O-Link identifies ALS phenoconversion markers!

 

There is a LOT to be excited about in this new study. 

This statement at the end of it, is....maybe not one of them.... but they specifically limited access to these data in the IRB documentation, so even if you wonder what personal information could possibly be contained within a targeted antibody panel, it's against the rules to make this publicly available. 

However - here we are with what might be the first win in ALS diagnostics with a proteomics technology in....ever....? 

Surprisingly, it's actually a small cohort. It's less than 70 individuals? But with a pile of blood / plasma draws so it works out to ~550 samples. So....also evidence that O-Link Explore targeted panels can provide statistically valid data without an n>1000? 

The end point isn't a new ALS diagnostic marker. It is, however, a panel of proteins that may allow earlier diagnosis. And maybe if it is caught earlier then there are ways to treat it and prolong lifespan and (as/more imporant) healthspan in this fucked up awful disease. 

Proteomics takes on the brain decay paradox! The what?!?

 

So....ummm...this is a thing....

...a gross thing....

I know a lot of people who worry about stuff like "post-mortem degradation" which is where you might not want to do proteomics on someone who has been dead and puppeted around for a month in the hot sun. 

However - and this is where it gets weird - sometimes the most fragile and easy to homogenize part of the body (the brain) ends up around IN ANCIENT BODIES. What? Gross? YES! 

I'm not sure I'm going to be able to eat after this. Maybe I'll stop. 

Meh. According to these people over 4,000 ANCIENT BRAINS have been recovered from the past. Some as old as 12,000 years??? Which sounds impossible. My postdoc advisor would time me getting brains out of mice because she was sure we wouldn't care about the proteins in the cells in the subventricular thingamabob if we didn't do it fast. 

It turns out that if you have the right conditions the brain doesn't just break down. Why? When? Proteomics and a very icky experimental design to the rescue! 

I can't spend a lot more time on this, but you should check it out. There is some DDA proteomics and some DIA and two different instruments AND there are proteins that last a LONG TIME and these authors work out the biochemical reasons for it! Super cool stuff. 

Air conditioner!

 

Edit: (Had to make a QR code for an emotional 5 year old at 6 AM. I can post anything here in like 10 seconds). 

Preprinted data featured at SCP2026 day 2!

Whoa. Day 1 kicked off with "you should get another espresso, Ben" this is some heavy stuff. Preprinted here, though! 

For you mass spec nerds the method is worth thinking about. What if you spiked each single cell with the same SILAC heavy bulk digest? It looks like it works really well, but what he cares about is intrinsic vs extrinsic noise in -omics datasets. 

Damn, what a cool work. They also do metabolic labeling and then single cell proteomics. And I honestly think the preprint contains every detail necessary to reproduce this method and analysis. I wouldn't even know where to start for processing SILAC diaPASEF data in DIA-NN, but - boom - they're all there! 

Oh. 

Ummmmm.......okay....so...this ISN'T preprinted yet, but I didn't beat 3 other people to basically the same question. So...maybe just watch out for an upcoming Parallel Squared preprint from Dr. Megan Elcheikhali where they succeeded in something that an extremely skilled former postdoc in my lab (and many other great scientists in other labs) have failed to do. I'm dying to know what the trick is. (Likely very very many tricks.) 

This happens to me all the time: 

Someone kicks in my office door and yells  "HEY NERD! I'm here to do single cell proteomics! I've got a bunch of brains or livers in this Yeti cooler in the trunk of my car!" And I have to say "Wait. What? Where do you get all these organs? And why did you freeze the whole thing?? If you froze it, the cell membranes definitely ruptured, so you can't sort them. And if they can't be sorted with an intact membrane, it doesn't work. 

So....if what she said is real then....about 9 out of ever 10 collaboration requests I turn down might actually be ....viable.... so.... this was a ridiculously important talk. 

Man, I really thought I was going to bug out and work on a proposal I really think is going to define the rest of my career, but - damn this panel talk was lit. 

Topics covered -

-Most biologists still don't know single cell proteomics is a thing. But the point was brought up that most biologists don't really know that proteomics is a thing. Not in the way we currently do it. 

-Slavov shared some tips for how he's finding all these amazing collaborations. Cutting out as much useless jargon as possible and engaging everyone he can in other fields. The 100 Nature family papers probably doesn't hurt. 

-Definite concerns about costs discussed by everyone. No real solution yet. 1,000 single cells from some weird cell line is still going to be expensive. 

I had to do some ...work...ugh...and I only half paid attention to the next couple of talks. 

This seems like the most recent paper out of one of them. Though you'll find these authors are prolific right now. 

I had an alarm set for Ronnie Cutler's talk and it didn't disappoint. I'm not sure what I can share from that one yet. Maybe, what if you really did look at integrating single cell transcriptomics - not the read count data, but the other data you get from it. At a single cell level. With PTMs you can target at those same levels, maybe you can find a depressing (for old people like me) story in it? 

It's after 3am when I'm posting whatever I typed in this orange box, because I did get to doing the work ...ugh... stuff I needed to. I did finally get to see a talk on how the AIP works from a guy with an amazing last name. If he was at Thermo, new people would infer that he was critically involved in the development of their long running series of flagships. And Bernard Delanghe found out that no one there wanted to look at mass spectra. I feel like there was another preprint I had in hand, but I forget. 

It was yet another amazing meeting in a long string of them. 

Preprinted data featured in Day 1 at SCP2026!

 

I've got to start a new page of notes for day 2 or OneNote will definitely crash. Obviously there is a lot of unpublished data here I don't know if I can share or not, but some of this is out or preprinted. 

If you very very carefully controlled pH and reaction kinetics could you label all of one side of a peptide with TMT and all of the other side with dimethyl labels? Apparently, yes.

Nikolai beat me to the question of "wait. better than 95% labeling efficiency ON BOTH TERMINI?"

The only link I can find to this publicly so far is a dissertation that is public (and really really well written) you can find here.

Now...the stochastic sampling appears to be a major issue because you have 3-plexes of each TMT tag. So you drop to a very low overlap from cell to cell. I'm personally about 90% sure that it's due to MIPs. That's a lot of complexity that is far outside of the model of averagine within a very tight m/z window, but it does still allow for separating very different cell types apart. They have tried semi-targeting and other intelligent acquisitions, but - this ain't a terrible start for huge throughput potential. Especially if they've worked out the double labeling kinetics so you and I don't have to. 

And there are always people at this meeting doing crazy stuff out there you never heard of, right? Like, where does Parallel Squared find these people? This was the first one of the meeting and it was preprinted a few months ago. 

Crazy and amazingly ambitious. So...what if you coupled expansion microscopy (where you put the diaper gel stuff on your tissue and stretch it out so you can image it? But you did that to de-crowd the spatial peptide domain enough that you could essentially do Edman single molecule degradation in a spatial context? You might immediately have objections about depth, complexity, and orders of magnitude or 6 that would be tough to reach, but - damn....I would have never ever thought of this, nor have I ever heard anything even remotely similar to this idea. Really really cool. 

One more. I don't understand this one, but it's another off-the-wall technology and I really liked the speaker and his animations for BALLISTIC MICROSCOPY!

MORE EMERIL! 

Day 2 is starting now! Let's go! 

It's finally here! SCP2026!

 

The world's first conference on Single Cell Proteomics is back - today! for it's 9th year. That doesn't seem possible, but I counted twice. 

I can't wait. The line up is amazing. Is it too late to register digitally? Probably! But you should have already, silly. If you do miss it, most of the talks every year end up curated and up on YouTube! I watch the old ones on my lunch breaks all the time. 

Got a backup tablet in my bag for notes if my primary's battery can't survive me writing for 10 hours!

It looks like an absolute ton of speakers today because of the 5 minute flash talks in the middle of the day. The schedule doesn't fit on a single screen? Well, I'll screenshot it so it feature the talk I'm most excited for at 4:45! 😮

It's official! THE Proteomics Show live at the British Mass Spec Society!

 

A couple days ago I found out about the iSCMS BMSS joint meeting in London in October. 

I was like "who is organizing this and how can I help?" 

So now I am! If you are at BMSS, you can put your name into a literal hat. Hopefully a fancy London hat! And get interviewed in front of a live audience for an episode of THE Proteomics Show.

Is it cold enough in October there for me to dress up like Tom Baker the whole time? Or will I be sweaty and itchy the whole time? Or both? You'll have to be at the BMSS meeting (October 9th!) to find out. 

New spatial mass spectrometry technology alert - Tippy Tapping-Mode ESI!

Are you interested in getting into spatial mass spectrometry but all the super expensive commercial technologies aren't doing it for you? 

Why don't you...

..introducing Tappy-mode scanning ESI! 

What's that? Okay, they didn't invent it for this paper, but they explain it better than I can! 

Wait a minute. Is it just like this except really fast and with an electrospray plume in the middle? 

Close enough! 

Okay, but analogies aside, we can move tissues at incredibly absurdly high resolutions. Think about the stages they use for electron microscopy! Great imaging mass spec today is like 20 micron. Every vendor will sell you a "5 micron resolution"capable device, but have you ever seen a mass spec imaging ..image...at 5 micron without inflating it with diaper gel? I sure haven't. But EM stages can move in like sub micron easy. The limitations are things like our laser pixels. And when you start talking to people who do anything with piezos (which more the bird beak or capillary), those people are talking about things running at 10-100 kHz (10,000 to 100,000 vibrations/second!)  So...I'm totally talking out my nose, but these authors say they're doing 10 and 5 micron and while a healthy truckload of skepticism is always a good idea, this doesn't sound all that far fetched.....

They couple the device to a Waters TOF and then use multiple commercial software solutions from Waters and Shimadzu to convert and extract the data before going to LipidMaps to match the molecules they extracted. (They did lipids for this, I was leaving that part for the end) but why couldn't you pick up a little piezo capillary worth of intact proteins or digested peptides and do the exact same thing? Cool idea, right? 

iSCMS is in London October 6-8 plus an extra day for BMSS October 9!

 

iSCMS 2026 was just announced and it's SO cool. 

One of my favorite 2 day conferences - not just single cell proteomics, but all single cell mass spectrometry. At King's College in London! 

And if that's not cool enough it's a joint conference. You can stay an extra day for the British Mass Spectrometry Society Meeting! Alejandro Brenes and Felicia Green are the plenaries for the latter! 

Did you think that you had to be 90 years old to be a plenary speaker? Not here you don't! Psyched for both talks. 

You can come for BMSS or iSCMS or both and register here. 

Here are some completely and totally unrelated facts about that same week in London that are, in no way, affecting my personal travel plans because I'm a grown up professional. 

However, THE HAUNTED are playing October 8th. I've never seen them live, but I'd clearly be responsibly in my hotel that night and preparing for BMSS the next day. Not navigating the tubes with ringing in my ears. 

I probably can't find a way to justify staying extra days, unless - I dunno - someone out there invites me to speak at their university or come by their company headquarters to talk about cool stuff. However, if you happen to be there and have flexibility -

Metal Gods - 

Amon Amarth

Soilwork 

with ORBIT CULTURE??? 

play an early show on Saturday (!?!?! WHAT !?!?!) I have no idea what a pound is in real money but 62 of anything seems like a bargain to see those 3 shows. 

Boost ultra super low input proteomics with 2 micron nanoLC columns....?

 

...ummm....how do you make a 2 um inner diameter LC column....? 

 Leaving it here so I can think about it later.

Obviously required addition to this post...