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
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.
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.
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.
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.
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.
We said we’d stopped doing round ups: but here goes anyway:
It’s about the psychology, stupid! George Orwell once noted that peoples’ political and religious beliefs often reflect their deep underlying emotional preoccupations. Which is why facts and reason so often fail to change minds. Never have we seen this argument so convincingly demonstrated as in this this short article by Magnus Linden, Claire Campbell and Fredrik Bjorklund for The Conversation: Maga Explained: How Personality and Context Shape radical Movements
The Unexpected was hiding in plain sight We always like it when that happens (remember birds and dinosaurs?) Now the inestimable Nature Briefing has a tale of how astrocytes, those formerly humble and overlooked cells of the brain may be pretty important after all The Silent Cells within our brains:
Astrocytes make up one-quarter of the brain, but were long thought to be merely the supporting act for the stars of the cognitive show: neurons. Now astrocytes are emerging as key players shaping our behaviour, mood and memory. The cells seem to orchestrate the molecular mix in the environment around synapses, varying that mix according to brain state — how alert or awake the brain is, for example. This, in turn, can determine whether neurons fire in response to a signal coming across the synapse. “Neurons and neural circuits are the main computing units of the brain, but it’s now clear just how much astrocytes shape that computation,” says neurobiologist Nicola Allen.Nature | 11 min read
Can GLP help you give up the booze? Sticking with Nature Briefing, that go-to source for science news of all kinds, we noticed this riff on all those weight loss drugs everyone seems to be taking lately, No wonder there’s no one left in the pub. Can GLP-1 drugs treat addiction?
Scientists are testing whether blockbuster drugs that mimic the hormone GLP-1 — sold under brand names such as Ozempic and Mounjaro — can help to cut cravings other than those for food. For years people prescribed GLP-1s for diabetes or weight loss have shared stories about finding themselves suddenly able to shake long-standing addictions to cigarettes, alcohol and other drugs. Now, data are starting to back them up, with results from more clinical trials expected soon. “At the end of the day, the neurobiological system that is activated by rewarding substances — food, sex, drugs, rock and roll — it’s the same system,” says psychopharmacologist Roger McIntyre.Nature | 11 min read
Will we ever lose our Bonds? We have noted before how deeply in hock governments around the world have become since the 2008 crisis and COVID 19. But better minds than ours, more deeply learned, have known it all along. Here’s Richard Partington writing before the Budget, Aditya Chakraborty afterwards: plus we wanted to give you Katie Martin of the FT too, but couldn’t get past the paywall.
Action at a distance? We don’t do a ;ot of physics here, sadly, so we hope this intriguing article about quantum entanglement from Jara Juana Bermejo Vega of El Pais will go some way to making amends. English monoglots be warned: you will need your translator app
Was the Cambrian period (538-486 million years ago) the most significant in the history of Life? [1] Was there really a kind of biological explosion where simple single celled creatures suddenly transformed them selves into complex multicellular beasts with nervous systems, eyes, guts and feeding strategies? It’s always been a bone of contention with some shouting emphatically “yes” and others being a little more sceptical. “Sampling bias”, they say: correctly adducing that there were plenty of multicellular creatures in the Pre-Cambrian, it’s just very difficult to find their remains.
Now the proponents of the Big Change Theory have found their case strenghtened. Recent research. described here by Kate Ravilious for the Guardian, suggests a natural mechanism which drove the changes and caused a sudden leap in the diversity of life. According to Kate
changes in solar energy caused climatic changes that altered the amount of weathering of land surfaces – especially at high latitudes – with periods of fast weathering releasing bursts of nutrients into the oceans, which drove photosynthesis and pushed up oxygen levels, fuelling the high speed evolutionary changes. [3]
And the interaction of these changes in solar output with variations in the earth’s orbit would explain the timing and nature of these sudden leaps for life.
And our take? Something happened around Cambrian times, gentle readers-there really is a step change, as shown by the appearance of shells, backbones and all the other markers of our modern phyla. And the idea of a coinciding, plausible mechanism is persuasive indeed. However as veterans of the paleontological wars we have a few questions. Did the Cambrian explosion a generate an increase in total biomass, or just complexity of forms? If this pattern of solar cycles and variable orbit repeats every two or three million years, why have we not seen at least one comparable event since (500 million years is a long time) Were there no volcanoes, tectonic plates or asteroids to muddy the waters in the Cambrian, the way they did in the Permian or Cretaceous, for examples? We love the Cambrian explosion and the way it has driven curiosity and much good research. But like every Big General Idea-in science , history, psychology, whatever- we see them more as pointing the way to more research, not a final answer.
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.
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.
Learning, Science and Society 