CRISPR meets Epigenetics: a marriage made in Heaven

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a natural defence system found in bacteria, which scientists have turned into a programmable way to edit genes with extraordinary precision. In practice, it comprises two parts: a guide RNA that acts like a GPS to find the exact spot in DNA, and a Cas9 enzyme that acts like molecular scissors to cut the DNA. Once the DNA is cut, scientists can delete, fix, or replace genetic sequences inside a living cell. Our first Cover seems to have been over six years ago (LSS 23 11 20), since when we have noted a startling range practical applications from areas as diverse as horse breeding, and sickle cell medicine, to its relationship with blue sky techniques such as Base Pair editing, CART and programmable therapeutics (LSS passim).

How gratifying then to see CRISPR-based tools now partnered with epigenetics, that other old favourite of these humble pages! Once again the lead is taken by the indispensable Nature Briefing, now our go-to for all new things Scientific Their summary CRISPR’s next act: editing the epigenome tells you most of what you need to know. But some readers may well wish to click on the handy link too

A handful of start-up firms are testing therapies that target specific epigenetic markers — essentially chemical groups that sit on DNA and the proteins that it is wound around — to treat everything from high cholesterol to a rare muscular disorder. Changing these chemical markers can switch genes on or off. Some existing medications influence epigenetic markers, but these drugs act broadly and lack specificity. A new cadre of scientists has found ways to precisely alter the epigenetic signals that influence specific genes.

Nature | 15 min read

There is much here to gladden the hearts of all who believe in Reason and Learning. The technique seemingly so radical a few short years ago is not only becoming routine, it is embedding itself into the wider corpus of medical and scientific practice. Practicable applications are multiplying and the opportunities to reduce human and animal suffering are thereby multiplying. If anyone asks us “why do you take such an interest in the progress of the Arts, Sciences and Letters?” one answer we give is: because of things like this.

If you want to know more about epigenetics, or molecular biology in general, then we cannot do better than recommend the works of the great Professor Carey:

Carey, Nessa. The Epigenetics Revolution: How Modern Biology Is Rewriting Our Understanding of Genetics, Disease, and Inheritance.London: Icon Books, 2011. New York: Columbia University Press, 2012. ISBN: 9781848312920 (Icon Books); 9780231530712 (Columbia UP).

Carey, Nessa. Hacking the Code of Life: How Gene Editing Will Rewrite Our Futures.London: Icon Books, 2019. New York: Columbia University Press, 2019. ISBN: 9781785784972 (Icon Books); 9780231549769 (Columbia UP).

#molecular biology #genetics #epigenetics #CRISPR Cas 9 #medicine #health #DNA #RNA

Gene Megacluster: a really big moment in antibiotic research

The idea of whole and unexpected possibilities in antibiotic research excites our highest hopes-and those of readers who have accompanied us on this journey for years. None more so than this report from Nature Briefing Gene Megacluster boosts antibiotic arsenal. We’ve set up their usual summary, plus links: and then we’ll try to answer a few of your questions as best we are able

A newly discovered gene ‘megacluster’ in Streptomyces bacteria enables them to produce a variety of potent antibiotic compounds. These compounds act as a multi-pronged offensive weapon against other species, with each targeting different stages of the bacterial metabolic process. It’s more difficult for bacteria to develop resistance to attacks that hit several targets, so the discovery could lead to the development of new antibiotics, experts say. The research has “discovered something new in a system so extensively studied — hidden in plain sight,” says medicinal chemist Mark Blaskovich

Nature | 4 min read
Reference: Nature paper

So, what is this gene megacluster? An unusual stretch of DNA in Streptomyces that encodes four distinct families of natural-product antibiotics, including: one compound entirely new to science, another never previously recognised as an antibiotic, and two known families deployed in a new coordinated fashion. Not a bad haul for one discovery, we think.

What does it do in Streptomyces? All four molecules target biotin (vitamin B7)—a universal cofactor required for growth, cell division, and metabolic enzyme function in most bacteria. They attack different points in the biotin pathway: production, uptake, use, and availability, aided by flanking streptavidin genes that bind up free biotin.

Why is this discovery genuinely new? Well , all sorts of reasons: here are a few of the best

–Co-location is unheard of: Antibiotic biosynthetic pathways are usually scattered across the genome. Here, four unrelated antibiotic families sit side-by-side, implying intentional evolutionary selection.

–Coordinated multi-antibiotic strategy: Natural antibiotics typically act alone. This cluster encodes a team of molecules that hit the same vulnerability from different angles—something not previously documented.

–Hidden in plain sight :Streptomyces genomes have been mined for decades, yet this megacluster was overlooked because genome-mining tools historically focused on single-product clusters. We love this bit, as regular readers will have already discerned

–It appears to be widespread. The megacluster is present across multiple Streptomyces species, suggesting an ancient, conserved strategy rather than a rare curiosity.

Could similar clusters exist in other organisms? Likely, yes. The discovery provides a road map for genome mining that looks for coordinated multi-pathway clusters, not just single biosynthetic islands Early research might do better to focus on procaryotes rather than eucaryotes-but who knows?

How could it help us to develop new antibiotics? This is the Big One for us , isn’t it? Lots of ways potentially, but as of late June 2026 three practical routes suggest themselves:

1. Direct development of the four biotin-targeting molecules. Because they attack different steps in the same essential pathway, they could be: used individually, combined as a cocktail, or engineered into hybrid molecules. Multi-target antibiotics are inherently harder for pathogens to resist. So that will teach them we’re serious this time.

2. Synthetic biology reconstruction. The megacluster’s architecture can be transplanted into: Streptomyces strains, E. coli or yeast expression systems, or modular cell-free platforms, permitting all sorts of scaling and production advantages

3. Drug discovery by analogy The discovery provides a template: look for clusters that coordinate attacks on other essential pathways (e.g., folate, isoprenoid synthesis, lipid II). Genome mining guided by this logic could uncover dozens of new multi-pronged antibiotic families.

4. Biotin-pathway inhibitors as a new class Biotin metabolism is conserved across many pathogens, including Gram-negatives—historically hard to target. These molecules could seed a new class of antibiotics that bypass existing resistance mechanisms

At this blog we tend to rate discoveries by the possibilities they open rather than the questions they answer. By that metric, this one is big indeed-and we think you’ll al agree with that.

#antibiotic research #antibiotic resistance #health #medicine #biotechnology #genetic engineering #research #bacteria

Programmable Therapeutics(here’s what they’ll be talking about in 2046)

In these happy, carefree days of 2026, we almost take the success of advanced techniques like CRISPR–Cas9 and CAR‑T for granted. Yet not so long ago they were obscure experimental curiosities, known only inside specialist laboratories. So we asked ourselves: is there something equally obscure in 2026 that will be the stock‑in‑trade of doctors in 2046? We think there might be: programmable cell therapeutics.[1]

The jumping‑off point is the logic behind CAR‑T. Readers will recall how T‑cells are removed from a patient, engineered to recognise the chemical signatures of their cancer, and then reinfused to hunt down malignant cells. Researchers are now extending this idea to a wider cast of immune cells, stem cells, and progenitors, so they can tackle diseases far beyond oncology.

What makes the next generation different is the importation of ideas from electrical engineering. Instead of a single engineered receptor, cells can be fitted with ON/OFF switches, logic gates, multi‑step decision pathways, and feedback loops. In other words, cells that don’t just attack — they compute. They sense the molecular environment, decide what’s happening, and act accordingly.

And thanks to delivery tools such as viral vectors and mRNA‑carrying nanoparticles, these circuits can increasingly be installed in vivo. Rather than the expensive choreography of removing cells, re‑engineering them, and putting them back, the ambition is to program the cell to reprogram itself. Why rebuild the army in the barracks when you can train the soldiers already in the field?

Gentle readers, we are always looking for ways to put you ahead of the curve — not what is happening now, but what will be happening in five, ten, or twenty years’ time. By 2046 we could plausibly see:

cancer therapies that activate only in tumour microenvironments
gene therapies that self‑limit to avoid toxicity
immune cells that make multi‑step decisions
RNA‑based switches that restore gene expression dynamically

All this, of course, depends on continued investment in scientific research and a strong ecosystem of independent universities and research institutes. Hopeful, isn’t it.

[1]Next-generation programmable cell therapies for precision medicine | Nature Reviews Genetics

#gene editing #medicine #health #cancer #mRNA #CRISPR #CAR-T #DNA

Progress on Multiple Sclerosis: When Big Data meets Molecular Genetics

Photo by Fayette Reynolds M.S. on Pexels.com

Few of us have not met someone who is suffering from Multiple Sclerosis, that terrible wasting disease wherein the immune system seems to turn on its own body, especially in the fatty sheaths around the neurons. Leading to a progressive deterioration in mobility before confining victims finally to a wheelchair-or even worse. The experience for families and victims was extra-bad because for many years the cause seemed unknown, making hope of any cure quite unlikely. Michael Marshall of the New Scientist has been covering this story most assiduously. And so we are pleased to showcase it, because it celebrates achievements in two our our favourite fields-big data and molecular biology-and the benefits which accrue when scientists from both work together.

We urge you to read Michael’s article either by buying the hard copy mag (there’s tons else to read inside it) or paywalling past the link below [1] Suffice it to say: #1 The molecular evidence that the Epstein Barr virus (which can cause glandular fever) is involved. #2 That this has a strong effect on both B cells and T cells in the immune system, which ,when they go rogue, are essentially responsible for the terrible lesions of MS #3 That not all hosts of Epstein Barr virus go on to develop MS, because the chances of that depends on certain genetic propensities and variants and, best of all #4 the above and more, which we report so glibly, has been elucidated by the use of huge data studies : 10 million people in one, 617, 186 in another, even 471 000 B cells in another-how’s that for numbers, folks?-which were only possible because: #5 places like the UK and USA have worked to build big collaborative things the the UK Biobank and All of us. Well some of the people in those countries have anyway.

All of which leads us to few reflections, some of which will not be uncongenial to regular readers. Firstly, it seems a pretty good idea to spend money on science, especially basic research, instead of cutting it. Secondly scientists these days work best in large teams whose members come from all sorts of backgrounds and this is especially true when you throw multidisciplinarygroups of them together. And that this also seems to be true of football teams: how far would Arsenal FC. for example, have enjoyed their current success if they had insisted on retaining a staff entirely composed of plucky British lads? [2] The implications in turn for visa systems, cultural openness and plain common sense are clear in turn.

[1]Huge study reveals how Epstein-Barr virus may cause multiple sclerosis | New Scientist

[2]‘Everything can happen’: Trossard confident of Arsenal’s chances in final | Arsenal | The Guardian

#multiple sclerosis #Ebpstein-Barr virus #T cells #B cells #autoimmune disease #medicine #health

Hydrogen from Microbiology-another hopeful story from Nature Briefing

You might be forgiven for thinking we’re against bacteria at this blog. Got a beef with them, want more antibiotics to kill them, especially that pesky little Escherichia coli that is always clogging up the pristine pages of our little website. Nothing could be further from the truth: we are simply against bacteria that kill people, that’s all, and we admire the little creatures for all the useful things they do

Nothing more useful it seems than generating hydrogen in clean green ways that massively reduce greenhouse gas emissions. Of course we need hydrogen for all sorts of things-food, drugs, plastics-but the way it is currently made is depressingly energy intensive Which is what this remarkable team of researchers at Edinburgh University have done, re purposing E coli to make hydrogen in amazingly clean ways Get this extract from the admirable Nature Briefing:

. The new process involves growing a strain of Escherichia coli that naturally produces hydrogen when deprived of oxygen. The researchers added a palladium catalyst and substrate for the hydrogen to bind to, and when they removed oxygen, hydrogen was bound to 94% of the substrate.

And they didn’t stop there:

The team then turned waste bread into a food source that could be given to the bacteria instead of glucose, to show that this type of food waste can be repurposed. The system resulted in a three-fold decrease in greenhouse-gas equivalent emissions compared with using fossil fuels, according to the team’s modelling.

There’s a lot to be said here. First our admiration for the amazing work and intelligence of the scientists[2] whose original paper we seem for once to be able to reproduce in full. The marvellous ways old things like bread and E coli are recycled to useful purposes. And a further point which the team at the admirable Nature Briefing know well. Progress, hope even, comes from the application of the scientific method. The use of evidence and reason to judge it in that order. Nothing else, however much you might want it to be so.

[2] Native H2 pathways enable biocompatible hydrogenation of metabolic alkenes in bacteria | Nature Chemistry

#microbiology #palladium #greenhoiuse gas# hydrogen# E coli #sustainabilityn #drugs #plastics

Breakthrough for blindness, an old lesson re-learned: and a mystery question

Leber congenital amaurosis, called LCA for short, is the most common form inherited sight loss in children[1] It’s caused by defects in a cluster of genes including RPE65 and until recently was quite untreatable. Now, as Ian Sample reports for the Guardian,[2] a team of researchers have effected a major new treatment called Luxturna: a gene‑replacement therapy delivered by injecting a working copy of the RPE65 gene directly under the retina. By giving retinal cells the functional gene they’re missing, it restores the visual cycle and can improve light sensitivity, visual function, and navigation ability in people with RPE65-related Leber congenital amaurosis. Interestingly the team comprises a husband and wife called Jean Bennett and Albert Maguire who share the prestigious Breakthough Prize [3] with their colleague Katherine High.

Regular readers will share our admiration for the work of this remarkable trio. They may note moreover that the researchers have something else to teach us, something that strongly concurs with opinions often expressed in this blog:

Bennett said it was a “tremendously exciting time” for scientific and medical research, but warned that the US administration’s attacks on science could “cause damage for generations to come”, leading her to fear a brain drain that the country would struggle to recover from.

“Agendas have become politicised, government agencies that support basic and applied research have been undermined, knowledgeable advisers and experts have been dismissed or have fled and revised guidelines contradict decades of rigorous research,”

Says it all really. But don’t just sit around reading it here:tell your friends and neighbours. For us there still remains outstanding question. Is Albert Maguire by any chance a relation of Ken Maguire, one of the best pub landlords of the 1990s, being sometime manager of the superb Latymers in Hammersmith Road London W14?

[1]Leber congenital amaurosis – Moorfields Eye Hospital

[2]‘Oscar of science’ awarded to team behind gene therapy that restores lost vision | Science | The Guardian

[3]Breakthrough Prize – Wikipedia

#LCA #Blindness #gene therapy #medicine #health #science #research #pub #beer

Two new stories give fresh hope on cancer

Two stories give us hope of real progress in understanding and treating cancer. The first from the excellent Emma Gritt of the Mail [1] concerns the work of the great Dr Mariano Barbacid whose work has been so crucial in elucidating and developing the whole theory of oncogenes and the role they play in cancer. His team has been studying the effects of three drugs on the KRAS gene, deeply implicated in the development of the pancreatic form of the disease. But: don’t read us, read Emma-she knows a lot more than we do

The second story, from the inimitable Ian Sample of the Guardian [2] concerns the application of the Google Deep Mind AI tool to study genetic drivers of cancer-and other diseases too. To quote Ian:

“We see AlphaGenome as a tool for understanding what the functional elements in the genome do, which we hope will accelerate our fundamental understanding of the code of life,” Natasha Latysheva, a DeepMind researcher, told a press briefing on the work.

Once again click!. You’ll get a lot more from Ian than you will from us.

Both stories blend into two of our old LSS favourites. Firstly, the use of AI to look at complex biological patterns which humans alone struggle to perceive. (LSS 1 12 20 et seq) Secondly, that repeatable frequencies in DNA may be tied, probabilistically, to repeatable patterns of symptoms. Veteran readers will recall our hopes that this methodology may apply to psychiatric disorders too: (LSS 18 12 25 and 29 12 25). Of course, we expect to learn of environmental and epigenetic factors as well. But if we are right, these genetic advances may provide a firmer starting point for future investigations than we have now. How much more is achieved when facts are sacrosanct, not convenient entities to be selected and disposed according to the immediate convenience of their user! A lesson which certain US politicians and the news channels which so fanatically support them would do well to learn.

[1] Huge pancreatic cancer breakthrough as scientists achieve ‘permanent disappearance’ of disease with new triple-threat approach tested in lab | Daily Mail Online

[2]Google DeepMind launches AI tool to help identify genetic drivers of disease | Genetics | The Guardian

#AI #deep mind #cancer #genes #DNA #medicine #health #oncogenes #psychiatric disorder #heart disease

Now AI is designing antibodies too

Photo by Nataliya Vaitkevich on Pexels.com

Do you understand the human immune system, or the even vaster world of immunology? Neither do we. Too big, too vast, too complicated. And that’s despite 43 years of trying and working along side some pretty nifty immunologists, back in the day. But AI does, Fresh from its triumphs on protein design (LSS passim) its superior intelligence has now been turned on the knotty problem of how to run up new antibodies. Read this, AI designed antibodies race towards trials from the indefatigable Nature Briefing

Scientists say they are on the cusp of turning antibodies designed by artificial intelligence (AI) into potential therapies just a year after they debuted the first example of an entirely AI-designed antibody. Previously, the structure of antibodies proved somewhat of a black box to AI models. But new and improved models — such as an updated version of AlphaFold — have more successfully predicted the shape of flexible structures that give antibodies the specificity they need to bind to foreign molecules. Researchers at several companies now say they’ve designed ‘drug-like’ antibodies. Nature | 5 min read

There’s a lot to unpick here, and we won’t try to do it all. The first thing that stands out is how quickly this is moving from proof of concept to clinical reality, The second is that the possibility that designed antibodies will target receptor sites hitherto off-limits to their natural predecessors. Think infectious diseases first, and rightly. But the implications for cancer therapy -and dare we hope, neurodegenerative diseases?- are clear after a moment’s reflection. Designer antibodies will greatly reduce the need for much animal immunisation and testing. And, perhaps a best of all, a thriving commercial ecosystem of start-up companies is beginning to form around the new learning, ready to turn it into everyday reality in a hospital or medical prectice near you, gentle reader.

Although we can’t claim credit for these advances-you all know us too well- we think it striking that they have come from the qualities we prize . Careful observation. Null hypotheses testing. Slow steady work. And always looking for what proves you wrong not what proves you right. Those qualities are what save lives and generally make them better. A shame that they are being abandoned now by a hysterical ignorant population and so many of its foolish leaders.

#immunology #antibodies #medicine #health #cancer #disease #biotechnology

Stem Cell Therapy: Lamarckism by Force Majeure

First of all hats off to Oliver Chu, the brave boy from California who has just undergone a successful trial of stem cell therapy for a terrible condition called Hunters Syndrome. [1] as Ian Sample of the Guardian explains. It’s caused by a simple mutation in a gene called IDS-1 which controls the production of a vital enzyme Iduronate-2-sulfatase; without which the body cannot break down key sugars, leading to organ damage of all sorts and cognitive decline. The trick has been to extract the stem cells from Oliver’s blood: replace the faulty gene with a true copy using a viral vector; and pop them back in to Oliver, whenceforth they will thrive happily, self reproducing from their own line, and producing bountiful quantities of the enzyme for life.

And this for us is the key part. Let’s repeat : the new stem cells with the engineered gene will start their own self replicating line. In Oliver. Now Oliver himself started from a single stem cell-a single fertilised ovum, as do all living things. With DNA that was used to build every single following cell as it grew . An Ur stem cell if you like. But now. young Oliver has two. All the cells from his original cell, Plus the new line, from the engineered stem cell. whose line is now flooding his system with the good enzyme..

The central tenet of biology up to now is that we all of us-tigers, pterodactyls, humans, whatever-have a single unmodifiable line of DNA in our cells. Random variations may be passed to the next generation and tested by Natural Selection. But the actual DNA deep in the cells cannot be changed or modified. That’s the Darwinian positioned its held up pretty well for centuries. The alternative, proposed by Lamarck is that organisms are modified by the environment and this information can be learned inthe genes and passed on. So far there has been no evidence to support this view whatsoever . But what if the environment contains clever humans who can choose to modify DNA, and thereby create what are in effect hybrid organisms with two separate DNA lines-like young Oliver? Is this Darwinian? It’s not how it happens in nature, and its been done by force majeur. But it sounds a lot like Lamarckism from where we sit.

[1]https://www.theguardian.com/science/2025/nov/24/groundbreaking-uk-gene-therapy-manchester-hunter-syndrome

#stem cells #hunters syndrome #darwin #lamarck #evolution #medicine #health

PERT: Next step in gene editing offers real hope for hereditary diseases

Almost a quarter of hereditary diseases can be put down to mutations which break an established pattern of DNA, so it can no longer be read. No wonder they are called nonsense mutations. Often these mutations are expressed as STOP codons: just a short three letter sequence that stops protein synthesis dead, like a bad piece of coding in a computer programme. Now a new technique called PERT (Prime Editing RNA Therapy)allows the cellular process to override glitch in the DNA and resume synthesis. The new technique equips cells with engineered tRNAs that override these stop signals, letting the ribosome continue translation and produce the full protein. Here once again is Nature Briefing with one of their excellent short explanations Versatile gene-editing tool fixes nonsense, plus hyperlinks if you wish to delve deeper.

A multipurpose gene-editing tool can correct several genetic conditions in mice by restoring proteins that have been cut short by disease-causing mutations. The method, called PERT, uses engineered RNA molecules that allow protein synthesis to continue even when a DNA mutation tells it to stop prematurely. These ‘nonsense mutations’ comprise nearly one-quarter of known disease-causing DNA variants. As such, if PERT proves effective in humans, it could overcome the need to design bespoke treatments for individual diseases.Nature | 5 min read
Reference: Nature paper

There’s a lot to like here. Firstly the prime editing is straight out of the same stable as the CRISPR and Base Pair Editing techniques which we have heralded here for years (LSS passim) Secondly, unlike most gene therapies, which must be tailored to each mutation, PERT could treat many different diseases with a single editing agent. This is a huge shift in scalability. And if the suppressor tRNA is permanently installed in the patients genome, it is possible that only one treatment may be needed. Once again we are reporting at the early stages (that’s our brief) so all parties are careful to emphasise we are nowhere near clinical applications yet. However, just as we learned during the COVID 19 pandemic , the ability to intervene at the RNA level, precisely between gene and protein, appears to be one of the most fertile areas in medical knowledge for years to come.

#hereditary disease #RNA #DNA #molecular biology #health #medicine