James Lingford

Private money cannot replace public funding of science Who should pay for American science? In the current political climate, many are looking to the private sector to compensate for cuts in public funding. At the Harvard School of Public Health—particula...

“Some have even argued that private funding is superior, maintaining that it is more flexible, less prone to groupthink, and reduces the “burden” on taxpayers. But can the private sector really replace public funding? History suggests not”

www.science.org/doi/10.1126/...

A minimal PyTorch re-implementation of AlphaFold2
github.com/ChrisHayduk/...

We need more stuff like this. The incentive is to always be making the new groundbreaking tool, while maintenance + improvement of "old" tools gets left behind. But there is still heaps to be gained in "old" tools

Aerobic syngas conversion: opportunities, challenges, and solutions
www.sciencedirect.com/science/arti...

l mondo è così complicato, aggrovigliato e sovraccarico che per vederci un po chiaro è necessario sfoltire, sfoltire. (The world is so complicated, tangled, and overloaded that to see into it with any clarity you must prune and prune.) Italo Calvino Se una notte d’inverno un viaggiatore (If on a Winters Night a Traveler)

Any paper that quotes Italo Calvino is an instant 10/10 in my book

'An Interpretation, Survey, and Outlook of Microbial Macroecology' by @shoestrapped.bsky.social ecoevorxiv.org/repository/v...

Temnothorax kinomurai, a workerless, parthenogenetic social parasite.

Insects were my first scientific love (before I knew about proteins). So I love hearing about some new weird insect

"Temnothorax kinomurai is the first ant species known to lack both workers and males and to consist exclusively of queens"
doi.org/10.1016/j.cu... @currentbiology.bsky.social

Conformational ensembles reveal the origins of serine protease catalysis Enzymes exist in ensembles of states that encode the energetics underlying their catalysis. Conformational ensembles built from 1231 structures of 17 serine proteases revealed atomic-level changes acr...

Their recent Science paper summarised in the review above, here: www.science.org/doi/full/10....

Understanding how enzymes work: the journey to ensemble–function studies
febs.onlinelibrary.wiley.com/doi/10.1111/...

This is an exceptionally well written review on how enzymes work. Rather than the structure-function relationship, Herschlag & Du analyse the ensemble-function relationship

Structural ontogeny of protein-protein interactions: www.science.org/doi/10.1126/...

Fundamental work on how PPIs (co)evolve, combining directed evolution and machine learning to reveal the role of chance and contingency.

Can we simulate realistic evolutionary trajectories and “replay the tape of life”? In this work, we propose a flexible, generalizable deep learning framework for modeling how the entire protein sequence evolves over time while capturing complex interactions across sites. 1/n
doi.org/10.64898/202...

You go, Katy! 🚀
I’m so proud of you, and so happy to finally see this in its final form!

Count me in on your corner to keep on cheering for you! Looking forward to doing more amazing science together 💪

Check @katyappler.bsky.social thread below for highlights and the full paper here: rdcu.be/e4A70

Asgard archaeal origin of microtubules: www.biorxiv.org/content/10.6...

"The SuiHyd Squad"

I present this extremely niche meme for the hydrogenase community

Totally agree. Lots of assumptions baked in there

Who is using AI to code? Global diffusion and impact of generative AI Generative coding tools promise big productivity gains, but uneven uptake could widen skill and income gaps. We train a neural classifier to spot artificial intelligence (AI)–generated Python function...

"GenAI increases output and helps programmers expand into new domains—but only for senior- level developers. Early-career developers, despite being the most enthusiastic adopters, see no measurable gains"
www.science.org/doi/10.1126/...

Very excited to share our work published today in Nature: ‘Oxygen metabolism in descendants of the archaeal-eukaryotic ancestor’. This was a huge effort led by the amazing Kathryn Appler from Brett…... Very excited to share our work published today in Nature: ‘Oxygen metabolism in descendants of the archaeal-eukaryotic ancestor’. This was a huge effort led by the amazing Kathryn Appler from Brett ...

Cross-post on LinkedIn, since everyone is on LinkedIn these days:
www.linkedin.com/posts/jamesl...

Thanks Kate 😊

Overview of the modular architecture of complex I–like respiratory complexes, from the fantastic review by Yu et al. (2021) JBC: https://www.jbc.org/article/S0021-9258(21)00529-9/fulltext

We found [NiFe]-hydrogenase complexes with structural architectures very similar to that of respiratory complex I. It's been known for a long time that [NiFe]-hydrogenase and complex I are evolutionarily related, but prior work showed that the configuration of their subunits differed (e.g., MBH)

Supplementary Fig. 46 | Overall structural architecture and shared subunit homology in Complex I-like and MBH-like complexes. AF2 multimer models are divided into structures that share a Complex I-like or an MBH-like structural architecture. For MBH-like complexes, the P. furiosus membrane-bound hydrogenase, MBH (PDB ID: 6CFW)26, is shown for comparison. The order and orientation of the membrane-arm subunits relative to the peripheral-arm subunits is characteristic of MBH and distinguishes those structures from Complex I-like complexes26,88. For Complex I-like complexes, the E. coli Complex I (PDB ID: 7P62)94 is shown for comparison. The order and orientation of membrane-arm subunits relative to the peripheral-arm subunits in these AF2 models is characteristic of Complex I. In other words, when all homologous antiporter subunits are viewed in the same register, the peripheral-arm subunits in MBH-like complexes will appear rotated at ~180° relative to Complex I-like peripheral-arm subunits. We have highlighted areas on our AF2 models where expected subunits are absent. Missing subunits may be a result of our annotation step failing to capture all relevant sequences for AF2 input. A table showing subunit names and their corresponding coloring in protein models is shown as a color key. Homologous subunits share the same coloring. The colors of different subunits are consistent across this manuscript unless stated otherwise. Acronyms for the complexes, removing the taxonomic suffix and adding numbering Kari-1 (GCA_015523565), Kari-2 (GCA_024280435), Njord-1 (M288), Njord-2 (D4998_C1112_H3_Bin_254), Hod-1 (M3_38_Bin_455), Hod-2 (GCA_024276395), Hod-3 (M3_30_Bin_130), Gerd (GCA_016839405), Asgard-1 (AB3033_2), and Asgard-2 (GCA_021162905).

Supplementary Fig. 29 | CombFold models of putative electron bifurcating complexes. a. The putative Nuo(EFG) 2-Mvh(ADG) 2-Etf(AB) 2-Hdr 2 electron bifurcating complex found in Hodarchaeales MAG GCA_016840025. Top: individual AF2 models of the NuoEFG, MvhADG, and EtfAB-Hdr modules forming part of the total complex. Bottom: the CombFold assembled model shown from three different views. Subunits are colored according to the labelling shown in the top panel. b. The putative Nuo(EFG)4- Frh(AG)4 electron bifurcating complex found in Hodarchaeales MAG GCA_020353515. Top: individual AF2 models of the NuoEFG and FrhAG modules forming part of the total complex. Bottom: the CombFold assembled model shown from three different views. Subunits are colored according to the labelling shown in the top panel. Frh: F 420-reducing hydrogenase (a [NiFe]-hydrogenase). Mvh: Methyl viologen-reducing hydrogenase (a [NiFe]-hydrogenase). Etf: electron transferring flavoprotein. Hdr: heterodisulfide reductase.

When we looked into the what sort of multimeric enzyme complexes these hydrogenases were predicted to make, we were amazed to see a menagerie of many new forms that were unlike anything we'd seen before (to our knowledge)

Supplementary Fig. 44 | AlphaFold2 monomer models of [NiFe]-hydrogenase large subunits Group 4. Maximum likelihood phylogeny was inferred from a supermatrix of 3007 sequences and 440 amino acid positions (from 2216 initial positions), displaying the diversity of Asgard archaea hydrogenases collapsed to highlight [NiFe]-Groups 4 (blue) identified by the external ring. The tree was generated using IQ-TREE v2.0.7 (1000 ultrafast bootstrap replicates and calculation of 1000 SH-alRT) with Q.pfam+C50+R8 best-fit model chosen according to Bayesian Information Criterion (BIC). Previously identified subgroups are labeled in black. The novel hydrogenase groups identified and named in this study are distinguished by branch and label color-coded according to the group. The black check marks highlight the 14 large catalytic subunits chosen for monomer modeling for subgroups 4j, 4l, 4p, and 4q. Support values are shown when ultrafast (UF) bootstrap support is greater than or equal to 95 and SH-aLRT support is greater than or equal to 80. Individual monomers colored by the predicted local distance difference test (pLDDT) scores. Only top ranked AF2 models are shown. The phylogeny was visualized with iTOL and midpoint rooted between the known hydrogenase clades and pruned to show each group, separately.

Supplementary Fig. 43 | AlphaFold2 monomer models of [NiFe]-hydrogenase large subunits Group 3. Maximum likelihood phylogeny was inferred from a supermatrix of 3007 sequences and 440 amino acid positions (from 2216 initial positions), displaying the diversity of Asgard archaea hydrogenases collapsed to highlight [NiFe]-Groups 3 (orange) identified by the external ring. The tree was generated using IQ- TREE v2.0.7 (1000 ultrafast bootstrap replicates and calculation of 1000 SH-alRT) with Q.pfam+C50+R8 best-fit model chosen according to Bayesian Information Criterion (BIC). Previously identified subgroups are labeled in black. The novel hydrogenase groups identified and named in this study are distinguished by branch and label color-coded according to the group. The black check marks highlight the 12 large catalytic subunits chosen for monomer modeling for subgroups 3a, 3b, 3e, 3f, and 3k. Support values are shown when ultrafast (UF) bootstrap support is greater than or equal to 95 and SH-aLRT support is greater than or equal to 80. Individual monomers colored by the predicted local distance difference test (pLDDT) scores. Only top ranked AF2 models are shown. The phylogeny was visualized with iTOL and midpoint rooted between the known hydrogenase clades and pruned to show each group, separately.

One particular protein family we focussed on were the [NiFe]-hydrogenases, which are ancient metalloenzymes that let microbes metabolise hydrogen gas (H2). @katyappler.bsky.social noticed that the Asgard have a lot of diverse hydrogenase sequences that we hadn't seen before.

Fig. 3 | Asgard archaea produce structurally diverse respiratory complexes. a, Phylogeny of hydrogen-evolving Group 4 [NiFe]-hydrogenases, displaying the novel subclades 4j–r with blue branches and the Asgard lineage in the second ring. AlphaFold2 Multimer structures outline the phylogeny, indicating a transition from an MBH-like to a Complex I-like structure. Asgardarchaeia structures from 4k and 4l form an MBH-like complex represented by cryogenic electron microscopy(cryo-EM)-validated Pyrococcus furiosus MBH (Protein Data Bank (PDB): 6CFW) and membrane-bound sulfane sulfur reductase (MBS) (PDB: 6U8Y) structures. The other complexes, 4m, 4p and 4q, have structures that are more similar to the E. coli Complex I (PDB: 7P62).

Since my background is in protein structure, one facet of this project that I find extremely interesting is that Asgard archaea contain weird and wonderful proteins that have never been seen before.

We used AlphaFold to predict and explore the structures of these Asgard proteins

This has very exciting implications for eukaryogenesis. The first eukaryotes arose during the 'great oxygenation event' (a time of great upheaval in the Earth's history). Our findings suggest that the Asgard/eukaryote ancestor may have benefited from this rise in oxygen through aerobic respiration.

@katyappler.bsky.social and @archaeal.bsky.social went and hunted down new Asgard archaea across the globe. They ~doubled the previously known genomic catalogue of Asgard archaea. From this treasure trove of new genomic information, we infer they have oxygen metabolism.

The Asgard archaea are the closest living relatives to eukaryotes, and can therefore tell us a lot about one of the most pivotal events in the history of evolution: the origin of eukaryotes.

Also, Carl Zimmer wrote a short story about this work! Great to see basic exploratory biological research like this get highlighted by such a huge name. Inspiring stuff. bsky.app/profile/carl...

Eukaryogenesis in light of an expanded catalogue of Asgard genomes. a, Simplified, scaled timeline spanning from before the Last Asgard archaea Common Ancestor (LAsCA) to today. Thin bands mark predicted time ranges of relevant events (for example, GOE), thicker bands represent processes (for example, eukaryogenesis), and brackets indicate the period shown in b. The timeline further highlights milestones, including potential early eukaryotic fossils60 and the modern-day co-occurrence of Heimdallarchaeia and Alphaproteobacteria observed in this study (interaction likely originated earlier).

Fig. 1 | Expanded genomic diversity of Asgard archaea. a, Maximum-likelihood phylogeny based on 47 non-ribosomal markers (NM47)using the WAG + C10 + R4 model with 100 nonparametric bootstrap pseudoreplicates, including 869 Asgardarchaeota MAGs and 309 outgroup genomes. The blue branches (lower right) indicate the new Asgardarchaeota classes, Ranarchaeia, and the recently proposed Asgardarchaeia4. The concentric rings denote (in to out): the predicted genome size, metabolic guilds based on Pfam clustering, sampling locations, and black stars on the outside mark MAGs added by this study. Asgard, Asgardarchaeia; Atabey, Atabeyarchaeia; Baldr, Baldrarchaeia; Frey/Jord, Frey/Jordarchaeia; Gerd, Gerdarchaeales; Heimdall, Heimdallarchaeaceae; Hel, Helarchaeales; Hermod, Hermodarchaeia; Hod, Hodarchaeales; Kari, Kariarchaeaceae; Loki, Lokiarchaeales; Njord, Njordarchaeales; Odin, Odinarchaeia; Ran, Ranarchaeia; Sif, Sifarchaeia; Thor, Thorarchaeia; Wukong, Wukongarchaeia. b, SR4-recoded phylogeny of the same genome set inferred with the model GTR + C60 + G and 100 nonparametric bootstrap pseudoreplicates (Methods). This updated catalogue constitutes a large increase in the medium- to high-quality publicly available genomes (completeness >50% and contamination and redundancy <10%) with 65.3% from the Guaymas Basin and 34.7% from the Bohai Sea. The encircled numbers represent MAGS added by this study. The scale bars in bothsubpanels represent the average number of substitutions per site.Map created in BioRender; Appler, K. https://biorender.com/147ieoc(2025).

Our work is published today: ‘Oxygen metabolism in descendants of the archaeal-eukaryotic ancestor’. This was a huge effort lead by @katyappler.bsky.social. Extremely grateful to have been a part of this amazing project! 😊🦠🧬

Links: www.nature.com/articles/s41...
www.nature.com/articles/s41...

Finally out in @nature.com: a new piece of the puzzle of how complex life evolved. Lead by @archaeal.bsky.social & @katyappler.bsky.social. Great collab with @greening.bsky.social and @kassipan.bsky.social. More pieces to follow soon! www.nature.com/articles/s41...

A pilot in a submersible vehicle collecting sediments samples in 30 meters of water looking for Asgards (microbial relatives of eukaryotes)

One of the biggest questions in biology is how complex cells evolved about 2 billion years ago. Here's my new story on how scientists are solving the mystery of eukaryotes like us. Gift link: nyti.ms/4qMbo22

Oxygen metabolism in descendants of the archaeal-eukaryotic ancestor - Nature Sequencing of marine sediments finds 136 newly identified Heimdallarchaeia and several novel lineages, and indicates that Heimdallarchaeia evolved distinct metabolic capabilities from other&nbsp;Asgar...

At long last! Check out the link to our publication in @nature.com to learn more. doi.org/10.1038/s415...
12/12

New paper from my team detailing a greatly expanded genomic database of Asgard archaea revealing of high energy metabolism those related to eukaryotes! Led by @katyappler.bsky.social lots of help from @jameslingford.bsky.social @valdeanda.bsky.social @kassipan.bsky.social doi.org/10.1038/s415...

AI can of course help with coding problems as a sprt of better Google search (it's helped me), but outsourcing all work to an AI sounds like a Faustian bargain. A
AI companies are making huge promises about how all jobs can be outsourced to an AI, but of course they say that, they want money.