A step towards psychedelics with none of the undesirable side effects/symptoms

Good news! Amazing stuff!

"Psychedelic drugs hold great promise for treating mental health conditions like depression and anxiety. But beyond their otherworldly hallucinogenic manifestations, many of these drugs also come with all-too-familiar side effects like nausea, vomiting, and gastrointestinal discomfort.

This occurs because the psychedelic compounds activate several off-target pathways as well as the intended serotonin receptors in the brain.

Reducing these unwanted interactions and the unpleasant symptoms that come with them is an important step for demonstrating the safety of psychedelics.

In a new study ... researchers pushed closer to this reality by re-engineering the synthetic psychedelic drug quipazine to activate only the desired receptors .

The pharmacologists began by examining quipazine atom-by-atom to identify how the drug could bind to both the target 5-HT2AR receptor and the 5-HT3R receptor that causes nausea and other gastrointestinal symptoms.

After singling out the nitrogen atom responsible, they replaced it and rearranged the whole molecule. The resultant drug could still bind to the desired 5-HT2AR receptor, but it bounced off 5-HT3R receptors.

To test the new psychedelic’s effectiveness, the researchers gave the drug to mice with symptoms of depression and anxiety. Once the hallucinogenic effects subsided, the mice exhibited fewer symptoms and showed no apparent discomfort. When they examined the animals’ brains, the researchers found an increased density of neuron structures called dendritic spines, a telltale sign that the psychedelic had restored some of the brain activity lost to depression. ..."

From the editor's summary and abstract:

"Editor’s summary

The clinical use of serotonergic psychedelics is limited by their side effects. Younkin et al. generated a derivative (called VCU-1012) of the psychedelic quipazine with greater activity at the serotonin receptor subtype that mediates the clinically desirable effects (5-HT2AR) than at the serotonin receptor subtype responsible for the undesirable ones.

Similar to quipazine, VCU-1012 exerted antidepressant and antianxiolytic effects in mice but without the gastrointestinal side effects of quipazine. Moreover, like other psychedelics, VCU-1012 increased dendritic spine density in the frontal cortex in a 5-HT2AR–dependent manner.

Thus, VCU-1012 shows promise as a 5-HT2AR agonist with a more favorable side effect profile than those of typical psychedelics. ...

Abstract

Psychedelics that target serotonin 2A receptors (5-HT2ARs) hold therapeutic promise for neuropsychiatric disorders but are often hindered by off-target actions. The 5-HT2AR agonist quipazine also activates 5-HT3R, which contributes to undesirable side effects.

Here, we developed VCU-1012, a quipazine-based, structurally distinct 5-HT2AR agonist devoid of 5-HT3R activity.

VCU-1012 was developed by applying a strategic chemical design that combined deconstruction to pinpoint the nitrogen atom critical for 5-HT2AR activation with structure-activity relationship studies to minimize 5-HT3R agonism.

We showed that VCU-1012 modulated dendritic spine structural plasticity in the frontal cortex and produced antidepressant-like effects in mice through 5-HT2AR without activating 5-HT3R, thereby avoiding the gastrointestinal side effects of quipazine.

In addition, our molecular modeling and mutant analysis suggested that VCU-1012 interacted in the canonical orthosteric binding pocket of 5-HT2AR.

Together, these findings establish VCU-1012 as a potential therapeutic agent with reduced gastrointestinal impact, emphasize how differences in ligand-receptor interactions influence ligand positioning in the receptor binding pocket, and provide guidance for designing psychedelics with targeted therapeutic benefits."

ScienceAdviser

Design of a new psychedelic quipazine analog with therapeutic efficacy and potentially fewer side effects (no public access)

Design and Synthesis of Quipazine Analogs for Programmable Control of Psychedelic Effects (A PhD thesis covering a similar topic. The author was not part of the team authoring the above research article.)

VCU-1012 (Wikipedia page indicating this psychedelic drug was already developed in 2024)

VCU-1012 2D chemical structure

Implanted synthetically engineered bacteria to sense pathology and deliver drugs long-term to the site locally

Amazing stuff! This could be a breakthrough!

"Patient recovery from many debilitating conditions and diseases could be sped up significantly and be more effective if drugs and therapeutic molecules were delivered right to where they are needed in the body, over the entire regenerative process, and in doses finely tuned to therapeutic needs. An intriguing way to achieve this is the use of implantable, synthetically engineered, living cells that can sense injury or disease-associated conditions in their environment and flexibly respond by producing the right amount of a therapeutic molecule.

Bacteria, in particular, are promising in this regard as they can thrive in harsh physiological environments within the body, such as within infected or inflamed tissues, tissues undergoing mechanical movements, and tumors.

Some of these microbial therapies have even advanced into clinical trials to treat certain cancers, metabolic disorders, and the progression of kidney stones. However, thus far, such trials have failed, and microbes are feared to also pose significant safety risks because they cannot be contained at specific sites in the body. ...

By encapsulating a genetically engineered, therapeutic strain of E. coli bacteria within a biomaterial made from a hydrogel that was specifically designed to regulate bacterial growth and resist mechanical stresses, like those present at physically active sites in the body, the bacteria could be confined for over six months.

The E. coli bacteria were equipped with a synthetic gene circuit that allowed them to sense pathogenic Pseudomonas aeruginosa bacteria causing infections and then respond by releasing a therapeutic molecule that killed the nearby residing pathogens.

Implanted into the joints of mice next to a specialized orthopedic implant designed to help heal femoral injuries, the ILM autonomously and effectively treated infections with P. aeruginosa, a common cause of often debilitating orthopedic device infections. ..."

From the abstract of the Perspective:

"Engineered cells can sense disease and deliver drugs at a site of pathology. These living therapeutics provide localized, self-sustaining responses to environmental changes, such as inflammation and pathogenic signals, that conventional drugs cannot offer ... 

A promising chassis for living therapeutics is bacteria, which can be genetically programmed to release drugs in response to an external signal. However, bacteria require physical enclosure to prevent uncontrolled spread and toxicity. Biomaterials such as hydrogels and core-shell capsules have only demonstrated short-term containment of up to 2 weeks in culture. 

On page 729 of this issue, Harimoto et al. report a hydrogel scaffold with engineered stiffness and toughness that confines bacteria for up to 6 months in culture. When the system harbored bacteria producing pyocin, it cleared an infection in a mouse model of joint replacement. This could advance living therapeutics from short-lived proof-of-concept systems to durable, programmable medicines."

From the editor's summary and abstract:

"Editor’s summary

Engineered bacteria could serve as a source of long-term drug delivery, but they tend to escape confinement because of their small size and robust viability. Harimoto et al. created a polyvinyl alcohol (PVA) hydrogel matrix engineered for both high stiffness and high toughness that can contain bacteria without killing them off ... The hydrogel is used to trap engineered Escherichia coli that expresses a sense-and-respond genetic circuit designed to trigger the release of a protein antibiotic to clear Pseudomonas infection. This system was tested in vivo over a 6-month period, revealing positive treatment outcomes in a murine joint infection model. ...

Abstract

Microbes are increasingly used as living therapeutics, yet their uncontrolled dissemination in the body has remained a clinical roadblock.

Physical containment remains largely unattainable owing to eventual bacteria escape.

In this work, we present an implantable material that encapsulates and confines bacteria, wherein synthetically engineered microbes produce therapeutic payloads from within.

We developed a hydrogel scaffold with dual mechanical features: high stiffness to regulate bacterial proliferation and high toughness to resist material fracture under physiological stress.

This design achieved complete bacterial containment for 6 months and withstood multiple forms of mechanical loading that otherwise caused catastrophic material failure.

By genetically engineering embedded bacteria, we endowed the material with environmental sensing and on-demand therapeutic release capabilities and demonstrated autonomous treatment in a murine prosthetic joint infection model."

ScienceAdviser

Materializing safe, on-demand living therapeutics (original news release)

Scaffolds toughen bacteria-based therapy (Perspective, no public access)

Implantable living materials autonomously deliver therapeutics using contained engineered bacteria (no public access)

Implantable Living Materials Autonomously Deliver Therapeutics from Contained Engineered Bacteria (preprint, open access)

This illustration explains how the team designed Implantable Living Materials (ILMs) as a living therapeutic that uses an optimized hydrogel to safely contain synthetically engineered bacteria that are able to sense a pathogenic stimulus and respond to it by secreting a therapeutic protein within living organisms. The material itself is sufficiently “stiff” so that bacteria pushing against it from the inside can’t break it apart, and sufficiently “tough” to provide to protect the enclosed bacteria against external physical stresses. Combined with the synthetically engineered bacteria, the new approach becomes a safe and autonomous functioning drug delivery device.

Fig. 1 Design and mechanical characterization of Implantable Living Materials (ILMs).

Fig. 2 ILMs maintain bacterial containment during long-term culture and mechanical loading.

Enzyme engineering opens door to novel therapies for Parkinson’s, cancers and other hard-to-target protein diseases

Good news! This could become a powerful new treatment option! This seems to be very promising.

"Now, a new study ... demonstrates a proof of concept for a new strategy: engineering proteases—enzymes that cut proteins at specific sites—to selectively degrade these elusive targets with high precision in the proteome of human cells. ...

the study shows how to reprogram a protease from botulinum toxin to target α-Synuclein—a protein with unstructured regions used here as a model. The study marks one proof point in a broader approach that could be applied to a wide range of targets across the proteome. 

“This work highlights how we can use the power of laboratory evolution to engineer proteases that offer a new way to treat diseases caused by hard-to-target proteins,” ...

To reprogram this precision for α-Synuclein, the research team modified the enzyme using directed evolution, a laboratory process that involves introducing mutations and selecting variants with improved function over multiple cycles.

The result: Protease 5. The challenge, however, wasn’t just reprogramming the protease to target α-Synuclein—it was ensuring that it attacked only α-Synuclein and nothing else. Past attempts to evolve proteases for therapeutic use have resulted in enzymes that targeted too broad a range of proteins, cleaving multiple unintended molecules and causing toxicity in cells.

“α-Synuclein is an incredibly hard protein to target because it doesn’t have a stable structure,”  ...

Although α-Synuclein plays a central role in Parkinson’s disease and related disorders, it was used in this study as a model protein representing a broader class known as intrinsically disordered proteins (IDPs)—proteins that lack a defined shape and are notoriously difficult to target with drugs. This instability makes such illnesses challenging to treat because traditional therapies typically work by attaching to stable pockets on proteins, like a key fitting inside a lock. However, α-Synuclein has no such binding site, leaving few viable treatment options. “That’s where proteases come in,” ... “Instead of needing a specific binding site, they can be engineered to recognize and cut α-Synuclein directly, preventing it from dangerously accumulating in the brain.” 

Using directed evolution, the team stepwise modified the botulinum protease, selecting variants that showed increasing preference for α-Synuclein. “Directed evolution works like selective breeding—just as farmers breed plants for better crops, scientists guide proteins through many small changes, choosing the best version at each step,” ... “Each round of modifications made the enzyme more specialized,” ... “until it could selectively degrade α-Synuclein while leaving other proteins untouched.”

When tested in human cells, Protease 5 nearly eliminated all α-Synuclein proteins, suggesting it could help prevent the harmful buildup seen in Parkinson’s disease. And because the enzyme was designed to precisely target α-Synuclein, it didn’t cause toxicity or disrupt essential cellular functions.  ..."

From the significance and abstract:

"Significance

The ability to evolve proteases that selectively cleave a desired protein in vivo could provide access to useful therapeutic agents.

This would be especially powerful when targeting intrinsically disordered proteins (IDPs), a hard-to-drug class of proteins involved in many human diseases including cancer and neurodegenerative diseases.

Here, we demonstrate the stepwise evolution of clinically used botulinum protease to proteolyze the IDP α-Synuclein which forms plaques in the brains of patients suffering from Parkinson’s disease.

Abstract

There is considerable interest in the targeted degradation of proteins implicated in human disease.

The use of sequence-specific proteases for this purpose is severely limited by the difficulty in engineering the numerous enzyme–substrate interactions required to yield highly selective proteases while maintaining catalytic activity.

Herein, we report a strategy to evolve a protease for the programmed degradation of α-Synuclein, a presynaptic protein closely linked to Parkinson’s disease. Our structure-guided evolution campaign uses the protease from botulinum neurotoxin and showcases the stepwise change of specificity from its native substrate SNAP25 to the selective degradation of α-Synuclein.

The protease’s selectivity is further demonstrated in human cells where near complete degradation of overexpressed human α-Synuclein is observed with no significant effects on cell proliferation. This stepwise strategy may serve as a general approach to evolve highly selective proteases targeting dysregulated proteins."

Enzyme engineering opens door to novel therapies for Parkinson’s, cancers and other hard-to-target protein diseases | Scripps Research "Researchers reprogrammed a botulinum toxin protease to selectively break down disease-causing proteins in human cells, providing proof of concept for developing new therapies for a wide range of illnesses."

Revolutionary Enzyme Engineering Paves the Way for Innovative Treatments in Parkinson’s Disease, Cancer, and Challenging Protein Disorders

Targeted degradation of α-Synuclein using an evolved botulinum toxin protease (no public access)

4D printed shape-shifting biomaterials for tissue engineering and regenerative medicine applications

I think, I personally prefer 5D printing! (just kidding). 3D printing just started to become mainstream.

From the abstract:

"The existing 3D printing methods exhibit certain fabrication-dependent limitations for printing curved constructs that are relevant for many tissues. Four-dimensional (4D) printing is an emerging technology that is expected to revolutionize the field of tissue engineering and regenerative medicine (TERM). 4D printing is based on 3D printing, featuring the introduction of time as the fourth dimension, in which there is a transition from a 3D printed scaffold to a new, distinct, and stable state, upon the application of one or more stimuli. Here, we present an overview of the current developments of the 4D printing technology for TERM, with a focus on approaches to achieve temporal changes of the shape of the printed constructs that would enable biofabrication of highly complex structures. To this aim, the printing methods, types of stimuli, shape-shifting mechanisms, and cell-incorporation strategies are critically reviewed. Furthermore, the challenges of this very recent biofabrication technology as well as the future research directions are discussed. Our findings show that the most common printing methods so far are stereolithography (SLA) and extrusion bioprinting, followed by fused deposition modelling, while the shape-shifting mechanisms used for TERM applications are shape-memory and differential swelling for 4D printing and 4D bioprinting, respectively. For shape-memory mechanism, there is a high prevalence of synthetic materials, such as polylactic acid (PLA), poly(glycerol dodecanoate) acrylate (PGDA), or polyurethanes. On the other hand, different acrylate combinations of alginate, hyaluronan, or gelatin have been used for differential swelling-based 4D transformations. TERM applications include bone, vascular, and cardiac tissues as the main target of the 4D (bio)printing technology. The field has great potential for further development by considering the combination of multiple stimuli, the use of a wider range of 4D techniques, and the implementation of computational-assisted strategies."

4D printed shape-shifting biomaterials for tissue engineering and regenerative medicine applications - IOPscience (open access)

Figure 2. 3D fabrication methods used in 4D (bio)printing and their presence in TERM applications.

Recording of cellular physiological event histories in self-assembling protein chains

Amazing stuff!

"As cells perform their everyday functions, they turn on a variety of genes and cellular pathways. MIT engineers have now coaxed cells to inscribe the history of these events in a long protein chain that can be imaged using a light microscope.

Cells programmed to produce these chains continuously add building blocks that encode particular cellular events. Later, the ordered protein chains can be labeled with fluorescent molecules and read under a microscope, allowing researchers to reconstruct the timing of the events. ..."

From the abstract:

"Observing cellular physiological histories is key to understanding normal and disease-related processes. Here we describe expression recording islands—a fully genetically encoded approach that enables both continual digital recording of biological information within cells and subsequent high-throughput readout in fixed cells. The information is stored in growing intracellular protein chains made of self-assembling subunits, human-designed filament-forming proteins bearing different epitope tags that each correspond to a different cellular state or function (for example, gene expression downstream of neural activity or pharmacological exposure), allowing the physiological history to be read out along the ordered subunits of protein chains with conventional optical microscopy. We use expression recording islands to record gene expression timecourse downstream of specific pharmacological and physiological stimuli in cultured neurons and in living mouse brain, with a time resolution of a fraction of a day, over periods of days to weeks."

Self-assembling proteins can store cellular “memories” | MIT News | Massachusetts Institute of Technology Using these engineered proteins, researchers can record histories that reveal when certain genes are activated or how cells respond to a drug.

Recording of cellular physiological histories along optically readable self-assembling protein chains (open access)

Fig. 1: Concept and development of linear protein self-assembly-based cellular physiology recording devices.

Frog skin cells turned themselves into living machines

Amazing stuff!

"Using blobs of skin cells from frog embryos, scientists have grown creatures unlike anything else on Earth, a new study reports. These microscopic “living machines” can swim, sweep up debris and heal themselves after a gash. ...

In a way, the bots were self-made. Scientists removed small clumps of skin stem cells from frog embryos, to see what these cells would do on their own. Separated from their usual spots in a growing frog embryo, the cells organized themselves into balls and grew. About three days later, the clusters, called xenobots, began to swim.

Normally, hairlike structures called cilia on frog skin repel pathogens and spread mucus around. But on the xenobots, cilia allowed them to motor around. ...

Xenobots have no nerve cells and no brains. Yet xenobots — each about half a millimeter wide — can swim through very thin tubes and traverse curvy mazes. When put into an arena littered with small particles of iron oxide, the xenobots can sweep the debris into piles. Xenobots can even heal themselves; after being cut, the bots zipper themselves back into their spherical shapes.

Scientists are still working out the basics of xenobot life. The creatures can live for about 10 days without food. When fed sugar, xenobots can live longer (though they don’t keep growing). “We’ve grown them for over four months in the lab,” ... “They do really interesting things if you grow them,” including forming strange balloon-like shapes. ..."

From the abstract:

"Robot swarms have, to date, been constructed from artificial materials. Motile biological constructs have been created from muscle cells grown on precisely shaped scaffolds. However, the exploitation of emergent self-organization and functional plasticity into a self-directed living machine has remained a major challenge. We report here a method for generation of in vitro biological robots from frog (Xenopus laevis) cells. These xenobots exhibit coordinated locomotion via cilia present on their surface. These cilia arise through normal tissue patterning and do not require complicated construction methods or genomic editing, making production amenable to high-throughput projects. The biological robots arise by cellular self-organization and do not require scaffolds or microprinting; the amphibian cells are highly amenable to surgical, genetic, chemical, and optical stimulation during the self-assembly process. We show that the xenobots can navigate aqueous environments in diverse ways, heal after damage, and show emergent group behaviors. We constructed a computational model to predict useful collective behaviors that can be elicited from a xenobot swarm. In addition, we provide proof of principle for a writable molecular memory using a photoconvertible protein that can record exposure to a specific wavelength of light. Together, these results introduce a platform that can be used to study many aspects of self-assembly, swarm behavior, and synthetic bioengineering, as well as provide versatile, soft-body living machines for numerous practical applications in biomedicine and the environment."

Frog skin cells turned themselves into living machines | Science News Newly created ‘xenobots’ swim and move particles around in their environment

A cellular platform for the development of synthetic living machines (open access)

Small clusters of skin cells taken from frog embryos grow into larger spheres, called xenobots (pictured), that can swim, move particles and heal themselves.

Conduit coated with bioink encourages damaged nerves to reconnect

Good news!

"A tube-like structure printed with a specially designed ink can repair broken neural circuits in vitro, new research shows. The conduit could be developed into a treatment to boost sensory and motor recovery in patients with nerve injuries. ..."

Conduit coated with bioink encourages damaged nerves to reconnect | Research | Chemistry World (behind paywall) New electro-conductive system is fully biodegradable

Here is an older article covering this subject:

Superior 'bio-ink' for 3D printing pioneered Researchers are developing materials to help grow human tissues