Ten years looking for new antibiotics: how are we doing?

How’s the campaign to get more antibiotics going?” We still sometimes get asked this in pub or supermarket. Not surprising really, after more than ten years on the job. And to answer that question we can think of no one better than the acute Julia Kollewe of the Guardian whose piece is as good a state-of- play message ( Pipeline of New Drugs to fight superbugs is “worryingly thin,” experts warn) as any we’ve seen for some time[1] So, what’s the score? How indeed is humanity meeting this existential challenge?

Not too well, actually. The bad news is that antibiotic resistant infections are still very much on the rise. More than 40% of known antibiotics lost potency between 2018 and 2023.[2] The number of antimicrobial projects run by big pharmaceutical companies has actually declined in the last five years. But you can read these and many other statistics from Julia and her linked organisations for yourself.

There are some bright spots: hats off to the UK’s GSK ,Japan’s Shionugi and Otsuka, and certain valiant American firms in California. But America’s real giant, Pfizer, seems to be falling off the pace-not surprising we think, given the political end cultural climate they now have to work in.

But for us Julia’s killer trope was to consult the learned Ara Darzi, an expert in cancer treatment. Who adduces the following gloomy thought:

New therapies mean cancer can be fought, “but then sadly patients succumb to an infection that was treatable a decade ago”, Lord Darzi said at the launch of the AMF report, adding: “You don’t win a game if you have three good strikers and your defence is weak.”

Cancer is indeed a deadly illness. And cures should be sought. But what’s the point if the poor patient dies three days later from an infection? That is why your interest in new antibiotics is still important, gentle reader: please keep supporting us.

[1] Pipeline of new drugs to fight superbugs is ‘worryingly thin’, experts warn | Pharmaceuticals industry | The Guardian

[2] Tools to fight AMR exist, but industry-wide action is needed to tilt the battle against superbugs | Access to Medicine

#antibiotic resistance #microbiology #health #medicine #drugs

VIR 5500: Promising new treatment for Prostate Cancer

Immunotherapy, which involves training the body’s own defence systems such as T-cells to attack cancerous tissues, has been one of the medical success stories of the last twenty years. Yet some cancers still demonstrate a certain recalcitrance in the face of the new ministrations. Unfortunately, one of them is Prostate cancer, the most common form of cancer in men, killing up to 1.5 million of them annually. But not only does this report by Nicola Davis of the Guardian [1] offer hope of real progress, it has some deeper lessons for those of us in the evidence-based thought-modulated community(EBTM). Which means you, gentle reader.

All immunotherapy depends on T Cell engagers (TCEs) which form a bridge between certain sites on the T Cell and on the tumour cell. Anyone working with them to try to cure prostate cancer encounters two difficulties. Generally, traditional TCEs can be pretty indiscriminate, leading to side issues like massive cytokine storms and problems with dose toxicity. Specifically, prostate cancer cells have a knack of resisting T cells, making immunotherapy especially hard to apply. Now a team led by the admirable Professor de Bono in collaboration with Vir Biotechnology[2] is trialling a new form of molecular cloaking treatment called VIR-5500 which masks the T-cells right up to the moment when they are in contact with the prostate cancer cells. A protease in the malign cells then activates the T-cells, unleashing their curative effect. We won’t spoil Nicola’s summary of the results, which you can read in her article. But you will find them impressive to say the least.

All of which goes to show what curiosity-driven basic science can achieve when money is spent on it. VIR -5500 could not have existed without decades of molecular immunology, protein engineering, tumour cytology and many other disciplines hidden away in unmanly places like university departments and research institutes. Which is ironic, because many of the butch types at the Dog and Duck, who routinely perform their masculinities by loudly decrying scientific research into things like climate change, will be the first to suffer when prostate cancer comes along. But History always teaches the same lesson to the deluded in the end.

[1] Researchers praise ‘stunning’ results of new prostate cancer treatment | Prostate cancer | The Guardian

[2] Our Strategy | Vir Biotechnology

#prostate cancer #immunotherapy #t cells #health #medicine #science #molecular biology

IsoDDE: mixed-race love child of Biology and Information Science has a great future

One of the most exciting stories we have followed at this blog is the way new AI systems are suddenly speeding up the production of new drugs and other biological molecules (see LSS 1 12 20 et al) This week has seen another exciting step in the form of a new AI tool from Isomorphic labs. Read this piece, Drug discovery AI is akin to Alpha Fold 4 from Nature Briefing

Isomorphic Labs — a biopharmaceutical spin-off of Google DeepMind — has unveiled a new, powerful artificial-intelligence tool for predicting how proteins interact with drugs. The tool, called IsoDDE, can outperform other AI systems such as the open-source Boltz-2 and physics-based methods at determining binding affinity between a protein and potential drug. These skills have impressed scientists, but they highlight that IsoDDE is proprietary, and the technical paper that accompanied its announcement offers scant insight into how to achieve similar results.

Nature | 5 min read

The research and development of new drugs is one of the most arduous tasks that befalls the intelligent community. The central problem is pretty simple: how do you get your marvellous new drug to stick to a protein, and make the whole thing work the way you want it to? Proteins are not hard rigid statues of marble: they are soft, spongy and change shape in unpredictable ways when you put a new drug up against them. That’s the gap in function into which all that time, money and thought disappears. In theory new AI tools like Iso DDE (and others on the way no doubt) should rapidly speed the whole process by predicting myriad of possible shape changes as the molecular systems are brought together.[2] Moreover, to predict new bits on the target protein which we hadn’t thought of, where the drug might be made to stick to, And possibly, to crunch the numbers around all those new bits of protein, polypeptide and other molecules which are thrown up in the research process, to see if they have any likely uses as well. When we were young, Information Science and Biology were completely different disciplines with different faculties, buildings and career paths. It’s funny to watch them coming together so fructiferously, to produce such exciting offspring

[2]https://storage.googleapis.com/isomorphiclabs-website-public-artifacts/isodde_technical_report.pdf

#drugs #medicines #researh #AI #biology #health

Can your cat save you from cancer?

Cats: our feline friends: variously cute, lovable, admirable and beautiful. They’re becoming more and popular as pets. Which brings several advantages in the treatment of cancer, believe it or not. Like dogs, their nearest rival, they are exposed to all the same molecular slings and arrows of everyday domestic life-cleaning products- foods, fuels, what have you-as we are. But we also share more genetic material with them then we do with our canine chums. Moreover cancer is rapidly becoming a major cause of mortality in middle aged to elderly cats just as it is to humans in that stage of. It’s a set up for ground breaking studies. And Miguel Ángel Criado for El País and Helen Briggs of the BBC have two excellent reports on a groundbreaking study which has done exactly that. (teaser: one of these links is in Spanish, and one in English-can you guess which?)

The study, co-led by the learned Dr Louise van der Weyden of the Wellcome-Sanger Institute is the first really large map of oncogenic(cancer related) aspects of the cat genome. It’s full of intriguing details, which you can read by clicking on the marvellous articles which we have hyperlinked. But we could not resist a tiny spoiler, concerning Dr Weyden’s discoveries around the gene FBXW7 , a tumour‑suppressor gene whose loss helps drive aggressive forms of human breast cancer. Intriguingly, the same gene is frequently mutated in feline tumours. This cross‑species echo suggests that cats and humans may share a conserved vulnerability in the FBXW7 pathway, making our kitties unexpected partners in understanding this cancer mechanism.

And the conclusion? We need to help cats to help us. You could give to a cancer charity [3] You could give to a cat charity[4] But knowing our readers to be generous types we have included sufficient hyperlinks for you to do both!

[1] El mayor mapa genético del cáncer de los gatos abre la puerta a tratamientos compartidos con humanos | Salud y bienestar | EL PAÍS

[2]https://www.bbc.co.uk/news/articles/cvg3n7j8xyqo?at_campaign_type=owned&at_link_type=web_link&at_format=link&at_ptr_name=facebook_page&at_link_origin=BBC_N

[3] https://www.cancerresearchuk.org/get-involved/donate?

[4] Cats Protection | UK’s Largest Cat Welfare Charity

#cancer #breast cancer #cats #medicine #health #research #genome #oncology

How a frozen bacterium might stop the great ESKAPE

For microbiologists the great ESKAPE is not an old film on the telly at Christmas. It’s a classification of the six most deadly antibiotic resistant bacteria which they work with. These are of course: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp.In other words, the bacteria that most effectively “escape” the effects of antibiotics, and thus sit at the heart of our current global antimicrobial‑resistance crisis. Now hope that they might be controlled is emerging from the icy caves of the Carpathian Mountains. And you might be forgiven for thinking that at first sight it actually makes things worse.

Because frozen in the ancient soil of Carpathian caves lies a bacteria with the snappy name Psychrobacter SC65A.3 -and it’s no less than 5,500 years old. We we’ve got two covers for you today: one in Spanish from that excellent newspaper El País by Miguel Ángel Criado and one from the Mail by Shivali Best. Both wax eloquent on its dangers: it seems resistant to at least a dozen of the best-known antibiotics. But here’s the rub: the same evolutionary toughness which let it develop these remarkable powers of resistance has also let it develop remarkable powers as an enemy of other bacteria. Including many of those on our ESKAPE list.

The natural tendency of people is to look at the scary side of anything: and thereby jump to the worst possible conclusions. We know that our readers are the ones who suspend belief a little longer, and always look deeper. In the long run that’s the only type of thinking that will release us from the antibiotics resistance crisis. And many others

[1] Hallada una bacteria helada hace 5.000 años capaz de plantar cara a superpatógenos | Ciencia | EL PAÍS

[2] Prehistoric killer superbug discovered in 5,000-year-old ice is resistant to 10 modern antibiotics, study warns | Daily Mail Online

#antibiotic resistance #microbiology #medicine #health #bacteria #ESKAPE

GCSE Revision: why humans became extinct

The following is a specimen answer to a History examination question set for GCSE students of the species Homo emergens in the year 2126 (year 76 NSE of the New Species Epoch)

Discuss the extinction of our predecessor species Homo sapiens in the middle of the 21st century and its replacement by Homo emergens

The factors that led to the downfall Homo sapiens, sometimes called humans, were in fact biological. Their cognitive capacities were no longer able to match the complexity of the world which their own technology had created.

Homo sapiens emerged from a group of similar hominin species such as Homo erectus and Neanderthals. It had evolved a brain structure which gave it an edge in cognitive reasoning. This allowed it not only to drive its competitor hominins to extinction: it allowed it to become, briefly, the biologically and ecologically dominant life form on this planet. And to form huge interconnected networks of information, trade and energy exchange called “cities”. Yet the brains of these creatures had not evolved beyond those of their ancestors. Who were adapted for survival in small hostile competing groups. The neurological architecture which had been so adaptive for that period was utterly inadequate for the complicated world which had been created in the last century of their existence. These cognitive inadequacies included confirmation bias, the sunk cost fallacy, motivated reasoning and a tendency to divide quickly into mutually jealous hostile groups. The primitive institutions which this species evolved were therefore plagued by short term bias, institutional inertia and deep patterns of hierarchical loyalty which left them unable to adapt to the rapidly changing complexities in which they operated. And none of these cognitive failures could be overcome, because they were part of the inherited biological adaptations of the species.

Thus the complications of the late human era such as climate change, Artificial Intelligence and disease pandemics represented a new environment to which this species could no longer adapt. Instead of solutions they caused economic decline, political polarisation and eventually The Great Final War of 2046. The massive falls in human population and its reduction to technological impotence provided the ecological niche into which our own species, Homo emergens, was able to move. Our current thriving is due to the same superior intellectual capacity which had allowed H sapiens to exterminate Homo erectus: as it in turn had done to the preceding Australopithecines. It is a mark of our intelligence that we have not exterminated our own predecessors but have confined their remnants to zoological parks where they may continue to be objects of scientific study and public amusement. Their fate shows that no species can survive if it is not well adapted to its environment: a lesson our own would do well to learn.

_{copyright: EmergentEdge Specimen solutions 76: “we write ’em- you pass ’em!”}

#biology #evolution #extinction #cognitive bias #war #climate change

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

Do the Twistronics-and change the world

What happens if you take two sheets of graphene and rotate one slightly relative to the other?” It’s a question all of us must have asked ourselves at one point or another (it is?-ed) but never really found time to answer. But two remarkably intelligent men did: Allan MacDonald, a theoretical physicist who posed it; and Pablo Jarillo‑Herrero who answered it by building ultra‑clean, precisely controlled graphene heterostructures –you know: the kind of devices where quantum subtleties become visible. Well, we said they were clever! Their work, and the prize which they won for it are admirably summarised by the erudite Selva Vargas Reátegui for El País [1]

Her excellent article contains much more on the details, so read it. Suffice it to say, the discovery not only revealed all sorts of weird and wonderful properties in graphene. It actually created a whole new field of learning: Twistronics. Because researchers soon learned to twist not just bilayers as in graphene, but trilayers, multilayers, and heterostructures of many 2D materials. The field exploded because twist angle becomes a new starting point for designing quantum matter. While still early, the work hints at possibilities such as: designer superconductors, quantum simulation platforms, ultra‑sensitive sensors and novel electronic devices based on correlated phases. Ok we are a tad shaky on one or two of these ourselves, but if it helps build something to do the ironing, we’re all in.

But the real point for us is conceptual. Changing the geometry alone can utterly change the properties of a material. It feels a bit like the time when some unknown genius in Old Mesopotamia started mixing tin with copper. As small, as unexpected and as potentially world changing. Oh, and another point: economics. The more you spend on basic science and research, the more your chances rise of repeating the trick somewhere else. Leaders of the world, you have nothing to lose but your accountants.

Premio Fronteras para los descubridores del ‘ángulo mágico’ que genera supermateriales | Ciencia | EL PAÍS English speakers: you need to hit the translation button

#Twistronics #graphene #quantum physics #geometry #bronze age #materials science

LSS v The Guardian: Clash of the Titans. And the battleground is antibiotics

Readers of LSS, we present today a true clash of titans: us versus the popular daily newspaper The Guardian. For they have just published a leader article on antibiotics progress which takes an altogether different view to our own sunnily optimistic piece (LSS 18 12 25) about humanity’s general progress in solving the problem of antibiotic resistance. [1]

Avid readers will recall our effort well. Riffing on the work of the guardians very own Kat Lay (brilliant writer) we noted how the new antibiotics Zoliflodacin and Gepotidicin offered startling new horizons in the battle against gonorrhoea and other other unpleasant diseases of-well you know, down there, as they say. We hoped that, as antibiotics for these diseases had been developed, those for other diseases might soon follow. And thanks to Ms. Lay, we discovered the work of the Global Antibiotic Research and Development Partnership (GARDP) whose work we will now champion for ever more. All in all, everything was in a much better place than when we started this crusade, eleven long years ago, we concluded.

Not so fast, says The Guardian. Humanity may actually be losing the race to develop these new drugs. Since 2017 only 16 new antibiotics have achieved approval, and none of them are very different to the old ones. Which means resistance to them can be expected very soon. Point to them, we concede. They namecheck GARDP again, noting its work as a positive. But that the financial structures designed to encourage pharmaceutical companies to step up to the mark are still rather new. And-more points to the team from York Place- there is a rather incisive survey of where all these new antibiotics are to come from. Old LSS favourites like natural sources and AI modelling are acknowledged. But they are not all-curing magic wands. And what to do with any new antibiotics anyway? Ration them carefully, so that resistance develops more slowly? How do you do that in a world of billions, where people and information flow so freely, and the profits of piracy are so temptingly in reach? Gentle readers, your editors did not think of those ones fully either.

OK, we throw in the towel. Guardian 3 LSS 0 (FT). When it comes to superior knowledge, close reasoning and intellectual power, they have got us beat. But we take consolation gentle readers, When the genetic dice roll, they roll evenly. They got all the brains. We got all the charm and good looks. As the last picture above demonstrates very clearly. And yes- we promise another cocktail recipe before New Year.

[1]https://www.theguardian.com/commentisfree/2025/dec/29/the-guardian-view-on-antibiotics-recent-breakthroughs-are-great-news-but-humanity-is-losing-the-bi

#antibiotic resistance #antibiotics #health #medicine #microbiology #epidemiology #GARDP

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