5/10/2024: New organelle just dropped

Hey there,

It’s been a wild week for biochemistry. With the release of AlphaFold3 and the AlphaFold Server a few days back, we’re seeing a huge proliferation in modeling and experimenting with protein structures.

Meanwhile—we’re still catching up with some of the biggest stories from the last month. Researchers at UC Santa Cruz just casually rewrote every cell biology textbook by announcing a new organelle—the Nitroplast.

We’re also really excited about the explosion of advancements happening in Immunology right now. Specifically, the ‘inverse vaccine’ being developed out of the University of Chicago’s Pritzker School of Molecular Engineering proved a critical concept about helping the immune system ‘forget’ autoimmune triggers.

And of course, there’s more awesome data coming from the Gene Therapy space with the New England Journal of Medicine reporting a CRISPR treatment showing 75% efficacy in improving a rare inherited form of blindness. And that’s barely scratching the surface.

A lot going on this week, so let’s dive right in:

programmed immune tolerance

Developing an Inverse Vaccine

Molecular engineers at UChicago may have just cracked the code for ‘fine-tuning’ the immune system to shut off autoimmune reactions

🔇What if we could mute the immune system when it goes haywire?

That’s the idea behind pGal-antigen therapy—an innovative new way to potentially stop autoimmune diseases without suppressing the whole immune system.

Researchers at the Pritzker School of Molecular Engineering developed pGal by iterating on a paper they published in 2019. Basically, pGal—or a polymer glycosylated with N-acetylgalactosamine—is attached to an antigen that the immune system normally reacts to.

This ‘tags’ the antigen to get absorbed by antigen-presenting cells in the liver or peripheral lymph nodes—which kicks off a process that promotes immune system tolerance of that antigen. Basically, pGal allows scientists to tag anything as ‘safe’ for your immune system to ignore. This has huge implications for autoimmune disease—and maybe even certain allergic conditions.

PROMOTING TOLERANCE

This latest paper on pGal used a ton of conditions to demonstrate that pGal-antigen therapy mutes immune responses in mouse cells. Researchers attached egg albumin proteins—a classic model molecule to test immune responses—to the pGal polymer and injected it into mice that already had a trained immune response to egg albumin.

Mice treated with pGal showed a reduction in T Cells responsible for recognizing egg proteins, and a promotion of regulatory cells that calm immune responses. The full immune response here is pretty complex for just an email newsletter—but the short version is that pGal effectively helped mute an induced immune response to egg proteins.

LEVEL 2: CRUSHING AUTOIMMUNE RESPONSES

But egg albumin only proves the model that pGal could operate with. So, the team at PME took this to the next level by testing it against a mouse model for Multiple Sclerosis.

They attached the pGal protein to a myelin oligodendrocyte glycoprotein (MOG) and injected it into mice who were suffering from a condition equivalent to MS in people. In folks who have MS, the immune system attacks proteins on the outside of the myelin sheath that insulates neurons—wreaking all sorts of havoc.

pGal-MOG therapy effectively stopped MS-like systems in mice and significantly reduced the immune response to myelin proteins. This is a resounding demonstration of pGal as a potential treatment for suppressing autoimmune conditions—but now there’s a lot of work that needs to be done before pGal-antigen therapy can be adapted for human use. Just a wild and almost beautifully simple way to demonstrate it’s possible to ‘teach’ our immune systems what to attack and what not to attack.

Given how complex the mammalian immune system is, pGal-antigen therapy is a massive step forward.

  | Check out the paper  | Here’s a solid write-up from UChicago Mag |

closing the nitrogen gap

Uncovering the Nitroplast

After years of observation—scientists are confident they have discovered a nitrogen-fixing organelle in B. bigelowii. That’s HUGE.

🌾 Evolutionary history just got rewritten

In a paper published last month, researchers at UC Santa Cruz demonstrated a pretty substantial body of evidence for a new organelle: the Nitroplast. This is the culmination of nearly 30 years of research and observations.

There are so many MASSIVE implications to unpack from this paper. Everything from Eukaryotes bridging the Nitrogen Gap™ to a new framework to better understand the transition from endosymbiosis to becoming a full-blown organelle. Let’s break it all down:

WHAT EVEN IS THE NITROPLAST?

So, this paper centers on UCYN-A, which was discovered all the way back in 1998. Scientists initially flagged UCYN-A as its own organism—a bacteria engaged in an endosymbiotic relationship with a regular single-celled marine photosynthesizing alga called Braarudosphaera bigelowii. UCYN-A is a nitrogen fixer—it turns atmospheric N2 gas into ammonia so living things can actually use it. UCYN-A provides ammonia while B. bigelowii provides food from photosynthesis and shelter. Nice.

WHAT MAKES AN ORGANELLE?

However, after gathering data for decades, scientists are now confident that UCYN-A has actually transitioned from being an endosymbiotic bacteria to a full-fledged organelle, just like mitochondria. This transition didn’t happen recently or anything, scientists just have a lot more data and are therefore UCYN-A is actually a nitroplast.

There are a bunch of observations currently backing this up:

• Soft X-ray tomography images show that UCYN-A is tightly integrated with the B. bigelowii cell. The structure even divides in a regular sequence with the rest of the protist, the same way organelles do.

• Analysis of proteins in UCYN-A demonstrates that it takes in a lot of proteins from B. bigelowii and effectively relies on the host cell for its own metabolism. If UCYN-A was just hanging out inside B. bigelowii out of symbiotic convenience—then these two cells wouldn’t be so metabolically intertwined.

Those are the two big ‘smoking guns’ that suggest this is a new organelle—the Nitroplast—instead of ‘just’ an old-school symbiotic relationship.

WHY IS THIS A BIG DEAL?

This paper is fairly groundbreaking as it builds on decades of observations and provides a framework for deciding if a structure is in a symbiotic relationship with a host cell or if it’s actually an organelle.

More importantly, this is the first observed evidence of a eukaryotic cell being able to fix nitrogen without help from a symbiotic relationship. Congrats, fellow eukaryotes—turns out we were able to cross the Nitrogen Gap™ after all.

| Read the paper here |

rebuilding those rods

CRISPR Therapy Demonstrates Incredible Efficacy in Treating Rare Blindness

Another win for gene therapy as 79% of participants in a new trial treating Leber Congenital Amaurosis showed improvement

 👀 Everything gets a CRISPR treatment these days

Even though we’re in the early innings of the CRISPR revolution, we’re still getting astonishing results from new therapies powered by CRISPR gene editing. In a new clinical trial published by the New England Journal of Medicine this week—a CRISPR therapy called EDIT-101 generated improvements in 79% of participants suffering from a rare kind of genetically inherited blindness. Let’s break down the details and rebuild some defective photoreceptors.

SHATTERING MICROTUBULES

EDIT-101 is a CRISPR gene therapy designed to fix Leber Congenital Amaurosis, Type 10. This is a super rare inherited genetic condition where a single mutation on the intron teeing-off the CEP290 gene causes the protein that DNA codes for to misfold and not work.

As a result of CEP290 dysfunction, microtubules in the middle of photoreceptor cells in the retina can’t achieve their full length. So, those photoreceptors take on a kind of deflated look that significantly impairs their ability to detect and translate light signals to the optic nerve. As a result, folks with this CEP290 mutation suffer from severe vision impairments and even blindness.

A NEW ANGLE FOR GENE THERAPY

To treat the LCA-10 condition, researchers had to develop a workaround because the CEP290 protein is over 2,400 amino acids long. It’s a big’ol protein with a super-long gene encoding it. This makes CEP290 and its mutation too long of a sequence to be edited by ‘traditional’ CRISPR methods.

However, since the mutation here is in an intron—EDIT-101 utilizes a pair of CRISPR tools to delete the intronic sequences on either side of the mutation. This basically slides the CEP290 gene back into proper alignment for transcription—which leads to the production of a function CEP290 gene.

With photoreceptors building CEP290 properly, microtubules in those cells can now properly ferry proteins to the functional disks at the top of these structures—restoring the proper shape of those cells.

STILL EARLY DAYS

In this latest clinical trial, 79% of LCA-10 patients demonstrated at least some improvements in their vision. However, that number comes with a lot of caveats:

Most importantly, this trial only follows 14 participants. So, that ‘79%' efficacy’ figure can change pretty drastically as larger trials are initiated.

Meanwhile, only 29% of participants showed ‘clinically significant’ improvement to their vision. While that’s still a great result, it definitely tempers expectations for EDIT-101 moving forward.

Regardless, it’s still a great time to be in the CRISPR business. We can’t wait to hear more about how this technology can be used to treat inherited diseases of all kinds.

 | Check out the paper here | Or an OHSU summary here |

we got games

Biology Connections #2

Test your life sciences cred with this specific take on the NYT connections format.

This section is brazenly adapted from the good folks over at Nerdfighteria’s We’re Here Newsletter

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