Protein degrader molecules are heralding a revolution in drug discovery, with more than 50 drugs of this type currently being tested in clinical trials for patients with diseases for which no other options exist.

The Centre for Targeted Protein Degradation (CeTPD) at the University of Dundee is one of the world’s leading centres for research into how protein degraders work and how they can most effectively be put to use for a new generation of drugs.

Now researchers have revealed previously invisible levels of detail and understanding of how the protein degraders work, which in turn is allowing for even more targeted use of them at the molecular level.

PhD student Charlotte Crowe, together with Dr Mark Nakasone, Senior Postdoctoral Scientist at CeTPD, used a technique called cryo-electron microscopy (cryo-EM), which enables scientists to see how biomolecules move and interact with each other.

This works by flash-freezing proteins and using a focused electron beam and a high-resolution camera to generate millions of 2D images of the protein. They then used sophisticated software and artificial intelligence (AI) models which allowed them to generate 3D snapshots of the degrader drugs working in action.

Their latest research is published in the journal Science Advances and is expected to constitute a landmark contribution to research in the field of TPD and ubiquitin mechanisms.

“We have reached a level of detail where we can see how these protein degraders work and can be deployed [to recruit the disease-causing protein ] and target the ‘bull’s eye’, in molecular terms,” said Charlotte Crowe, who carried out the research together with a wider team of Dundee researchers.

“Protein degrader molecules work in a way that is fundamentally different from the way conventional drugs work. However, until recently the exact details of how this process works at the molecular level had remained elusive.

“Proteins are typically a few nanometres large, which is 1 billionth of a metre, or 1 millionth of the width of a hair. So being able to ‘see’ them in action has not been possible, up until now.

“We have now been able to build a moving image of how it all happens, which means we can more specifically control the process with an incredible level of detail.”

Professor Alessio Ciulli, Director of CeTPD and one of the world leaders in the field of targeted protein degradation, said, “This is incredibly exciting work and opens up the possibility of even more effectively targeted drugs able to finally treat some diseases which up until now have been too difficult to tackle.”

How it works

Proteins are essential for our cells to function properly, but when these do not work correctly they can cause disease.

Targeted protein degradation involves redirecting protein recycling systems in our cells to destroy the disease-causing proteins.

Protein degraders work by capturing the disease-causing protein and making it stick like a glue to the cellular protein-recycling machinery, which then tags the protein as expired in order to destroy it.

The tag is a small protein called ubiquitin, which effectively gets fired at the disease-causing protein like a bullet. In order for the process to work effectively, ubiquitin must hit the right spots on the target protein so that it gets tagged effectively. The new work by the Dundee team enables them to see how the bullet hits the proverbial bull’s eye.

Working with a protein degrader molecule called MZ1, which was developed in the Ciulli laboratory at Dundee, and using high-end mass spectrometry, they were able to identify exactly where on the target protein the vital ‘tags’ are added.

The work shows how degrader drugs hold onto and position disease-causing proteins, making them good targets for receiving ubiquitin molecules (ie. “ubiquitin-atable”) which then leads to their destruction inside the cell.

Protein degradation efficiency and productivity is dependent on the degrader molecule’s ability to hold tight onto the disease-causing protein, and in a position where it can most effectively act. This latest research paints a bull’s eye and holds it steady enough for the molecule to be accurately targeted.

Professor Ciulli said this and other recently published papers were contributing to rapid development of an exciting field of science and drug discovery.

“This rapidly expanding field is fascinating and complementary articles on how this cellular protein-recycling machinery works to fire ubiquitin molecules at target proteins were recently published by the laboratories of biochemists Brenda Schulman (Max-Planck Institute of Biochemistry) and Gary Kleiger (University of Nevada, Las Vegas).

“Our collective work provides a leap forward in understanding that will accelerate development of new TPD drugs in future.”

“As a physician, I help to care for children who have the most severe symptoms, and as a researcher, I’m driven to understand why they become so sick,” said corresponding author Melody G. Duvall, MD, PhD, of the Division of Pulmonary and Critical Care Medicine at Brigham and Women’s Hospital (BWH) and the Division of Critical Care Medicine at Boston Children’s Hospital. “NK cells are important first responders during viral infection — but they can also contribute to lung inflammation. Interestingly, our findings fit with data from some studies in COVID-19, which reported that patients with the most severe symptoms also had increased NK cells in their airways. Together with previous studies, our data link NK cells with serious viral illness, suggesting that these cellular pathways merit additional investigation.”

Duvall and colleagues, including lead author Roisin B. Reilly of the Division of Pulmonary and Critical Care Medicine at BWH, looked at samples from 47 children critically ill with RSV, analyzing immune cells found in their airways and peripheral blood. Compared to uninfected children, those with severe illness had elevated levels of NK cells in their airways and decreased NK cells in their blood. In addition, they found that the cells themselves were altered, both in appearance and in their ability to perform their immunological function of killing diseased cells.

Duvall and co-authors have previously described a post-pandemic surge in pediatric RSV infections. While clinicians can only provide supportive care to the most severely sick children, vaccines to prevent RSV are now available for children 19 months and younger, adults 60 years and over, and people who are pregnant.

Researchers from MIT and Delft University of Technology have now introduced a more efficient, less wasteful, and higher-precision technique that leverages heat-responsive materials to print objects that have multiple colors, shades, and textures in one step.

Their method, called speed-modulated ironing, utilizes a dual-nozzle 3D printer. The first nozzle deposits a heat-responsive filament and the second nozzle passes over the printed material to activate certain responses, such as changes in opacity or coarseness, using heat.

By controlling the speed of the second nozzle, the researchers can heat the material to specific temperatures, finely tuning the color, shade, and roughness of the heat-responsive filaments. Importantly, this method does not require any hardware modifications.

The researchers developed a model that predicts the amount of heat the “ironing” nozzle will transfer to the material based on its speed. They used this model as the foundation for a user interface that automatically generates printing instructions which achieve color, shade, and texture specifications.

One could use speed-modulated ironing to create artistic effects by varying the color on a printed object. The technique could also produce textured handles that would be easier to grasp for individuals with weakness in their hands.

“Today, we have desktop printers that use a smart combination of a few inks to generate a range of shades and textures. We want to be able to do the same thing with a 3D printer — use a limited set of materials to create a much more diverse set of characteristics for 3D-printed objects,” says Mustafa Doga Dogan PhD ’24, co-author of a paper on speed-modulated ironing.

This project is a collaboration between the research groups of Zjenja Doubrovski, assistant professor at TU Delft, and Stefanie Mueller, the TIBCO Career Development Professor in the Department of Electrical Engineering and Computer Science (EECS) at MIT and a member of the MIT Computer Science and Artificial Intelligence Laboratory (CSAIL). Dogan worked closely with lead author Mehmet Ozdemir of TU Delft; Marwa AlAlawi, a mechanical engineering graduate student at MIT; and Jose Martinez Castro of TU Delft. The research will be presented at the ACM Symposium on User Interface Software and Technology.

Modulating speed to control temperature

The researchers launched the project to explore better ways to achieve multiproperty 3D printing with a single material. The use of heat-responsive filaments was promising, but most existing methods use a single nozzle to do printing and heating. The printer always needs to first heat the nozzle to the desired target temperature before depositing the material.

However, heating and cooling the nozzle takes a long time, and there is a danger that the filament in the nozzle might degrade as it reaches higher temperatures.

To prevent these problems, the team developed an ironing technique where material is printed using one nozzle, then activated by a second, empty nozzle which only reheats it. Instead of adjusting the temperature to trigger the material response, the researchers keep the temperature of the second nozzle constant and vary the speed at which it moves over the printed material, slightly touching the top of the layer.

In speed-modulated ironing, the first nozzle of a dual-nozzle 3D printer deposits a heat-responsive filament and then the second nozzle passes over the printed material to activate certain responses, such as changes in opacity or coarseness, using heat. “As we modulate the speed, that allows the printed layer we are ironing to reach different temperatures. It is similar to what happens if you move your finger over a flame. If you move it quickly, you might not be burned, but if you drag it across the flame slowly, your finger will reach a higher temperature,” AlAlawi says.

The MIT team collaborated with the TU Delft researchers to develop the theoretical model that predicts how fast the second nozzle must move to heat the material to a specific temperature.

The model correlates a material’s output temperature with its heat-responsive properties to determine the exact nozzle speed which will achieve certain colors, shades, or textures in the printed object.

“There are a lot of inputs that can affect the results we get. We are modeling something that is very complicated, but we also want to make sure the results are fine-grained,” AlAlawi says.

The team dug into scientific literature to determine proper heat transfer coefficients for a set of unique materials, which they built into their model. They also had to contend with an array of unpredictable variables, such as heat that may be dissipated by fans and the air temperature in the room where the object is being printed.

They incorporated the model into a user-friendly interface that simplifies the scientific process, automatically translating the pixels in a maker’s 3D model into a set of machine instructions that control the speed at which the object is printed and ironed by the dual nozzles.

Faster, finer fabrication

They tested their approach with three heat-responsive filaments. The first, a foaming polymer with particles that expand as they are heated, yields different shades, translucencies, and textures. They also experimented with a filament filled with wood fibers and one with cork fibers, both of which can be charred to produce increasingly darker shades.

The researchers demonstrated how their method could produce objects like water bottles that are partially translucent. To make the water bottles, they ironed the foaming polymer at low speeds to create opaque regions and higher speeds to create translucent ones. They also utilized the foaming polymer to fabricate a bike handle with varied roughness to improve a rider’s grip.

Trying to produce similar objects using traditional multimaterial 3D printing took far more time, sometimes adding hours to the printing process, and consumed more energy and material. In addition, speed-modulated ironing could produce fine-grained shade and texture gradients that other methods could not achieve.

In the future, the researchers want to experiment with other thermally responsive materials, such as plastics. They also hope to explore the use of speed-modulated ironing to modify the mechanical and acoustic properties of certain materials.

Astronomers used Uranus as a proxy for similar planets beyond our solar system, known as exoplanets, comparing high-resolution images from Hubble to the more-distant view from New Horizons. This combined perspective will help scientists learn more about what to expect while imaging planets around other stars with future telescopes.

“While we expected Uranus to appear differently in each filter of the observations, we found that Uranus was actually dimmer than predicted in the New Horizons data taken from a different viewpoint,” said lead author Samantha Hasler of the Massachusetts Institute of Technology in Cambridge and New Horizons science team collaborator.

Direct imaging of exoplanets is a key technique for learning about their potential habitability, and offers new clues to the origin and formation of our own solar system. Astronomers use both direct imaging and spectroscopy to collect light from the observed planet and compare its brightness at different wavelengths. However, imaging exoplanets is a notoriously difficult process because they’re so far away. Their images are mere pinpoints and so are not as detailed as the close-up views that we have of worlds orbiting our Sun. Researchers can also only directly image exoplanets at “partial phases,” when only a portion of the planet is illuminated by their star as seen from Earth.

Uranus was an ideal target as a test for understanding future distant observations of exoplanets by other telescopes for a few reasons. First, many known exoplanets are also gas giants similar in nature. Also, at the time of the observations, New Horizons was on the far side of Uranus, 6.5 billion miles away, allowing its twilight crescent to be studied — something that cannot be done from Earth. At that distance, the New Horizons view of the planet was just several pixels in its color camera, called the Multispectral Visible Imaging Camera.

On the other hand, Hubble, with its high resolution, and in its low-Earth orbit 1.7 billion miles away from Uranus, was able to see atmospheric features such as clouds and storms on the day side of the gaseous world.

“Uranus appears as just a small dot on the New Horizons observations, similar to the dots seen of directly-imaged exoplanets from observatories like Webb or ground-based observatories,” added Hasler. “Hubble provides context for what the atmosphere is doing when it was observed with New Horizons.”

The gas giant planets in our solar system have dynamic and variable atmospheres with changing cloud cover. How common is this among exoplanets? By knowing the details of what the clouds on Uranus looked like from Hubble, researchers are able to verify what is interpreted from the New Horizons data. In the case of Uranus, both Hubble and New Horizons saw that the brightness did not vary as the planet rotated, which indicates that the cloud features were not changing with the planet’s rotation.

However, the importance of the detection by New Horizons has to do with how the planet reflects light at a different phase than what Hubble, or other observatories on or near Earth, can see. New Horizons showed that exoplanets may be dimmer than predicted at partial and high phase angles, and that the atmosphere reflects light differently at partial phase.

NASA has two major upcoming observatories in the works to advance studies of exoplanet atmospheres and potential habitability.

“These landmark New Horizons studies of Uranus from a vantage point unobservable by any other means add to the mission’s treasure trove of new scientific knowledge, and have, like many other datasets obtained in the mission, yielded surprising new insights into the worlds of our solar system,” added New Horizons principal investigator Alan Stern of the Southwest Research Institute.

NASA’s upcoming Nancy Grace Roman Space Telescope, set to launch by 2027, will use a coronagraph to block out a star’s light to directly see gas giant exoplanets. NASA’s Habitable Worlds Observatory, in an early planning phase, will be the first telescope designed specifically to search for atmospheric biosignatures on Earth-sized, rocky planets orbiting other stars.

“Studying how known benchmarks like Uranus appear in distant imaging can help us have more robust expectations when preparing for these future missions,” concluded Hasler. “And that will be critical to our success.”

Launched in January 2006, New Horizons made the historic flyby of Pluto and its moons in July 2015, before giving humankind its first close-up look at one of these planetary building block and Kuiper Belt object, Arrokoth, in January 2019. New Horizons is now in its second extended mission, studying distant Kuiper Belt objects, characterizing the outer heliosphere of the Sun, and making important astrophysical observations from its unmatched vantage point in distant regions of the solar system.

The Uranus results are being presented this week at the 56th annual meeting of the American Astronomical Society Division for Planetary Sciences, in Boise, Idaho.

The Hubble Space Telescope has been operating for over three decades and continues to make ground-breaking discoveries that shape our fundamental understanding of the universe. Hubble is a project of international cooperation between NASA and ESA (European Space Agency). NASA’s Goddard Space Flight Center in Greenbelt, Maryland, manages the telescope and mission operations. Lockheed Martin Space, based in Denver, Colorado, also supports mission operations at Goddard. The Space Telescope Science Institute in Baltimore, Maryland, which is operated by the Association of Universities for Research in Astronomy, conducts Hubble science operations for NASA.

The Johns Hopkins Applied Physics Laboratory (APL) in Laurel, Maryland, built and operates the New Horizons spacecraft and manages the mission for NASA’s Science Mission Directorate. Southwest Research Institute, based in San Antonio and Boulder, Colorado, directs the mission via Principal Investigator Alan Stern and leads the science team, payload operations and encounter science planning. New Horizons is part of NASA’s New Frontiers program, managed by NASA’s Marshall Space Flight Center in Huntsville, Alabama.

Volatiles are elements or compounds that change into vapour at relatively low temperatures. They include the six most common elements found in living organisms, as well as water. The zinc found in meteorites has a unique composition, which can be used to identify the sources of Earth’s volatiles.

The researchers, from the University of Cambridge and Imperial College London, have previously found that Earth’s zinc came from different parts of our Solar System: about half came from beyond Jupiter and half originated closer to Earth.

“One of the most fundamental questions on the origin of life is where the materials we need for life to evolve came from,” said Dr Rayssa Martins from Cambridge’s Department of Earth Sciences. “If we can understand how these materials came to be on Earth, it might give us clues to how life originated here, and how it might emerge elsewhere.”

Planetesimals are the main building blocks of rocky planets, such as Earth. These small bodies are formed through a process called accretion, where particles around a young star start to stick together, and form progressively larger bodies.

But not all planetesimals are made equal. The earliest planetesimals that formed in the Solar System were exposed to high levels of radioactivity, which caused them to melt and lose their volatiles. But some planetesimals formed after these sources of radioactivity were mostly extinct, which helped them survive the melting process and preserved more of their volatiles.

In a study published in the journal Science Advances, Martins and her colleagues looked at the different forms of zinc that arrived on Earth from these planetesimals. The researchers measured the zinc from a large sample of meteorites originating from different planetesimals and used this data to model how Earth got its zinc, by tracing the entire period of the Earth’s accretion, which took tens of millions of years.

Their results show that while these ‘melted’ planetesimals contributed about 70% of Earth’s overall mass, they only provided around 10% of its zinc.

According to the model, the rest of Earth’s zinc came from materials that didn’t melt and lose their volatile elements. Their findings suggest that unmelted, or ‘primitive’ materials were an essential source of volatiles for Earth.

“We know that the distance between a planet and its star is a determining a factor in establishing the necessary conditions for that planet to sustain liquid water on its surface,” said Martins, the study’s lead author. “But our results show that there’s no guarantee that planets incorporate the right materials to have enough water and other volatiles in the first place — regardless of their physical state.”

The ability to trace elements through millions or even billions of years of evolution could be a vital tool in the search for life elsewhere, such as on Mars, or on planets outside our Solar System.

“Similar conditions and processes are also likely in other young planetary systems,” said Martins. “The roles these different materials play in supplying volatiles is something we should keep in mind when looking for habitable planets elsewhere.”

The research was supported in part by Imperial College London, the European Research Council, and UK Research and Innovation (UKRI).