The secrets of carbon capture

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

 🚀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

🏹 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.

☀ 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)