Hey there,

With the academic year kicking off—Whole mountains of new research are hitting publication. It genuinely feels like the science world snaps awake every September. We’ll have a new video next week, but for now let’s take a quick look at all the research that’s hitting the industry.

We’ve got everything from a new DNA Methylation sensor to a wild process for isolating a novel virus via Cryo-EM alone.

Let’s check out the latest molecular findings in this week’s Clockwork:

antiviral microscopy

Solving an Agricultural Pandemic with Cryo-EM

When there’s nothing left to sequence—sometimes you can just find that needle in a haystack

The full virion assembly of the Zophobas morio black wasting virus—discovered by a team at Rutgers University

 🐛 There’s been a mystery illness threatening America’s bug supply

Zophobas Morio is a critical link in the U.S. agricultural supply chain. This little larvae is similar to mealworms—they are a protein-rich grub that are farmed as food for feed animals like chickens. They even have potential as an alternative protein source for human consumption as well

For the past few years, several farms producing these bugs have been hit with a mysterious pandemic that’s wiped out entire populations of these critters. It’s been hard to pin down what causes this mysterious disease until a team at Rutgers University used—get this—cryo em microscopy—to identify a novel virus that’s causing this disease. In a world where sequencing is advanced enough to allow you to identify dang-near anything, why would a team resort to Cryo-Em identification here?

Let’s get into it:

SEQUENCING IS NOT ENOUGH

When trying to figure out the cause of an illness—the go-to technology right now is sequencing. Sequencing tech has blown up in the past decade—allowing research teams to extract incredible amounts of data from small samples.

However, in virology, sometimes sequencing isn’t that big of a help. If what you’re looking for is potentially a new virus that’s not in any current databases—it can be hard to sift through sequencing data if your target isn’t already a part of a wider database.

But advances in Cryo Electron Microscopy have made it cheap enough and high resolution enough for researchers to infer protein sequences from density maps alone. So the team at Rutgers decided to effectively go looking for the novel virus that was causing this potentially devastating mealworm outbreak.

CONNECTING THE DOTS

The team at Rutgers managed to isolate two regions of potential viral protein from an infected tissue sample. A more buoyant layer turned out to be hollow viral capsids, while the lower region was whole virions with genetic code still inside.

Using newer Cryo-Em techniques—the researchers managed to solidly determine the shape of the viral capsid. While that’s not enough to determine precisely what this virus was, it was enough to allow the team to connect the dots a little.

By identifying the rough sequence of the viral capsid—scientists were able to figure out that this mystery pathogen was probably a parvovirus. This is huge because the team was then able to look for DNA fragments similar to parvoviruses in their sequencing data.

Combining those two data points allowed the team to quickly identify and isolate this novel virus. The capsid is pictured above.

NEED FOR SPEED

One of the wildest things about this paper is that the team at Rutgers was able to identify a potential mitigation strategy for the genus of this virus within 10 days of receiving their first sample. They then locked in a full identification within 48 days—which is warp speed when you’re dealing with a pandemic that could start spreading exponentially at any moment. This is a great primer for how far Cryo-EM processing techniques have come. We’re eating good over here in Molecular Biology.

| Read the paper here |

Tag, you’re muted

New Epigenetic Sensor Uncovered

A newly isolated mechanism helps cells detect methylated DNA

CDCA7 (orange) binding to a methylated DNA sequence—gearing up to recruit Chromatin-modifying enzymes for genome maintenance

 🧬 Meet your gene editor.

If every single one of your cells has a full copy of your entire genome—then how do your skin cells…know…they’re supposed to be expressing skin genes and not anything else?

The answer to that question is pretty complicated—but one mechanism that allows your cells to switch genes on and off depending on what they need to do is called methylation. Basically, proteins ‘tag’ a cytosine base in a gene with a methyl group—and that tag allows maintenance proteins to latch onto that DNA during the cell cycle. By tightly editing the genome itself via these tags—your cells ensure that skin cells stay skin cells.

However, these methylation tags can go haywire over time and cause all sorts of diseases. Not only that—but these epigenetic markers are also inheritable—meaning that any changes that happen during someone’s life can be passed on to their children. This makes epigenetics are really critical area of study right now as we understand precisely how our cells fine-tune gene expression.

This field got a huge boost this month when researchers associated with Rockefeller University, the University of Tokyo and Yokohama City University identified a protein called CDCA7 as a sensor that detects methylated DNA.

In short: This is huge because science was only aware of one other methylation sensor before. Our understanding of gene maintenance just experienced a huge leap

DNA TAGS

So, CDCA7 has a region that binds to methylated DNA in the outer major groove of a DNA molecule. The other protein associated with DNA tagging—UHRF1—can’t bind to regions like this. This helps fill in some gaps in our understanding of how gene maintenance happens.

More importantly—it gives researchers more mechanistic insight into how gene tags are maintained. CDCA7 dysfunction has been connected to disorders caused by hypomethylation (not enough gene tags) so this discovery helps illuminate why.

  | Read the paper here  |

Hey there,

We are so back. After a minor hiatus—the first episode of our new season is out on YouTube.

Things got pretty gnarly in the final stages of rendering that episode—so I had to briefly pause the newsletter side of operations while I ironed out those last details.

The good news is—we’ll have a much smoother time rendering future episodes. Episode 1 came out 2 months late so that we can enjoy consistent, monthly new episodes moving forward.

And—incredibly—that new video about DNA replication basically became outdated 48 hours after release when a brilliant new paper came out describing some of the error correction processes inside DNA Polymerase Epsilon.

There’s still a lot of incredible science to cover, so let’s explore the big findings here in the world of biochemistry:

new video (finally)

Meet Your Replisome

In our latest episode, we unpack the incredible complexity of copying your entire genome every single cell division

POLA and the rest of the primosome extending a DNA primer (orange) on the lagging strand during DNA replication

 🧬 Eukaryotes sure like to make things complicated.

Every time your cells need to divide—they need to copy your entire genome first. We usually learn the basics of how cells do this in school, but that usually focuses on prokaryotic DNA replication.

Eukaryotes like us have a way more complicated replication story for a variety of reasons. Let’s break down a few here.

SPLITTING THAT DNA

I was forced to cut so much from this video in order to get it published in a reasonable amount of time. We glossed over a lot of incredible details to focus on the more entry-level topics. One of my favorite structures I’ve ever animated is the core of the eukaryotic replisome: CMG Helicase.

CMG has it all. It has support structures that help guide parent DNA into its core motor—and channels that simultaneously unwind and split parent DNA into two independent strands. New research shows that splitting the leading and lagging strands might be a more gentle and gradual process than using a single point to break the complementary strands apart.

YOU HAVE THREE POLYMERASES

The biggest change eukaryotes make here is relying on specific variants of DNA polymerase for specific jobs.

DNA Polymerase Epsilon (POLE) docks directly to the replisome’s CMG helicase and just spits out the leading strand with no issues. That simplicity is huge—but scroll down a bit to see how our understanding of POLE is getting stronger and stronger.

Meanwhile—DNA Polymerase Alpha exists entirely to extend the RNA primer made by Primase every time replication needs to start. This only happens once on the leading strand, but has to be constantly repeated on the lagging strand. POLA only prints ~30 nucleotides per primer and therefore does not have any proofreading exonuclease domains. POLE and POLD have the ability to proofread the DNA they are replicating while they synthesize their respective strands. POLA is (potentially) physically restrained by the primosome during primer extension, so that it can’t print errors while making a big enough hook for POLE or POLD to attach to.

In prokaryotes—both leading and lagging strand polymerases are physically linked by a clamp loader complex. While eukaryotes have clamp-loaders as well, there isn’t a lot of evidence suggesting that DNA Polymerase Delta has a physical interaction with the replisome. Instead—POLD independently synthesizes the lagging strand after the primosome adds a primer to it. Some experiments have shown that POLD loses efficiency if it is not close to the core replisome—so there’s still a lot of research to be done as we unravel the complexities of eukaryotic DNA replication.

  | watch the video here  |

thank you parasite, very cool

Maybe Brain Parasites Make Good Drug-Delivery Systems

Some folks will resort to just about anything to beat the blood-brain barrier

Toxo releasing the therapeutic protein MeCP2 (purple) attached to their GRA16 and toxofilin secretions.

 🧠 Gene editing just entered a bold new chapter

One of the toughest problems in medicine right now is getting therapeutic compounds across the blood-brain barrier. Your body is extremely proficient at blocking suspect chemicals from getting into your brain. Large molecule treatments that can help alleviate specific conditions are basically impossible to get across.

So, scientists have been cooking up newer and wilder delivery systems to try and consistently get across this barrier.

And after decades of development—one team appears to have landed on a wild new possibility. Engineering the single-celled brain parasite Toxoplasmosis gondii into being less of a parasite and more of a drug-delivery system.

A new paper in Nature has some pretty wild results from a new trial testing this system. Let’s get into it:

BESPOKE DRUG FACTORY

So yeah—Toxoplasmosis Gondii is a classic protozoan parasite that can infect the nervous tissue of any warm-blooded animal. Toxo exists in the popular imagination as the parasite that can infect you if you mishandle cat litter or any other mammalian waste.

Toxo can cross the blood-brain barrier in its granular form—which is how it ends up being a successful parasite. Once inside nerve cells, Toxo sets up shop and bombards its host with a whole mess of proteins designed to basically allow it to survive. Those proteins can do anything from affecting the metabolism of their host cell—to even crossing the nuclear envelope.

So—if you can figure out a way to make the Toxo parasite benign—then you might just have a solid way to deliver treatments beyond the blood-brain barrier. But how can you get therapeutic compounds inside Toxo in the first place?

DIY DRUG SYNTHESIS

The main large-molecule treatments that get blocked by the blood-brain barrier are chunky proteins. Since Toxoplasmosis Gondii is a living cell—researchers engineered its genome to manufacture therapeutic compounds.

But that’s not far enough. Those proteins also need to get to the correct part of a patient’s nerve cells to actually receive treatment. So—this team of researchers engineered Toxo to synthesize its own proteins with therapeutic ones attached to them. That way, the therapy actually gets to where it needs to go.

Toxo infiltrates nerve cells during a larval stage—so you can’t just fill it up with small-molecule drugs and release it. This method only works with peptide drugs that can be manufactured inside cellular machinery.

The team targeted two proteins and two delivery systems—the GRA16 dense granule protein that can infiltrate a host cell’s nucleus and a common fiber called Toxofilin. They engineered Toxo to produce MePC2 attached to these proteins.

MePC2 is a solid therapy for Rett Syndrome—a debilitating neurodegenerative condition of the brain and neural tissue. Rett Syndrome is a non-inherited genetic disease stemming from a single mutation of a single gene on the X chromosome in early life. Folks afflicted with Rett Syndrome can’t build MePC2 in the right shape—and that causes a cascade of issues that impair development over time.

With this engineered Toxo delivery system—folks afflicted with Rett Syndrome can get access to a constant supply of MePC2 and therefore mitigate that condition.

LONG WAY TO GO

The researchers behind this paper demonstrated that GRA16 did a solid job of delivering MePC2 to brain cells in mice. Of course—this treatment platform is barely entering into the ‘proof of concept’ phase. There’s a lot to refine in order to make sure that engineered Toxo cells don’t also generate some of the negative side effects of wild-type Toxoplasmosis infection.

For now—this simply stands as a triumph for synthetic biology. With gene-editing technology pretty much ubiquitous and relatively cheap as we race through the second decade of the CRISPR era—it’s genuinely exciting to see what new platforms we can develop to safely deliver highly targeted therapies like this.

BETTER OUTLETS FOR THIS SAME STORY

After I finished writing this article—Julia Bauman produced a far stronger video summary of this paper.  Bauman is a PhD student at Stanford and easily one of the top science communicators in the current vertical video meta. Her TikTok page is invaluable for folks trying to keep up with the cutting edge of life sciences research.

| Read the paper here |

no more errors

Human DNA Polymerase Has Autocorrect

A new paper demonstrates how POLE removes mistakes automatically during DNA replication

POLE removing a Cytosine nucleotide (green) from a growing leading strand during DNA synthesis

🎯 How can our cells target and remove DNA errors?

Every time your cells divide—they have to fully copy your entire genome. Your cells divide legitimately billions of times a day and they have to copy ~3 billion base pairs each time they do. With quadrillions of opportunities for catastrophic error—how on Earth does this operation run smoothly?

While there are a lot of well-understood mechanisms that correct errors in DNA replication after the fact—it turns out that our polymerases also have an autocorrect feature that helps prevent DNA errors from happening in the first place.

This is incredibly well-illustrated in a new paper from the Yeeles Lab at the MRC. This is the same team that resolved the initial structures of a human replisome used in my clockwork video.

This new paper shows how DNA Polymerase Epsilon changes conformations to guide new nucleotides into the emerging leading strand of DNA. It also shows how POLE can block RNA nucleotides from entering the active site and remove DNA errors automatically.

Let’s get into it:

REFINING OUR VIEW OF POL-E

The first big finding here is a set of states that show how DNA Polymerase Epsilon opens and closes in order to help new nucleotides join the template DNA of the leading strand. POLE has an ‘open’ and ‘closed’ state it moves between to help push individual nucleotides into the proper shape for binding to template DNA.

The team at the Yeeles Lab also found a third conformation—the ajar state—which appears to help block RNA nucleotides from mistakenly getting added to the growing DNA strand.

The key actor here is the ‘finger’ domain of POLE. Polymerases have three main regions we learn about in school: the ‘fingers’ the ‘thumb’ and the catalytic ‘palm’ where DNA synthesis actually happens.

In POLE—the fingers swivel on a hinge, opening and closing over the active site to guide new nucleotides into the template strand.

But that’s not the only shape this team found.

AUTOCORRECT EVERYTHING

POLE also has an automatic set of conformation changes that kick off when the wrong nucleotide gets added to the template strand.

In this model—a Cytosine nucleotide joined the strand where a Guanine should have instead. Incredibly, the team resolved subsequent structures that show how that erroneous Cytosine letter is pushed away from the template strand and cleaved from the daughter strand by POLE’s exonuclease domain.

Basically—Cytosine really has no business bonding with Thymine. Those two bases can form a kind of hydrogen bond—but since they are both pyrimidines (y’know, the short DNA letters), they form a little kink in the synthesized DNA.

This shape change is enough to push the daughter strand off to the side a little, where it can get picked up by other residues and handed off to the space between the thumb and exonuclease domains. There—the DNA error can get snipped off, allowing POLE to get back to regular DNA synthesis.

This is another one of those beautiful illustrations of how balanced things are at the molecular level. Protein structures are so delicate and malleable that a single, minor shape change can directly set off a cascade of other conformational changes that end up correcting an error and looping back to the original structure. It takes incredible effort to master your understanding of how all these different residues interact with an overall structure—but it is so satisfying once you start making intuitive sense of precisely how a protein’s structure helps to determine its function.

 | Read the paper here  | Animated loop here |

Hey there,

Welcome to a big biomedical week. We’ve got lots of wild findings out of the pharmaceutical space. With a first-line cancer drug proving efficacy well beyond anyone’s expectations and a diabetes treatment helping clear senescent cells—there’s a lot of really cool plot twists to uncover this week.

Meanwhile—Team Immunology™ is still firing on all cylinders with researchers potentially unlocking new insights into how autoantibodies (potentially) contribute to long COVID symptoms.

There’s so much to cover this week, so let’s jump in without wasting any time:

breath of fresh air

A Lung Cancer Drug Just Proved Incredible Survival Rates

A 5-year study into the efficacy of Lorlatinib achieved 60% survival rates. That is a meteoric jump.

Lorlatinib (gold) binding to ALK receptors in the cytoplasm of a cancer cell

🌬️ Get ready for some truly ground-breaking cancer news.

A new study from the American Society of Clinical Oncology just printed with some brain-breaking results. After 5 years of treatment with Pfizer’s Lorlatinib drug—60% of patients with Non–Small Cell Lung Cancer had demonstrated progression-free survival.

That may not seem like a big deal at first—but patients being treated with a comparable drug had only 8% PFS rates after 5 years.

This is a huge result that runs counter to even the most wildly optimistic expectations for treating NSCLC. Let’s explore how Lorlatinib works and the mechanics behind these great results:

LORLATINIB BASICS:

To keep it short—Lorlatinib is a drug that shuts down a critical receptor inside certain kinds of cancer cells. Inside cells that turn cancerous, a tyrosine kinase receptor called ALK mutates and goes haywire. ALK mutations lead to truly malicious cancers that spread quickly and are hard to treat.

Drugs like Lorlatinib bind to the ATP pocket of these ALK receptors inside cancer cells. This deactivates the receptor and blocks it from working. This slows the progression of NSCLC cancers—giving oncologists a chance to work on other areas of their treatment plan.

This makes ALK-blockers a great first-line treatment for these cancers. But—since cancer is crafty—they’re usually not even close to enough.

JUST MAKE A NEW ALK

First and second-generation ALK treatments don’t work for long because eventually, cancer cells divide enough to mutate a different form of the ALK receptor that doesn't get blocked by the drug. This is why those earlier medications have single-digit 5-year PFS rates.

These Lorlatinab results have potentially flipped the playing field.

LORLATINIB’S BREAKTHROUGH

Lorlatinib rules because it can also penetrate the blood-brain barrier and deactivate cancer cells that have metastisized all the way into those tissues. It is so effective that it appears to not even give these cancers a chance to develop mutations in their ALK receptors.

While there’s still a lot to learn about ALK receptors and how to treat cancers that have them—this Lorlatinib data is incredibly encouraging and opens up really cool new avenues for treatment.

 | Check out the trial data here  |

metabolism all the way down

Inhibiting SGLT2 Pumps Helps Alleviate Aging Symptoms

Another day, another diabetes drug with broad efficacy treating much bigger problems

SGLT2 Pumps getting inhibited and allowing for better clearance of senescent cells

🧹 Your body needs help clearing out old cells.

This is one of the critical mechanisms that causes diseases related to aging. As you get older and your cells continue to divide—more and more of them hit a limit.

To oversimplify, most of your cells have an internal clock that limits them to a certain number of divisions to help prevent things like cancer. Once cells hit that limit, they enter a state called senescence and stop dividing. When you’re young, your immune system does a pretty solid job of cleaning up these senescent cells and keeping you healthy. However, over time—senescent cells build up and your immune system can’t clear them as well anymore. A big build-up of these senescent cells is associated with a lot of the negative effects caused by aging.

Therefore, a lot of research has explored ways we can help clean up senescent cells without accidentally kicking off a tidal wave of cancer generation.

Which is why it’s completely incredible that a new paper has demonstrated that a type II diabetes medication has demonstrated a strong side affect that helps clean up senescent cells and alleviate some of the negative symptoms associated with aging. It is amazing to see just how much people’s lives improve when these small metabolic dysfunctions get corrected.

Let’s explore what we know so far:

MEET SGLT2

So this isn’t anything like well-known diabetes medications like Ozempic. This class of drug inhibits a pump inside kidney cells called SGLT2. Basically, inhibitors here block glucose from getting reabsorbed by the kidneys and therefore lower blood sugar. This is great if you have type-II diabetes—but how does this help with aging?

INCREASING SENESCENT CELL CLEARANCE

While there is a lot of research still being done to directly pin down the mechanism here—we have some critical clues.

Treating folks with insulin to lower blood sugar doesn’t directly lead to improved senescent clearance in the same way that SGLT2 inhibition does. So it can’t just be lower blood sugar = improved aging symptoms.

The team that did this study noted that SGLT2 inhibitors also upregulate a metabolite called AICAR. AICAR plays a role in a whole bunch of metabolic pathways—and a bunch of metabolic diseases. But the mechanisms that AICAR powers are still being unraveled. It could be that AICAR improves signaling—which in turn helps immune cells find and clear senescent cells.

Either way—this is a potentially massive breakthrough. It’s cool to discover an indirect pathway to help clear senescent cells—and it gives a solid jumping-off point for further unraveling the cellular mechanisms behind aging and age-related diseases.

I found this paper thanks to Friday Links by Niko McCarty

| Read the paper here | 

unraveling long COVID

Antibodies from Long COVID Patients Cause Disease in Mice

In a wild new study—researchers have shed light on the autoimmune nature of Long COVID

IgG antibodies from Long COVID patients along with GFAP, NFL, and other Long COVID biomarkers

 🦠 We’re starting to crack the code of Long COVID.

An alarming number of COVID infections lead to Long COVID—which is a big basket of symptoms that can range from inconvenient to completely debilitating.

With COVID sticking around for the long term—it is critical to unravel precisely what causes Long COVID symptoms so we can better treat this condition.

A new study out of the Amsterdam University Medical Center may help crack that code and prove an autoimmune link causing Long COVID.

The team injected mice with antibodies isolated from Long COVID patients—which resulted in a handful of measurable symptoms in those mice. While these results can’t really prove anything—they suggest a strong autoimmune foundation to Long COVID symptoms.

Let’s break down everything this paper explores:

COVID REACTIONS CAN LINGER

Right off the bat, this paper does a great job of summarizing a bunch of Long COVID biomarkers doctors can now test for. Folks who suffer from Long COVID have massively elevated levels of a fiber protein called GFAP that could be generated by neural inflammation and damage. Other big biomarkers in these patients include proteins like NFL and Tau along with immune signals like type-1 interfereons.

All of these proteins can indicate chronic inflammation associated with auto-antibodies generated by fighting off an initial COVID infection. So, researchers isolated IgG antibodies from Long COVID patients and injected them into mice.

ANTIBODY DISEASES

The team split Long COVID patients into 3 tiers based on serum levels of some of these biomarkers and the severity of their symptoms. Patients suffering from 2 of these 3 cohorts had antibodies that caused mice to become sick when they were injected with them.

The team at AUMC focused on neurological symptoms and found that mice injected with these antibodies displayed measurable increases in hypersensitivity and immobility. This is a critical piece of the Long COVID puzzle.

WHAT COMES NEXT?

There’s still a whole mountain of information researchers need to unravel before we fully can understand and treat Long COVID. However, it’s important to have definitive pieces of data like this study. If Long COVID is exclusively caused by autoantibodies sticking around and wreaking havoc long after the end of a COVID infection—then immunologists have a solid chance of developing treatments to alleviate those symptoms.

Still—it’s important to point out that we’re still in the early days of discovering the mechanics here.

  | Check out the paper here  |

we got games

Biology Connections #6

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

Share your results on social media—but make sure you include a link back to our newsletter (https://clockwork.beehiiv.com/subscribe)

Hey there,

It’s another catch-up week here. There’s a lot of great research that came out earlier in the year that we really want to dive into.

So check out this week’s roundup of some of the best research from the first half of 2024! We’re covering new insights into the precise mechanism that triggers the opening of stomata in plants.

Meanwhile—new data on PROTAC antibiotics is adding to hopes that we have another weapon for fighting pathogens like drug-resistant Tuberculosis.

And finally—let’s check in on a fresh mechanism that helps mitigate inflammation during periods of cellular stress by cleaning up leaky mitochondrial DNA.

There’s never a dull moment here on the cutting edge of the life sciences! Let’s dive into the research:

spreading those stomata

New Insights into How Stomata Open

A clever study has resolved our understanding on how light opens plant pores down to a single subunit of a single proton pump

PM Proton Pumps in a Stomatal Guard Cell getting phosphorylated by BLUS1 and BHP ahead of activation.

 🍃 Leaves need to open up.

One of the most important steps that activates photosynthesis in vascular plants is opening up the stoma. Stoma are the little pores in the plant epidermis that let CO2 in and allow water to evaporate out. For years, scientists have been refining our understanding of how this works, and we might have just unlocked the final step.

Let’s explore how a single residue—Threonine 881—kicks off the photosynthetic party.

WHAT DO STOMATA DO?

For background: stomata are little pores found on the surface of every vascular plant. Their main job is to open up and allow water to evaporate out. This creates upward pressure that helps plants bring water up through their roots—which also helps bring in nutrients and minerals from the soil.

Plants use those resources to power their photosynthetic activity during the day—so stomata are light-activated. Basically, in the presence of blue or red light, proton pumps in the membranes of guard cells surrounding the stoma will activate and shove as many protons out as possible. This creates a negative charge that brings potassium ions into the guard cell—which allows them to retain more water. The influx of water causes the guard cells to swell. Guard cells are so well-anchored to the tissue around them that they end up bowing outward—which leads to a fully opened stoma.

That’s cool—but what actually kicks this off? How do these proton pumps sense blue/ red light?

DISCOVERING THR881

There’s been a lot of great research surrounding the photoreceptors that detect light in these guard cells and kick off stomatal opening.

And our understanding has now been refined to the single residue level in Arabidopsis thaliana plants thanks to a new paper in Nature Communications.

Basically, scientists at Nagoya University in Japan did enough testing to determine that a single threonine residue—Thr881—gets phosphorylated by photoreceptors in the guard cell cytoplasm. That single phosphorylation opens up a tag on the tail-end of the PM Proton Pump, allowing a 14-3-3 protein to bind there and activate the proton pump.

That phosphorylation is passed on to the PM proton pump via photoreceptors BLUS1 and BHP. These photoreceptors get activated by blue light and ‘pass on’ that phosphorylation to the THR881 residue.

WHAT COMES NEXT?

There’s still a lot to learn here as scientists continue sussing out this mechanism. The main next step is determining exactly how Thr881 phosphorylation helps 14-3-3 bind to the PM proton pump. There are a lot of possibilities and plenty of new avenues for future experimentation.

For now, a better understanding of this mechanism can help us find treatments for certain kinds of plant disease—and can even assist in the design of new engineered signaling mechanisms that can make plants hardier or better able to manage their resources.

  | Check out the paper here  | And this write-up from Nagoya University  |

taking out the trash

Tuberculosis Gets Hijacked by New Class of Antibiotics

Every weapon that helps us beat drug-resistant TB is a huge deal.

CLPC1 binding to a Homo-BacPROTAC and gearing up to destroy itself. Whoops.

🦠Congrats TB, you played yourself.

At least that’s what scientists are saying after looking over the results generated by a new class of anti-TB drugs called Homo Bacterial Proteolysis Targeting Chimeras. Let’s call them Homo-BacPROTACs for short.

PROTACs are nothing new in the world of antibiotics. Basically, scientists have been frantically hunting for new ways to combat drug-resistant bacteria—and PROTACs may be a great solution.

To really oversimplify how PROTACs work—these are compounds that basically hijack ‘clean-up’ machines inside bacteria that normally break down old and unused proteins. Regular PROTACs reprogram the bacterial clean-up crew to attack and destroy necessary proteins—which in turn then kill the bacterium.

In a new study printed in Nature—scientists announced their development of Homo-BacPROTACs. This twist on the PROTAC technology has some serious advantages—especially in fighting drug-resistant variants of Tuberculosis. Let’s break down the breakdown here:

KILL THE GARBAGE MAN

PROTACs can basically ‘tag’ any protein for the bacterial clean-up system—CLPC1—to blow up. So, this research team made Homo-BacPROTACs that target the clean-up system itself. So CLPC1 gets directed to destroy other copies of itself—effectively disrupting the bacterial garbage system.

REMARKABLE EFFICACY

Cells are pretty crowded as it is, so without an active degradation system, trash piles up and prevents cellular activity from continuing. In short, Homo-BacPROTACs kill TB cells by stabbing them in their little bacterial kidneys.

The best part about these PROTACs is they attack the trash system in prokaryotes only. Us Eukaryotic folks have a completely different set of machinery that degrades our old and unused proteins—so side effects could be really limited in PROTAC treatment.

More importantly, PROTACs kill a wide spectrum of TB variants—and even kill TB cells locked away inside human macrophages. This has huge implications for TB specifically—as PROTAC treatment might be able to stop TB much earlier in the infection cycle.

Ultimately—this is a really exciting new weapon we’re testing in one of the longest wars we’ve ever fought as a species. TB has been infecting us since before we were even human—and it is high time we found more ways to put the world’s deadliest pathogen in the rear-view mirror.

 | Check out the paper here  |

don’t stress

Discovering a new clean-up system for Mitochondrial DNA

New insights into TFAM help scientists understand how cells clear loose mtDNA after moments of stress

TFAM bound to mitochondrial DNA and signaling LC3 proteins

⚡ Sometimes the powerhouse gets leaky.

Stress is a wild process at the biochemical level. When your cells experience stress or strain—the mitochondria that power your cells can get overactive. This causes mitochondrial DNA (mtDNA) to leak into the surrounding cytoplasm.

This is bad—because DNA material of any kind found loose in your cytoplasm will kick off inflammatory responses that can just amplify cellular stress.

But now, scientists at Guangzhou Medical University have identified a key clean-up mechanism that helps clear mtDNA when it slips into the cytoplasm. Turns out, the classic Mitochondrial Transcription Factor A—or TFAM—can tag mtDNA to be cleared by an established cellular pathway.

Let’s explore the details:

MEET TFAM

TFAM is an important ‘shepherd’ molecule that helps manage and maintain the Mitochondrial genome. Mitochondria aren’t just static powerhouses—they have their own DNA and internal processes that are necessary to maintain ATP production (and a LOT more).

TFAM is a classic transcription factor that helps package and prepare mtDNA for replication. But apparently, now there’s more to this little protein shepherd.

TFAM’S NEW SECRET

Scientists at Guangzhou Medical University in China have uncovered a binding domain on TFAM that attracts IL3, an autophagy protein that helps ‘tag’ unwanted compounds for destruction.

This is a huge discovery—because it helps us better understand how cells work their way out of stressful situations. It also gives folks a new angle to study diseases centered around mitochondrial dysfunction. Maybe TFAM can be a new angle for developing better treatments for these kinds of diseases.

| Read the paper here | 

we got games

Biology Connections #5

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

Share your results on social media—but make sure you include a link back to our newsletter (https://clockwork.beehiiv.com/subscribe)

Hey there,

Hello to all our new subscribers! With the Clockwork YouTube channel experiencing a breakout, we’re seeing a massive influx of folks here as well. It’s great that we already have such a strong community.

This week, we’re going to see how Australian researchers might have unlocked a huge detail inside the carboxysome—maybe one of the most important cellular structures in the whole history of life on Earth. Can this also unlock a more efficient path to sequestering all this excess carbon our atmosphere is dealing with?

Meanwhile, a new HIV vaccine is showing a lot of promise, while immunology researchers might have just supercharged CAR-T Cell cancer therapies with a new perk: Velocity Receptors™

This edition is jam-packed with gene editing, stunning results, and world-saving implications. Let’s explore this week in the life sciences:

tumor gear solid

Anti-Cancer Cells Unlock a Speed Buff

Researchers have potentially supercharged CAR-T Cell therapy by designing ‘velocity receptors’ that massively improve solid tumor penetration

Velocity Receptors targeting IL5 help a CAR-T cell penetrate into a solid lung tumor

 🚀Defeating cancer might have just gotten a lot faster.

It is an incredible time to be in immunology thanks to CRISPR technology. There are all sorts of incredible advancements happening as clinicians use gene editing to ‘fine tune’ the immune system and use it to fight way more than standard infections.

In particular—Chimeric Antigen Receptor T cells are an incredible tool. And researchers at Johns Hopkins University might have just made this therapy an even more powerful way to fight cancer.

The team has published results from their attempt to modify CAR T-Cells with receptors that can enhance tumor penetration. The results from these ‘velocity receptors‘ have been pretty wild so far.

But let’s break down some context first.

CAR-T CELLS ALREADY WRECK CANCER

T-Cells modified with Chimeric Antigen Receptors—CAR T-Cells—are one of the most exciting areas of study in immunology right now. In particular, these engineered cells are showing a lot of promise for treating various cancers.

To massively oversimplify here: cancer can only spread and cause issues if it can successfully cloak itself from your immune system. Thanks to CRISPR technology, researchers are now able to engineer receptors on the surface of patient T-cells called Chimeric Antigen Receptors. These engineered proteins give your immune system the tools it needs to attack cancer—and other things like autoimmune diseases—on their own.

While cancer treatments like chemotherapy and radiation treatments are the equivalent of carpet-bombing your body to defeat your cancer—CAR T-Cells are a surgical strike that attacks cancer at the cellular level. There’s so much promise here for this technology to blow the doors off of cancer therapy as more and more treatments are put through clinical trials.

This is great—but for cancers that have already progressed to a more solid tumor stage—CAR-T Cells can actually be quite slow. The cancer-attacking cells don’t penetrate solid tumors quickly.

That changes with the development of velocity receptors 

ADDING VELOCITY

Velocity receptors came from a simple idea. Researchers at Johns Hopkins noticed that certain kinds of T-cells are more mobile than others. T-Cells patrol all over your tissues and occasionally have to move between cells to take down pathogens. More mobile T-Cells interact with cytokines via a branch of the paracrine pathway.

So, the Johns Hopkins team engineered T-Cells to express receptors that both target those cytokines and signal through the receptors those cytokines bind to. They then programmed T Cells to express both cancer-fighting CAR proteins as well as a set of these velocity receptors.

MORE FAST MORE FURIOUS

And these results are incredible. CAR T-Cells modified with velocity receptors objectively have an easier time fully penetrating solid tumors—at least in the mouse models used in this study.

In models that simulate pancreatic and lung cancers, CAR T-Cells coupled with velocity receptors that target the cytokine IL-5 crushed tumor growth within days of treatment.

This is a genuinely exciting breakthrough that can greatly enhance how we develop CAR T-Cell technology for all kinds of therapies

  | Check out the paper here  |

defeating HIV

New Vaccine Makes Progress Against HIV

A new treatment targeting a structural protein on the HIV virion had patients producing critical antibodies after two immunizations

Broadly Neutralizing antibodies attaching to the gp41 domain on the surface of an HIV virion

🏹 HIV might have an Achilles Heel.

In a new clinical trial, researchers were able to generate a 95% serum response rate for a vaccine targeting HIV. New results published in Cell last week outline how scientists might be able to refine this treatment to develop a full-proof vaccine for HIV.

HIV IS SNEAKY

HIV has historically been really difficult to treat and vaccinate against. The HIV virus literally targets your immune system, so it’s difficult to develop vaccines that effectively target the virus.

More importantly, HIV also mutates so quickly that just targeting a receptor protein on the virus’s surface won’t be effective.

So, researchers have been developing a new vaccine that targets a foundational HIV protein domain in a new and exciting way.

ATTACK THE CORE

First of all, this new vaccine is targeting the gp41 region of the HIV virus’s surface. This is a structure at the base of the envelope protein HIV uses to infect host cells.

Across a wide range of HIV mutants, the structure of GP41 usually stays the same—making it a strong candidate for vaccine development. It takes years to approve a vaccine via medical trials, and by the time a treatment gets approved, the virus could have mutated enough to make it useless.

But, how did researchers manage to get the immune system to target GP41?

BETTER INSTRUCTIONS

Thanks to advancements in delivery tech, the researchers behind this HIV vaccine were able to develop liposomes—basically little membrane bubbles—small enough to deliver just a small segment of the GP41 protein. Upon being injected with these liposomes, 95% of patients in this clinical trial all experienced an immune response that developed antibodies.

Researchers then tested the antibodies produced here and concluded that these were Broadly Neutralizing Antibodies (bnAbs). Basically, these antibodies attack and pacify many different strains of HIV—which is enough to make this treatment a candidate for further study. This is huge, but like all clinical trials it comes with a lot of caveats.

Most importantly, this clinical trial only had 5 participants. You can get all sorts of wild results from a sample size that small. More clinical trials will help refine these results and further demonstrate the efficacy of this treatment strategy.

Meanwhile—

With how complicated AD is to treat and understand—every clear and coherent target for therapy is a borderline miracle. We’re years away from having any concrete data about whether this FN1 mutation could be used to treat Alzheimer’s more broadly, but this is definitely a treatment angle to watch.

| Read the paper here |

cracking the carboxysome

A New Key to Speedy Photosynthesis Emerges

Researchers have proven what regulates the Carbon Dioxide Concentrating Mechanism in cyanobacteria. This is a huge deal.

A carbonic anhydrase trimer complexed with RuBisCo

☀ Can we speed up photosynthesis?

That’s an interesting new question being raised by a fresh study out of The Australian National University. There, scientists have demonstrated how the Carbon Dioxide Concentrating Mechanism (CCM) in cyanobacteria is regulated. This has potentially huge implications—but at its core, this is just an amazing new piece of foundational knowledge that helps us understand photosynthesis and the Calvin Cycle.

Heck, this might be the discovery that helps us build new tools to fight global warming.

But let’s not get ahead of ourselves—we’ll take this research one step at a time:

MEET THE CARBOXYSOME

Sure, the trees outside your window are doing their fair share of photosynthesis—but the lion’s share of photosynthetic activity is done by cyanobacteria. These ancient bugs are also the organisms that pioneered photosynthesis in the first place and effectively terraformed the ancient Earth—making it habitable for airsick landlubbers like you and me. Their combined effort sucks down ~12% of the world’s CO₂ every year.

Unlike your average redwood, cyanobacteria are really delicate and can only photosynthesize under very specific conditions. Because of that—cyanobacteria turn CO₂ into glucose and other sugars much faster than plants do. Most cyanobacteria pull this off thanks to a structure called the Carboxysome. This is a cool, angular protein pocket that concentrates all of the cyanobacteria’s dissolved CO₂ in order to roll through the Calvin Cycle as quickly as possible.

Pumps on the outside of the Carboxysome shove dissolved CO₂ (in the form of bicarbonate ions) into the interior space, where a special variant of Carbonic Anhydrase converts back into regular CO₂ that can be reduced by RuBisCo.

This is really important—as RuBisCo is famously one of the least efficient enzymes known to science. RuBisCo is painfully bad at its job. But—a big concentration of CO₂ boosts RuBisCo’s efficiency and stops reverse reactions from taking place. RuBisCo’s main job is to take the CO₂ made by Carbonic Anhydrase and combine it with the proto-sugar RuBP. The entire Calvin Cycle works just to produce more RuBP to feed RuBisCo.

But the critical question is—what gives Carbonic Anhydrase in these carboxysomes the signal to convert in the CO₂ first place?

HERE’S THE DISCOVERY

Turns out—Carbonic Anhydrase is regulated by RuBP. Carbonic Anhydrase in carboxysomes has a binding site for RuBP that ‘turns on’ the catalytic conversion of CO₂ for RuBisCo. When there’s a critical mass of RuBP in the carboxysome, some of it will bond to Carbonic Anhydrase and change its shape into a more optimal conformation for CO₂ conversion

This is called allosteric regulation—and examples of this are all over most biological systems.

 WHY DOES THIS EVEN MATTER?

This is honestly a massive discovery because we’ve determined a strong model for precisely how RuBP allosterically regulates carbonic anhydrase activity in the carboxysome.

This gives us a better framework for testing how we can ‘speed up’ photosynthesis in other organisms. The research team from ANU mentioned the possibility of engineering plants with a bigger ‘appetite’ for carbon—which can be another pathway to developing a carbon sequestration process that can actually scale. Given our massive carbon excess—anything even remotely promising is worth a shot.

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

we got games

Biology Connections #4

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

Share your results on social media—but make sure you include a link back to our newsletter (https://clockwork.beehiiv.com/subscribe)

Hey there,

The biochem world is still reeling from the AlphaFold3 Launch. There’s so much great development happening behind the scenes right now. But, we’re still catching up with research from earlier in the year in this edition of the Clockwork newsletter. A big hello to all the new folks here after we announced that season 2 is just a month away.

There’s still a lot of great research to cover. Researchers at Perdue have finally isolated a receptor on petunias that can give us the framework we need to decode the molecular language plants use to communicate.

Meanwhile, a groundbreaking study may have just given us a target to help block Alzheimer’s Disease. One small malfunctioning fiber can completely crush one of the deadliest inherited risk factors for the disease.

And finally, we’re dipping back into 2023 because not nearly enough people are talking about the Harvard study that finally identified a biochemical trigger for itching. One of the body’s strangest and least understood sensations is only now coming into focus.

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

petunia rumors

The Key to Decoding Plant Language

Using a range of techniques, researchers have identified a critical receptor that will help them further decode and study how plants ‘talk’

(-) germacrene D binding with PhKAI2ia receptors on a petunia Pistil cell

📢 Plants are far louder than you think.

Communication between plants is a really exciting new frontier in Botany that’s been expanding for the past few years. Turns out, plants aren’t nearly as static as they seem. There’s been a lot of great discoveries illuminating a wide spectrum of airborne chemical signals put out by plants.

Now, a new paper out of Purdue has discovered another ‘word’ petunias use to communicate.

Let’s explore (-) Germacrene D and sus out exactly what ‘communication’ is in plants.

THE FLOWERS ARE TALKING?

Turns out, plants can detect all sorts of signals in the air and via their root systems in the soil. While it may seem like plants are just hanging out and photosynthesizing or whatever—they can biochemically adapt to all sorts of stimuli at the cell level.

In particular, flowers are the ‘loudest’ part of a plant. Flowers have been observed pushing out chemicals that can attract pollinators, repel pesky herbivores, or even warn other plants about infectious bacteria.

Now, researchers at Purdue have identified a new signal petunias are listening for—a smoke-like volatile called (-) Germacrene D. More importantly, the team also isolated the receptor that reacts to germacrene. This protein—PhKAI2ia—could be the critical link that allows researchers to fully unravel the complex language plants use.

THE FLOWERS ARE LISTENING??

This same team published a great paper back in 2019 describing how Petunias emit volatile organic chemicals (like germacrene) to communicate between different parts of the same flower.

All of this research has been really exciting in the Botany community—but learning that flowers communicate can’t give us a lot of insight into precisely HOW they communicate. We need to know the mechanism that allows plants to ‘hear’ as well.

That’s what makes this latest paper so exciting. The team at Purdue has effectively isolated a hyper-specific receptor—PhKAI2ia—that binds to a very specific signaling molecule. In short, they demonstrated that PhKAI2ia binds to (-) Germacrene D and activates a signaling pathway inside petunia cells. This is massive.

A KEY THAT UNLOCKS PETUNIA LANGUAGE

The Purdue team isolated PhKAI2ia based off of genes expressed in petunia cells in the presence of (-) germacrene D. They then built the structure of the receptor with germacrene in AlphaFold 2 and determined how the signal could bind to this receptor.

These steps are critical for future research, as now scientists have a way to measure if a signal has been ‘heard’ by a plant—as well as a repeatable framework for finding more receptors that ‘listen’ for these chemical signals. With these frameworks in place, we’re a giant step closer to fully decoding the intricate and delicate way plants communicate.

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

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blocking the amyloid door

Faulty Fiber Blocks Alzheimer’s

In an exciting new development, clinicians have discovered a new angle to protect folks from developing Alzheimer’s Disease

Fibronectin bound to an integrin protein within the blood-brain barrier

🎯 New Alzheimer’s target just dropped.

In a potentially groundbreaking paper, scientists at Columbia University may have just discovered a new angle to attack Alzheimer’s Disease.

Basically, folks who have a rare mutation in a kind of cellular fiber—fibronectin FN1—appear to completely block the onset of Alzheimer’s disease if they are susceptible to it.

This mutation only protects from the effects of another gene—APOEε4—but this discovery may help offer new insights into new ways to stop Alzheimer’s from forming in the first place.

LET’S BREAK DOWN APOEε4 FIRST

APOEε4 is a mutated variant of a near-ubiquitous protein in your brain and other organs. This little machine basically helps build little lipid bubbles that move proteins and fats around your cells. The ε4 variant of APOE is extremely bad news. Folks with two copies of the faulty ε4 APOE gene essentially have a near 100% chance of developing Alzheimer’s disease. They also generally experience symptoms far earlier in life and don’t live as long.

APOEε4 is so bad that some researchers call it ‘the most pathogenic mutation in history.’

Alzheimer’s is incredibly complicated and difficult to study—so we don’t fully understand the mechanism that causes APOEε4 to either kick off or worsen Alzheimer’s. It could be that as APOE goes haywire, it pushes all sorts of cellular junk through the blood-brain barrier, causing amyloid plaques to build up in critical parts of the brain.

But in this new paper out of Columbia—researchers showed that a rare mutation in another protein—Fibronectin—seems to stop folks with the APOEε4 from developing Alzheimer’s Disease. What gives?

HOW COULD FIBRONECTIN STOP APOEε4?

To be clear—this was a genetic study. Researchers found folks who had the APOEε4 mutation but no symptoms and found they had a rare mutation of Fibronectin in common. This FN1 variant of Fibronectin basically makes it non-functional.

Fibronectin is one of the many fibers on the outside of your cells that helps hold junctions together. It also helps with signaling. In the image above, Fibronectin is bonded to an integrin at the basal membrane in the blood-brain barrier—which will allow that integrin protein to open up and let stuff into the brain.

So, one mechanism here could be that fibronectin is the doorway that faulty APOE uses to bring all sorts of gunk across the BBB. If the door is broken, the bad stuff can’t accumulate and cause Alzheimer’s Disease. Slick.

SO, WHY IS THIS A BIG DEAL?

While on the surface this seems like a niche discovery that will only help a small cohort of people—there’s actually a lot going on here.

First of all, as we get more data on APOEε4—even the non-mutated version of this protein looks more and more like a potential cause of AD. If we can block the mechanism that makes APOEε4, that could potentially be a route to treating Alzheimer’s more broadly.

More importantly—this FN1 mutation of Fibronectin is small enough to use in CRISPR therapy. Finding a rare mutation that alleviates a disease is one of the ways scientists developed really successful CRISPR therapies for sickle cell anemia.

With how complicated AD is to treat and understand—every clear and coherent target for therapy is a borderline miracle. We’re years away from having any concrete data about whether this FN1 mutation could be used to treat Alzheimer’s more broadly, but this is definitely a treatment angle to watch.

| Read the paper here |

scratching the biochemical itch

Harvard Scientists Uncover Critical Clue About What Causes Itching

After years of confounding the medical profession—we have our first real biochemical source of itching

The V8 protease from S. aureus cleaving and activating the PAR-1 receptor in an epidermal neuron

 🤏 Itching has been a serious medical mystery for years.

But scientists at Harvard Medical School recently published research that illustrates a biochemical mechanism that can at least offer relief to folks suffering from chronic itching caused by certain bacteria.

MEET THE V8 PROTEASE

The team at HMS focused on the bacteria Staphylococcus aureus—a usually benign member of the human microbiome. S. aureus colonizes about 30% of people with no issue. However, S. aureus can go hogwild in some cases and cause conditions like eczema. The itch that develops when folks get hit with an S. aureus dermatitis is particularly pervasive and uncomfortable.

Using mouse models, HMS scientists discovered a new protein put out by S. aureus—the V8 protease. This nasty little molecule might help unlock a treatment path for itching broadly.

PAR-1 FOR THE COURSE

To keep it quick—V8 protease attacks and cuts PAR-1 receptors on sensory neurons in your skin. PAR-1 is a pretty classic signaling receptor that has a lot of jobs across your cellular landscape.

Since PAR-1 does so much across the body—there’s already drugs that inhibit this receptor. The Harvard team used one of these treatments on mice who were exposed to S. aureus itching and found that the PAR-1 itching response completely stopped.

While this finding doesn’t help explain the mechanism for how the V8 protease and PAR-1 lead to an itch signal—it still unlocks a lot of different angles for studying new ways to treat chronic scratching.

 | Check out the paper here | Or a HMS summary here |

we got games

Biology Connections #3

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

Share your results on social media—but make sure you include a link back to our newsletter (https://clockwork.beehiiv.com/subscribe)

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

simplified render of pGal-OVA binding to the MHC

🔇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

CEP290 proteins associated with microtubules in retinal rod cells. The mutated cysteine residue is highlighted in yellow

 👀 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

Share your results on social media—but make sure you include a link back to our newsletter (https://clockwork.beehiiv.com/subscribe)

You can’t play directly in the newsletter (yet)

Hey there,

Welcome to the first newsletter edition of Clockwork! This has already been a wild year for Biochemistry, so honestly these first few posts are going to be playing catch up with the industry.

Immunology is really leading the charge right now with a new CAR-T Cell treatment showing efficacy in treating Multiple Sclerosis—while a new antibody therapy had promising results clearing α-synuclein in Parkinson’s patients. Meanwhile, a new GLP-1 drug also showed efficacy in treating Parkinson’s—which is just par for the course considering that it appears Ozempic and other GLP-1 medications are receiving promising data for treating just about everything.

But, the biggest news of the month came out of the world of Molecular Biology—where scientists at the Max Planck Insitute for Terrestrial Microbiology discovered the evolution and mechanism for citrate synthase to arrange into first and second-order fractals. Specifically, this enzyme was found to self-assemble into Sierpiński triangles. Do fractals provide some kind of evolutionary advantage? Probably not. Is it still awesome to see abstract mathematical structures emerge in nature? Heck yes.

There’s a lot more to cover, so let’s dive in:

clearing that synuclein

Two Parkinson’s Drugs Show Promise

New tech is allowing scientists to make incredible progress treating neurodegenerative disease

🧠 We’re witnessing some huge advancements in treating Parkinson’s Disease

This neurodegenerative condition has been brutally difficult to cure—thanks to the small yet complex mechanism that helps the condition progress in folks. One of the main symptom drivers for Parkinson’s is an accumulation of misfolded neuron proteins called α-synuclein. Basically, α-synuclein misfolds in the neurons of Parkinson’s patients and then gets stuck together in messy clumps near synaptic junctions where neurons meet and communicate. This disrupts communication between neurons and leads to the progression of Parkinson’s symptoms.

Parkinson’s propagates a lot like prion disease—where misfolded α-synuclein from neuron can ‘infect’ adjacent cells, causing them to misfold as well.

But now, two new treatments are demonstrating novel paths to slow the progression of Parkinson’s symptoms—adding to hopes that the disease can become more treatable

PRASINEZUMAB CLEARS OUT α-SYNUCLEIN PLAQUES

Recently, the antibody foundry Prothena released phase II trial data for their Parkinson’s treatment Prasinezumab. This is a new antibody designed to bind to and clean α-synuclein plaques in the brain.

Based on this small sample size, Prasinezumab appears to be able to slow the progression of Parkinson’s symptoms. On the right side of the image above, you can see this antibody binding to a single misfolded α-synuclein protein, marking it to be removed by the immense system.

To be fair, this treatment only showed a significant slowing of symptom progression in one of three major parts of the Parkinson’s Disease Rating Scale. However, the scientists who designed this study pointed out that it would take a lot longer to show progress in the scale that Prasinezumab missed.

For now, these results are encouraging, and help point to α-synuclein as a primary driver in the onset of Parkinson’s disease. However, Phase II trials have such small sample sizes that it’s hard to say if antibody treatments like Prasinezumab will work at a larger scale.

GLP-1 DRUGS SHOW EFFICACY TOO

Meanwhile, GLP-1 drugs continue to also demonstrate efficacy in slowing the progression of Parkinson’s. The latest winner comes from a clinical trial testing Lixisenatide—seen bound to GLP-1 receptors on the left half of the image above.

Lixisenatide isn’t the first GLP-1 treatment that’s helped Parkinson’s. Two other clinical trials have been pretty encouraging as well. Basically, GLP-1 drugs have been shown to reduce inflammation throughout the body. One thing that causes Parkinson’s to get worse is a steady rise of inflammation in the brain. While Lixisenatide also didn’t show a lot of progress in two of the three components of the Parkinson’s Disease Rating Scale—this trial was conducted over the course of a single year. It would take a lot longer to show progress in the more foundational symptoms of Parkinson’s. But, this is still a really exciting time in the fight against neurodegenerative conditions like Parkinson’s.

  | Read the report on Prasinezumab  | Check out the Lixisenatide data |

getting fractal

Meet The Fractal Protein

Yes, scientists have discovered a naturally occurring molecular triforce in the bacteria Synechococcus elongatus

 📐 Why would proteins form fractal patterns?

That was the question facing a research team at the Max Planck Insitute for Terrestrial Microbiology when Cryo-Electron Microscopy images revealed that a cyanobacteria called Synechococcus elongatus was producing enzymes arranged in a factual pattern known as the Sierpiński triangle. How does this happen?

TRIANGLES BREAK ALL THE RULES

While nature produces complex fractal patterns all the time—something as geometric as a straight-up triforce doesn’t really fit the rules of how proteins form arrangements normally. Turns out, S. elongatus was producing citrate synthase enzymes that could break local symmetry when they came together in 6-unit hexamers. Basically, the shape of this enzyme could change a little when they came together in a triangular complex. This allowed 1st and 2nd order fractals to emerge. Three triangular hexamers produced an 18-unit triforce, and three of those could combine into the 54-unit Sierpiński triangle shown at the center of the image above.

WHAT IS THE EVOLUTIONARY BENEFIT OF FRACTALS?

But why was this happening? After digging deeper into trying to understand the point of the Sierpiński arrangement—researchers found that the efficiency of these citrate synthase enzymes decreased when they assembled into this pattern. Basically, S. elongatus could slow down its metabolism by going Sierpiński-mode™.

However, removing S. elongatus’s ability to do this had no material affect on the health of the bacteria. Sure, it’s cool that Sierpiński Mode™ can function as a regulatory mechanism—but S. elongatus wasn’t relying on the fractal arrangement for anything practical.

It’s important to remember that evolution is blind—and sometimes stable mutations don’t necessarily produce anything super-useful. Sometimes, the universe accidentally produces something that’s just cool to notice.

 | Read the paper here | Here’s a solid Twitter summary  |

immune cell assassins

New Therapy Slows Multiple Sclerosis

Kyverna’s groundbreaking KYV-101 Chimeric Antigen Receptor T-Cell treatment just cleared a massive hurdle in medical trials

🧬 CAR-T Cells keep shattering expectations

This new technology—where immunologists modify patient T-Cells with CRISPR to attack cancer and auto-immune disease—continues to show so much promise.

In a new introductory trial, biotech player Kyverna demonstrated the safe use of their new fully-human CAR-T Cell treatment for patients with Multiple Sclerosis. How did they pull this off?

HOW DO CAR-T CELLS WORK?

To massively oversimplify here—immunologists have been engineering T-cells in patients that express a transmembrane protein complex called a Chimeric Antigen Receptor in order to ‘train’ a person’s immune system to attack malignant cells in their body. CAR-T-cells are programmed to attack the receptors expressed on ‘bad actors’ in the body like leukemia cells—or the immune cells that go haywire. The best surgeon in the world is your own immune system, so CAR-T Cells are an extremely exciting new technology.

For Kyverna, they programmed this KYV-101 treatment to go after the CD19 receptor on B cells that have gone rogue and started attacking the myelin sheaths of neurons. This is the underlying autoimmune cause of Multiple Sclerosis—and therefore this treatment could halt or even reverse the progression of the disease.

HOW DID THIS TRIAL GO THO?

This initial trial for KYV-101 was a safety demonstration for the treatment. CAR-T Cell therapy can have fairly intense side effects, and Kyverna can’t initiate broader trials without confirming that KYV-101 doesn’t kick off some of these side issues like Cytokine Release Syndrome (CRS) and Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS).

So, this demonstration only had two patients—which is way too small a sample size to generate any meaningful data. With that said, KYV-101 didn’t lead to any secondary issues like CRS or ICANS. Even though this was just a single infusion of CAR-T Cells, KYV-101 demonstrated a slowing of MS symptom progression in both patients. This data is a great start, but meaningless until Kyverna can conduct a larger trial.

CAR-T Cells remain a very new technology that needs a lot more analysis before anyone can declare these therapies as a potential cure for the issues they’re designed to treat. Stay tuned for a later newsletter where we’ll examine a new study trying to determine if CAR-T Cell therapy might cause rare secondary cancers in folks treated with them.

Either way, CAR-T Cell therapies like KYV 101 are a strong demonstration of just how much platforms like CRISPR have completely transformed how we think about and design medicines. You could not pick a more transformational moment to be in the immunology business.

| Check out the trial data here |

we got games

Biology Connections #1

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

Share your results on social media—but make sure you include a link back to our newsletter (https://clockwork.beehiiv.com/subscribe)

You can’t play directly in the newsletter (yet)

Hey there,

It’s exciting to be back. After a period of redevelopment, Clockwork is relaunching with a stronger model to ensure the media we produce is more valuable to scientists and science educators.

The response to the initial run Clockwork had on YouTube was nothing short of extraordinary. It was amazing to discover there’s a real appetite for media that explores the deeper topics in Biology.

However, converting the fundamentally 3-dimensional world of Biochemistry into 2D abstractions is incredibly time-consuming and doesn't provide any real benefit to educators.

At the same time, new tools and a meteoric advancement in GPU technology have made it shockingly possible to create animations using real scientific data from the Protein Data Bank. Using real data allows Clockwork to create far more useful media. So, I’ve spent this development period adapting the Clockwork style to a 3d workflow.

TLDR:

clockwork is going 3-dimensional

Sample render from an upcoming post.

Clockwork is sticking with roughly the same style and color palette with mild adjustments to smooth out this transition to 3d.

In addition, I’m adding new media branches to the Clockwork brand to ensure we cover a better variety of topics. This is also going to make sure that Clockwork has a more sustainable business model moving forward so I can release seasons of core Clockwork videos more consistently.

Clockwork will come to you in a few major branches:

• A curated newsletter bringing you the top stories coming out of Biology (weekly for now)

• Deep-dive image posts on Instagram and other platforms exploring the latest developments in the life sciences (daily)

• Shorter, punchier animations exploring biochemistry on Reels or TikTok (semi-weekly, pushing toward daily.

• Core Clockwork videos exploring the foundations of Biochemistry on YouTube. (Monthly for now).

  Season 2 of Clockwork will be released in June on YouTube. In the meantime, there’s still plenty of Biochem to explore. Let’s check out the new branches in detail:

email remains undefeated

The Clockwork Newsletter

A weekly exploration of new papers and discoveries coming out of the life sciences at a pivotal moment

📰 We need a home base outside of the algorithms

Algorithmic channels like Instagram and YouTube are great for discovery, but they are fundamentally unreliable and force creators to make drastic shifts over time. Maintaining a newsletter with a robust email list gives us a strong foundation to fall back on in the event of shifts in any of the big algorithms.

Plus, a newsletter allows us to stay up-to-date with cutting-edge scientific research in Biology. A platform like this better connects the channel with the wider scientific community. Since this channel only exists to highlight the advanced life scientists and elevate the brilliant researchers expanding our understanding of life at the molecular level—making a newsletter is a real no-brainer here.

Plus, while I’ve been developing Clockwork, my full-time job has been building and growing email newsletters. This is the format I have the most professional experience in and therefore it’s the medium I can spin up the fastest without impacting daily operations too drastically.

SO WHAT WILL THIS NEWSLETTER LOOK LIKE?

Expect this exact format. We’ll have quick, digestible summaries of the most impactful papers coming out of the Life Sciences space every week. I’m going to be biased towards anything that comes with an entry into the Protein Data Bank. We’ll expand into areas like Bioinformatics, Computational Biology, and even the Pharmaceutical Industry based on where the news is.

We’ll explore the top 3-4 stories of the week in Biology every Thursday moving forward. Make sure you’re subscribed so you don’t miss a single update!

  | Check out everything we’re doing at watchclockwork.com  |

life in pictures

Expanding our Instagram Footprint

For every video, we can make dozens of static images

📷️ There’s just so much happening in Biology right now

Unfortunately, writing and fact-checking scripts alone significantly limits our ability to produce full YouTube videos. However, the transition to 3D production makes it much faster to produce static images and shorter videos for Instagram and TikTok (until it gets banned lol).

EVERY NEWSLETTER POST WILL HAVE A COMPANION PIECE ON INSTAGRAM

The Instagram algorithm has come a long way in the past few years and now appears to be a strong choice for educational posts. So, every story I post to the newsletter will have a companion Instagram piece that expands and elaborates on the subject matter.

AND MORE EXPERIMENTS WITH SHORTER VIDEO

As the newsletter builds momentum, I’ll also add shorter animations to Instagram Reels and TikTok.

Make sure you’re following us on Instagram | May as well on TikTok too 

going 3d

Our Biggest Plans are on Youtube

Using scientifically accurate data unlocks so much potential

 🔬 Most of the redevelopment work has been focused on new YouTube videos

We have a handful of scripts already baked out and ready to fully animate. Now that I have enough of a handle on rendering real PDB models—I’m hard at work bringing these scripts to life for the launch of Season 2 in June.

SEASON 2 STARTS WITH THE CENTRAL DOGMA

DNA replication is one of those ‘holy grail’ molecular processes to animate. I’m going to take things up a notch by focusing on the Human Replisome. Buckle up.

AND WE WILL GRADUALLY WORK INTO IMMUNOLOGY

Sure, it will take dozens of videos—but we will tackle a molecule-by-molecule view of the Immune System throughout season 2. I couldn’t be more excited for this.

From there, we’ll be covering lots of different pathways. The real goal of Season 2 is to develop an efficient enough workflow to post YouTube videos every 2 weeks instead of monthly. Right now, that goal looks achievable, especially if we have enough success to expand our GPU infrastructure.

 | Make sure you’re subscribed to Clockwork on YouTube |