We said Base Pair editing would outshine CRISPR. This breakthrough proves we were wrong. Or not

When is CRISPR- Cas-9 Base Pair Editing, and when is Base Pair editing CRISPR Cas-9?. Readers of this blog may be forgiven for thinking Base Pair Editing was the exciting new kid in town that was going to make CRISPR look like VHS tapes ( what they?–ed) But according to reports of a recent breakthrough in medicine, they are, sort of, one and the same thing.

Perhaps we had better start with the breakthrough. Doctors in Pennsylvania in the USA have used gene editing techniques to treat a poor little boy whose liver lacked the necessary enzyme system to process ammonia. Our reports come firstly from Ian Sample of the Guardian and the New England Journal of medicine via hyperlink) , where Base Pair is very much to the fore While Nature Briefing has the following take , again with the hyperlink to the NEJM, Baby Boy Receives CRISPR for One Therapy

A baby boy with a devastating genetic disease is thriving after becoming the first known person to receive a bespoke, CRISPR therapy-for-one. KJ Muldoon, now almost 10 months old, received three doses of a gene-editing treatment designed to repair his specific disease-causing mutation, which impaired his body’s ability to process protein. While Muldoon appears healthy, it is too soon to use the word “cure”, says paediatrician Rebecca Ahrens-Nicklas. “This is still really early days.”Nature | 5 min read
Reference: New England Journal of Medicine paper

From all of which we have obtain the following Learning Points for your Edification , gentle reader:

1 It matters less what you call it, and more that it works-the kid’s OK now!

2 Maybe Base Pair Editing is a subset of CRISPR the way that Hammersmith is a region of London. OK, it’s Hammersmith. But it’s London too. What’s the big deal?

3 It would be interesting to learn if other big cities like New York or Madrid for examples, contain smaller areas with funny names. But we will leave that to another day.

4 If you educate people, teach them critical thinking skills and give them some money to buy test tubes with, things like this can happen

5 If you keep people working long hours for little money, educate them to a minimum and give them things like Fox News to watch, societal outcomes may be very different

[1]https://www.theguardian.com/science/2025/may/15/us-doctors-rewrite-dna-of-infant-with-severe-genetic-disorder-in-medical-first?CMP=Share_iOSApp_Other

also: see LSS 23 7 2022 and follow ups

#gene therapies #base pair editing #CRISPR Cas-9 #medicine #health

Evolution is happening right now in South Korea

We tend to think of Evolution as something happening over millions of years. First, all those trilobites and early fish swimming in the warm Devonian seas. Then early newts and scorpions slithering out onto land, followed by dinosaurs and pterosaurs dodging the cycads; and finally those desperate battles between humans and mammoths in the frozen wastes of the tundra. Millions of years-billions if you look at things like bacteria and red algae.

But evolution isn’t like that. The change of one species into another is a by product some something much smaller, local and more rapid. It is about the environment selecting a gene here, now, for one small purpose. Read this from Nature Briefing, No Diver is an island

A tradition of diving on the South Korean island of Jeju might have influenced the genomes of all of the islanders. The Haenyeo — meaning ‘women of the sea’ — have been cold-water diving year-round and without any breathing apparatus for centuries. A genetic analysis revealed that gene variants associated with reduced blood pressure, cold water tolerance and red blood cell count — which is related to oxygen-carrying capacity — are more common in people from Jeju, regardless of whether they dive themselves, than in other South Koreans.CNN | 7 min read
Reference: Cell Reports paper

In other words, good old fashioned Darwin-Mendel natural selection of the central DNA of the organism. Because one gene variant conveys a selective advantage which the other allele doesn’t. Textbook case: on single genetic change will transform a bacterium into an antibiotic-resistant organism, with profound consequences millions. Of course, if you have enough of these over time, you might eventually transform a tabby into a tiger, or a dinosaur into a bird. But those are second order consequences.Recent discoveries have made our understanding a little more complicated. We have to factor in epigenetics (the great Nessa Carey is good guide [1] ) and even the possibility of some environmental feedback into the genome, to which we have alluded here sometimes(LSS passim)

Every so often we come across some fool, usually a pub bore or right wing columnist, who loudly declaims” I don’t believe in evolution-why would a fish want to transform itself into a salamander?” Here is your answer. The majestic old Darwinian model still functions, Right at the heart of one of the most modern countries in the world.[2]

[1]https://en.wikipedia.org/wiki/Nessa_Carey

[2]https://en.wikipedia.org/wiki/Haenyeo

#natural selection #evolution #epigenetics #darwin #mendel #dna #gene #south korea

Gepotidacin marches on

Gentle readers we’re more than happy to present the next chapter in the story of Gepotidacin. Against all the gloom and doom we serve up here, it really is a wonderful new class of antibiotic We have covered it before (LSS 30 1 23 ; 17 4 23) but today Manuel Ansede of El País [1] serves up a handy little resumé, not only of where we are now, where we have come form, and all kinds of hyperlinks to bring you up to speed. We can add little but to such erudition as Manuel’s. But for the sake of long term readers will riff on these few -humbly derived- observations

Firstly, this really is a new class of antibiotic., going by the snappy name of triazaacenaphthylene bacterial topoisomerase inhibitors. Unlike traditional antibiotics that target bacterial cell walls or protein synthesis, gepotidacin disrupts bacterial DNA replication by inhibiting two essential enzymes: DNA gyrase and topoisomerase IV. Which as most readers will instantly recall, are crucial for bacterial DNA replication and cell division. Thought so.

Secondly its already showing real world efficacy against all kinds of bacteria, including antibiotic-resistant strains like methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Neisseria gonorrhoeae. Get that: real science works.

Thirdly, to make our old LSS point: effective action in medicine takes time. It requires teams of intelligent people. Who do not act alone, but exist in an ecosystem of universities . research institutes and government agencies. Which in turn requires careful nurturing , funds and right to feel safe enough to make long term plans without bullying and interference from the proudly ignorant and impulsive. American readers take note.

[1]https://elpais.com/ciencia/2025-04-14/el-primer-antibiotico-descubierto-en-30-anos-llega-justo-a-tiempo-de-evitar-que-la-supergonorrea-sea-imposible-de-tratar.

#gepotidacin #antibiotics #antibiotic resistance #health #medicine

Is that an Antibiotic in the Azaleas?

We started out as an antibiotics blogs, and we’ll always defer to it when a good story comes up. So don’t be surprised as we offer you a really good story, which we found in Nature Briefing, that inestimable source of the very best stories on science and all its ramifications. Scientists unearth new anitbiotic-literally

Researchers searching far and wide for new antibiotic molecules have discovered one in their own backyard. The new molecule — found in soil samples collected from a lab technician’s garden — targets a broad range of disease-causing bacteria and doesn’t appear to be toxic to human cells. From the soil samples, the team spotted a lasso-shaped molecule they named lariocidin, which is produced by Paenibacillus bacteria. Lariocidin attaches to structures called ribosomes in bacteria, which disrupts their protein production. The molecule slowed the growth of a range of common bacterial pathogens, including many multidrug-resistant strains.Nature | 4 min read
Reference: Nature paper

We know, gentle readers that we can occasionally overdo the bad news a tad on these pages. Today we’re glad to tip the balance back a little the other way.

If you want to receive the very latest on science and cutting edge technology, you won’t do beetr than sign up to Nature Briefing. We don’t know of anything as good as this which is still absolutely free. What’s more they have some sub briefing sites on more specialist areas if your want to keep up with a particular area why not visit these sites and see for yourself?

briefing@nature.co

Nature Briefing: Careers — insights, advice and award-winning journalism to help you optimize your working life
Nature Briefing: Microbiology — the most abundant living entities on our planet – microorganisms – and the role they play in health, the environment and food systems
Nature Briefing: Anthropocene — climate change, biodiversity, sustainability and geoengineering
Nature Briefing: AI & Robotics — 100% written by humans, of course
Nature Briefing: Cancer — a weekly newsletter written with cancer researchers in mind
Nature Briefing: Translational Research — covers biotechnology, drug discovery and pharma
#antibiotic resistance #bacteria #microorganisms #medicine #health #research

Alphafold for RNA?

Model – Flu Virus Protein, CSIRO, circa 2000 by Photographer: Rodney Start is licensed under CC-BY 4.0

Back in 2023 we praised the achievements of Google Deep Mind and its Alphafold system for predicting protein structures (LSS 23 2 23) The step change in productivity , (no disrespect to human biochemists) was so remarkable that we compared it to the invention of stone tools. Since when it has pretty much become a standard tool in medical research.

So much for proteins. What about RNA? Advances in understanding its structure, maybe even making a little of our own, might convey enormous medical benefits. Read this from Nature Briefings Seeking an alphafold moment for RNA

Protein-structure-prediction tools such as AlphaFold have transformed biology. But RNA is a tougher nut to crack: it poses unique molecular challenges, and relatively few data are available to train computational models. So researchers have been getting creative, building a toolkit to aid the prediction of RNA structure that incorporates the latest developments in artificial intelligence.Nature | 10 min read

“A tough nut to crack” Indeed. For one thing RNA has always suffered from that “middle child” syndrome, lost between its more glamorous siblings, DNA and proteins. So there is a lot less data to feed into the AIs. And even the main forms, t-RNA and m-RNA are fiendishly complicated, like any biological macromolecule. Fortunately, there is a superb article from the main part of Nature by Diana Kwon[1] which lays out the problems and challenges with great clarity; well worth a glance, However the advantage of getting on top of RNA and bringing it, so to speak, into the twenty first century could be colossal, Never forget that it was an m-RNA vaccine that finally got the SARS-Cov-2 virus on the run. That is a glimpse of what might one day be acheived.

[1]https://www.nature.com/articles/d41586-025-00920-8?utm_source=Live+Audience&utm_campaign=bc74eaec70-nature-briefing-daily-20250326&utm_medium=em

#rna #AI #alphafold #medical research #biotechnology #nucleic acids #proteins #vaccines

Recycling the way to new antibiotics

If there was one thing that has always been too much for us, it is trying to understand the fiendish complexity of the immune system. At school, at our various universities, trying again during the COVID pandemic…..we have never really got past T and B. So when the BBC announced this morning that a whole new part of it had been discovered,[1][2] you might have expected us to hold our collective heads in our hands and groan.

Far from it, gentle reader. For the new discovery has opened the possibility of a whole new class of antibiotics sitting right there in every cell of the body. An astute group of scientists led by Professor Yifal Herbl at Israel’s prestigious Weiszman Institute of Science have found that proteases, a regular part of cell function, may be able to unleash significant antibacterial function. A protease normally functions like the recycle department of your local council, chopping down old proteins and getting them ready for use. But the team found that many of the little peptides produced have strong antibiotic properties. Like the good scientists that they are, they then ran two objective tests. Do the proteases work as well as conventional antibiotics? And if you disable them, does the cell become more vulnerable to infection? To which the answers, broadly speaking, are Yes and Yes.

Once again we stress that this research, and its development into useful therapies, is still at early stages. Which we always do when we cover new points of departure like this. Yet it is, indubitably, a new departure, And it has been sitting there unnoticed until now. Something which has always tickled our fancy here, as regular readers will know. Hats off to Professor Herbl and her team. And-readers! Every tome a journalist publishes on the antibiotics crisis, why not write a very short e mail of thanks to them? They’ll love you for it.

_{with thanks to Gaynor Lynch}

A note on today’s links We have two straight news stories and a link to the Weiszman Institute, to give you staring points. However, we could not get past paywalls to the Nature articles, and we doubt you will be able to as well

[1]https://www.bbc.co.uk/news/articles/cpv4jww3r4eo

[2]https://phys.org/news/2025-03-cellular-trash-reveals-immune-defense.html

[3]https://www.weizmann.ac.il/pages/

#antibiotics #proteases #immune system #peptides #microbes #bacteria #ealth #medicine

Human Genome Editing: A Frankenstein Future?

Technology always advances faster than ethics. Leaving society and individuals floundering in it wake. The printing press transformed European society in the sixteenth century. The cotton gin transformed the economy of the US South, arguably deepening Slavery, and instituting a pattern of violence and cultural wars which have lasted to this day. In the last century, the development of nuclear fission and computing have effected changes as profound as any known in History. It is with these examples in mind that we approach the subject of Human Genome Editing, which may make everything before look silly.

This has been a decade in which the effective manipulation of nucleic acids in living systems has become routine. We have covered such exciting techniques as CRISPR Cas-9 and Base Pair Editing. While all educated people stand in awe of the rapid advance of mRNA vaccine technology, which did so much to stem the COVID-19 pandemic and now offers real hope of new cancer treatments. But, without disparaging the intellectual brilliance or immense hard work of their creators, these technologies are relatively small scale in the size of the biological interventions which they entail. So now read this from Nature Briefings:

Brace for the arrival of Gene editing Modifying multiple DNA variants in human embryos at the same time, a process called polygenic genome editing, could substantially reduce the likelihood of certain diseases occurring. But it also raises concerns, say the authors of a Nature analysis — not least the renewed threat of eugenics. “This is not a hypothetical issue,” argues an accompanying Nature editorial. While such genome editing might be decades off, societies need to consider its possible benefits and risks now to avoid having to play regulatory catch-up when the technology becomes available.Nature | 4 min read
Reference: Nature paper

Imagine a society where the very richest may edit the DNA of themselves and their offspring so that they, and they alone form a race of superbeings. The future for the rest of human kind, the untermenschen if you will, looks grim, and may be very brief. Such evolutionary bottlenecks have occurred in the past; and those on the wrong side(always the majority) “fly forgotten as a dream, flies at the end of day” as the old hymn puts it. Time to consider this very seriously indeed we think. Nature thinks you may have 30 years: we suspect it to be much shorter than that.

#gene editing #dna #biology #biochemistry #CRISPR #Base pair editing #genetics

Apologies for big mistake in that last blog!

Oh God, oh God, why do we keep doing this? In last week’s blog Plastic Pollution, killed by neo liberalism and how we can’t keep up, we forgot to include anything that covered that last bit! Tiredness, information overkill, whatever the reason we apologise utterly un-reservedly. This is what we were going to say:

There has been yet another discovery in Biochemistry. A noble and intriguing discovery no doubt. But one which has left us reeling, longing for the simplicity of earlier times. Before we start, read this: The study of RNA’s strangest form, from the admirable Nature Briefings

Circular RNAs (circRNAs) — molecules in which an unusual version of the standard RNA-splicing process folds the strand back on itself — are implicated in diseases from cancer to Alzheimer’s, but exactly what they do is still a mystery. This is in part because circRNAs are so rare, and distinguishing their impact from that of their linear cousins isn’t easy. Fortunately, researchers are quickly assembling a toolbox of materials and methods to recognize, quantify and uncover the functions of these puzzling loops. The database circAtlas is helping to clarify the landscape by requiring listed circRNAs to be identified by two tools, and biotech company Arraystar is designing microarrays to hunt for circRNA in human samples.Nature | 11 min read.

Admirable indeed. But we couldn’t help an odd nostalgia for an age when RNA came in two forms. When there were only three TV channels(in the UK) There was only beer to drink. Do you sometimes, just sometimes, feel the same?

There, Happy Now?

https://en.wikipedia.org/wiki/RNA

#rna #biochemistry #information #nostalgia

Reason or Unreason: which will give you a better life?

What happens when you apply reason to solve your problems? And what happens when you give way to emotions, like fear or anger? Two stories from Nature Briefings illustrate the consequences rather nicely, we think.

Reason: New developments in RNA therapies Older readers, who remember as far back as the Covid-19 pandemic of 2020, may recall how a little thing called an RNA vaccine began to make a big difference. Since when a lot of time has passed, and RNA medical technology has come on leaps and bounds. Don’t take our word for it, read this, RNA treatments nearing reality

As early as the mid-1990s, scientists suggested editing molecules of RNA as a treatment for certain diseases, but at the time, they lacked the tools to do so. Around thirty years later, those tools are at our disposal. Editing RNA instead of DNA has several advantages. It’s a process that cells perform naturally, it doesn’t risk permanently altering a person’s genes and it doesn’t introduce bacterial enzymes to human cells as CRISPR-Cas9 gene therapies do. The field of RNA editing may be in its infancy, but pharma companies are already testing its use in some types of eye disease and cancer.Science | 13 min read

For the record, it’s worth clicking on the link, because the article is very clear, with some truly awesome graphics

Unreason: Let’s chuck foreigners out of our Universities Now try this:

A surge in far-right parties entering governments across Europe is raising concerns for science. Policy experts warn that these parties typically show no interest in research and innovation, leaving scientists vulnerable to budget cuts. In the Netherlands, researchers are bracing for €1 billion (US$1.1 billion) in cuts to the university and research budget under a coalition government including the anti-Islam Party for Freedom. The coalition also wants to limit the intake of international students and implement rules that would require universities to apply for permission to teach courses in English, which could trigger an exodus of foreign academics who don’t want to, or can’t, teach in Dutch.Nature | 5 min read

Chuck out foreigners! Don’t let those evil English speakers corrupt the purity of our language! The really odd thing about this for us is the parallel with football . The most successful Universities are like the most successful clubs(compare the Imperial College with Manchester City, if you like) The trick is to create centres of excellence, drawing in the very best talent you can find, and taking a relaxed view of things like native language, dress sense and marital customs. There is often a strong overlap between certain types of football fan and support for right wing parties. Do they really want their favourite team to send home all the foreign players?

#football #university #learning #reason #unreason

Round Up: New Brains for old, Fungal resistance, do we need growth?

Could CRISPR Cas-9 Rebuild your brain? As the brain ages, cells and circuits die off. Hence the unprecedented rise of neurodegenerative diseases in our ageing populations. Hope that this could one day be treated comes from several sources. None more so than this new development in CRISPR Cas 9 gene editing, a much touted favourite on these pages, we admit. Here’s the inimitable Nature Briefings:

Reducing the activity of one particular gene in ageing mice rejuvenates brain stem cells, allowing them to proliferate and provide a supply of fresh neurons. Researchers used CRISPR-Cas9 genome editing to systematically disrupt 23,000 genes and test the effects on neural stem cells. Messing with one such gene, Slc2a4, reduced stem cells’ glucose intake and increased their power to proliferate in old animals, but didn’t affect the cells in young mice. The results provide crucial information for the design of cell therapies that might one day treat neurodegenerative conditions, says neuroscientist Saul Villeda.Nature | 5 min read
Reference: Nature paper

Fungal resistance: a growing problem. Regular readers of these illustrious pages could be forgiven for thinking we spend too much time on antibacterial resistance among bacteria, and not enough on fungi. We hope this very prescient article from The Conversation may go some way to correcting this imbalance

https://theconversation.com/antifungal-resistance-is-not-getting-nearly-as-much-attention-as-antibiotic-resistance-yet-the-risks-to-global-health-are-just-as-serious-239677?utm

Good Growth/Bad Growth The difference in utility between having a small family car, such as a Vauxhall Corsa, and no car at all, is very great indeed. The differences between having that same Corsa and a Rolls Royce are, we humbly submit, rather marginal. Unless you count the awe-inspiring status statement which the latter brings. Growth is good for raising people out of poverty. Yet for centuries it has been based on the production and consumption of status goods rather than useful ones. The complexities of this issue are so fiendish, that we have never known where to begin to understand it. But Larry Elliott of the Guardian makes a brave first try at untying the Gordian knot:

https://www.theguardian.com/business/2024/oct/20/degrowth-image-problem-solve-planet-climate

#veblen #growth #status #antimicrobial resistance #CRISPR Cas 9 #alzheimers #medicine #health