic-editing aspirations. Recently, however, Moonwalk has shifted its attention to siRNAs.
Such hiccups are to be expected. Molecular biology is a young science and its mechanisms, kludged together by 4bn years of evolution, are hard to disentangle and tinker with successfully. Investors are not always patient creatures. And rival approaches are always waiting to pounce. Epigenetic editing does, though, look like a field with a bright future. Given a fair wind it seems likely to establish itself as an important part of the medicine of the mid-21st century. ■