5/1/2024: Meet the Molecular Triforce

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

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