For decades, researchers have believed that a class of drugs called microtubule poisons treat cancerous tumors by halting mitosis, or the division of cells. Now, a team of UW-Madison scientists has found that in patients, microtubule poisons don’t actually stop cancer cells from dividing. Instead, these drugs alter mitosis — sometimes enough to cause new cancer cells to die and the disease to regress.

Cancers grow and spread because cancerous cells divide and multiply indefinitely, unlike normal cells which are limited in the number of times they can split into new cells. The assumption that microtubule poisons stop cancer cells from dividing is based on lab studies demonstrating just that.

The new study was led by Beth Weaver, a professor in the departments of oncology and cell and regenerative biology, in collaboration with Mark Burkard in the departments of oncology and medicine. Published Oct. 26 in the journal PLOS Biology and supported in part by the National Institutes of Health, the study broadens previous findings the group made about a specific microtubule poison called paclitaxel. Sometimes prescribed under the brand name Taxol, paclitaxel is used to treat common malignancies including those originating in the ovaries and lungs.

“This was sort of mind-blowing,” Weaver says about the previous research. “For decades, we all thought that the way paclitaxel works in patient tumors is by arresting them in mitosis. This is what I was taught as a graduate student. We all ‘knew’ this. In cells in a dish, labs all over the world have shown this. The problem was we were all using it at concentrations higher than those that actually get into the tumor.”

Weaver and her colleagues wanted to know if other microtubule poisons work the same way as paclitaxel — not by stopping mitosis but by messing it up.

The question has significant implications for scientists searching for new cancer treatments. That’s because drug discovery efforts often hinge on identifying, reproducing and improving upon the mechanisms believed to be responsible for a compound’s therapeutic effect.

While microtubule poisons are no panacea, they are effective for many patients, and researchers have long sought to develop other therapies that mimic what they believe the drugs do. These efforts are ongoing even though past attempts to identify new compounds that treat cancer by stopping cell division have reached frustrating dead ends.

“There’s still a lot of the scientific community that’s investigating mitotic arrest as a mechanism to kill tumors,” Weaver says. “We wanted to know — does that matter for patients?”

With Burkard, the team studied tumor samples taken from breast cancer patients who received standard anti-microtubule chemotherapy at the UW Carbone Cancer Center.

They measured how much of the drugs made it into the tumors and studied how the tumor cells responded. They found that while the cells continued to divide after being exposed to the drug, they did so abnormally. This abnormal division can lead to tumor cell death.

Normally, a cell’s chromosomes are duplicated before the two identical sets migrate to opposite ends of the cell mitosis in a process called chromosomal segregation. One set of chromosomes is sorted into each of two new cells.

This migration occurs because the chromosomes are attached to a cellular machine known as the mitotic spindle. Spindles are made from cellular building blocks called microtubules. Normal spindles have two ends, known as spindle poles.

Weaver and her colleagues found that paclitaxel and other microtubule poisons cause abnormalities that lead cells to form three, four or sometimes five poles during mitosis even as they continue to make just one copy of chromosomes. These poles then attract the two complete sets of chromosomes in more than two directions, scrambling the genome.

“So, after mitosis you have daughter cells that are no longer genetically identical and have lost chromosomes,” Weaver says. “We calculated that if a cell loses at least 20% of its DNA content, it is very likely going to die.”

These findings reveal the likely reason why microtubule poisons are effective for many patients. Importantly, they also help explain why attempts to find new chemo drugs based solely on stopping mitosis have been so disappointing, Weaver says.

“We’ve been barking up the wrong tree,” she says. “We need to refocus our efforts on screwing up mitosis — on making chromosomal segregation worse.”

This research was supported in part by the National Institutes of Health (P30 CA014520; R01CA234904; T32 GM008688; T32 CA009135; F31CA254247; T32 GM141013).

Energy-efficient substitute

“Spin waves are waves in a magnetic material that we can use to transmit information,” explains Michael Borst, who led the experiment. “Because spin waves can be a promising building block for an energy-efficient replacement for electronics, scientists have been searching for an efficient way to control and manipulate spin waves for years.”

Theory predicts that metal electrodes give control over spin waves, but physicists have barely seen such effects in experiments until now. “The breakthrough of our research team is that we show that we can indeed control spin waves properly if we use a superconducting electrode,” says Toeno van der Sar, Associate Professor in the Department of Quantum Nanoscience.

Superconducting mirror

It works as follows: a spin wave generates a magnetic field that in turn generates a supercurrent in the superconductor. That supercurrent acts as a mirror for the spin wave: the superconducting electrode reflects the magnetic field back to the spin wave. The superconducting mirror causes spin waves to move up and down more slowly, and that makes the waves easily controllable. Borst: “When spin waves pass under the superconducting electrode, it turns out that their wavelength changes completely! And by varying the temperature of the electrode slightly, we can tune the magnitude of the change very accurately.”

“We started with a thin magnetic layer of yttrium iron garnet (YIG), known as the best magnet on Earth. On top of that we laid a superconducting electrode and another electrode to induce the spin waves. By cooling to -268 degrees, we got the electrode into a superconducting state,” Van der Sar says. “It was amazing to see that the spin waves got slower and slower as it got colder. That gives us a unique handle to manipulate the spin waves; we can deflect them, reflect them, make them resonate and more. But it also gives us tremendous new insights into the properties of superconductors.”

Unique sensor

The researchers imaged the spin waves by measuring their magnetic field with a unique sensor, something that was essential to the experiment. Van der Sar: “We use electrons in diamond as sensors for the magnetic fields of the spin waves. Our lab is pioneering that technique. The cool thing about it is that we can look through the opaque superconductor at the spin waves underneath, just like an MRI scanner can look through the skin into someone’s body.”

New circuits

“Spin wave technology is still in its infancy,” Borst says. “For example, to make energy-efficient computers with this technology, we first have to start building small circuits to perform calculations. Our discovery opens a door: superconducting electrodes allow countless new and energy-efficient spin-wave circuits.”

“We can now design devices based on spin waves and superconductors that produce little heat and sound waves,” Van der Sar adds. “Think of the spintronics version of frequency filters or resonators, components that can be found in electronic circuits of cell phones, for example. Or circuits that can serve as transistors or connectors between qubits in a quantum computer.”

Now scientists have shed some light on why this forecasting challenge has been so difficult to overcome: there’s more than one mechanism that causes rapid intensification. New research by scientists at the U.S. National Science Foundation (NSF) National Center for Atmospheric Research (NCAR) uses the latest computer modeling techniques to identify two entirely different modes of rapid intensification. The findings may lead to better understanding and prediction of these dangerous events.

“Trying to find the holy grail behind rapid intensification is the wrong approach because there isn’t just one holy grail,” said NCAR scientist Falko Judt, lead author of the new study. “There are at least two different modes or flavors of rapid intensification, and each one has a different set of conditions that must be met in order for the storm to strengthen so quickly.”

One of the modes discussed by Judt and his co-authors occurs when a hurricane intensifies symmetrically, fueled by favorable environmental conditions such as warm surface waters and low wind shear. This type of abrupt strengthening is associated with some of the most destructive storms in history, such as Hurricanes Andrew, Katrina, and Maria. Meteorologists were stunned this week when the winds of Hurricane Otis defied predictions and exploded by 110 miles per hour in just 24 hours, plowing into the west coast of Mexico at category 5 strength.

Judt and his co-authors also identified a second mode of rapid intensification that had previously been overlooked because it doesn’t lead to peak winds reaching such destructive levels. In the case of this mode, the strengthening can be linked to major bursts of thunderstorms far from the storm’s center. These bursts trigger a reconfiguration of the cyclone’s circulation, enabling it to intensify rapidly, reaching category 1 or 2 intensity within a matter of hours.

This second mode is more unexpected because it typically occurs in the face of unfavorable conditions, such as countervailing upper-level winds that shear the storm by blowing the top in a different direction than the bottom.

“Those storms are not as memorable and they’re not as significant,” Judt said. “But forecasters need to be aware that even a storm that’s strongly sheared and asymmetric can undergo a mode of rapid intensification.”

The new study appeared in the Monthly Weather Review, a journal of the American Meteorological Society. It was funded by the U.S. Navy Office of Naval Research and by the U.S. National Science Foundation, which is NCAR’s sponsor. It was co-authored by NCAR scientists Rosimar Rios-Berrios and George Bryan.

A serendipitous finding

Rapid intensification occurs when the winds of a tropical cyclone increase by 30 knots (about 35 miles per hour) in a 24-hour period. Judt came across the two modes of rapid intensification when working on an unrelated project.

The discovery emerged after Judt produced a very high-resolution, 40-day computer simulation of the global atmosphere, using the NCAR-based Model for Prediction Across Scales (MPAS). That simulation, run at the NCAR-Wyoming Supercomputing Center, was designed for an international project comparing the output of leading atmospheric models, which have achieved unprecedented detail because of increasingly powerful supercomputers.

Once Judt produced the model, he was curious to examine storms in the simulation that rapidly intensified. By looking at a number of cases across the world’s ocean basins, he noticed that rapid intensification occurred in two distinct ways. This had not previously been apparent in models, partly because previous simulations captured only individual regions instead of allowing scientists to track a spectrum of hurricanes and typhoons across the world’s oceans.

Judt and his co-authors then combed through actual observations of tropical cyclones and found a number of real-world instances of both modes of rapid intensification.

“It was kind of a serendipitous finding,” Judt said. “Just by looking at the storms in the simulation and making plots, I realized that storms that rapidly intensify fall into two different camps. One is the canonical mode in which there’s a tropical storm when you go to bed and when you wake up it’s a category 4. But then there’s another mode that goes from a tropical storm to a category 1 or 2, and it fits the definition of rapid intensification. Since nobody has those storms on their radar, that mode of rapid intensification went undetected until I went through the simulation.”

Meteorologists have long known that favorable environmental conditions, including very warm surface waters and minimal wind shear, can generate rapid intensification and bring a cyclone to category 4 or 5 strength with sustained winds of 130 mph or higher. In their new paper, Judt and his co-authors referred to that mode of rapid intensification as a marathon because the storm keeps intensifying symmetrically at a moderate pace while the primary vortex steadily amplifies.

Judt described Hurricane Otis as a fast marathon because it intensified symmetrically but at an unusually rapid pace, marked by an 80 mph increase in wind speed during a 12-hour period.

The study team labeled the other mode of rapid intensification as a sprint because the intensification is extremely quick but generally doesn’t last as long, with storms peaking at category 1 or 2 strength and sustained winds of 110 mph or less. In such cases, explosive bursts of thunderstorms lead to a rearrangement of the cyclone and the emergence of a new center, enabling the storm to become more powerful — even in the face of adverse environmental conditions.

The paper concludes that the two modes may represent opposite ends of a spectrum, with many cases of rapid intensification falling somewhere in between. For instance, rapid intensification may begin with a chain of discrete events such as a burst of thunderstorms that are characteristic of the sprint mode, but then transition into a more symmetrical mode of intensification that is characteristic of the marathon mode.

A question for future research is why bursts of thunderstorms can cause about 10% of storms in an unconducive environment to rapidly intensify, even though the other 90% do not, Judt said.

“There could be a mechanism we haven’t discovered yet that would enable us to identify the 10 from the 90,” he said. “My working hypothesis is that it’s random, but it’s important for forecasters to be aware that rapid intensification is a typical process even in an unfavorable environment.”

A process developed by Rice University chemical and biomolecular engineer Aditya Mohite and collaborators at Northwestern University, the University of Pennsylvania and the University of Rennes yields 2D perovskite-based semiconductor layers of ideal thickness and purity by controlling the temperature and duration of the crystallization process.

Known as kinetically controlled space confinement, the process could help improve the stability and reduce the cost of halide perovskite-based emerging technologies like optoelectronics and photovoltaics.

“Producing 2D perovskite crystals with layer thicknesses ⎯ or quantum well thickness, also known as ‘n value’⎯ greater than two is a major bottleneck,” said Jin Hou, a Ph.D. student in Rice’s George R. Brown School of Engineering who is a lead author on a study about the process published in Nature Synthesis. “An n value higher than four means materials have a narrower band gap and higher electrical conductivity ⎯ a crucial factor for application in electronic devices.”

As they form into crystals, atoms or molecules arrange themselves into highly organized, regular lattices. Ice, for instance, has 18 possible atomic arrangements, or phases. Like the hydrogen and oxygen atoms in ice, the particles that make up halide perovskites can also form multiple lattice arrangements. Because material properties are phase-dependent, scientists aim to synthesize 2D halide perovskite layers that exhibit only a single phase throughout. The problem, however, is that traditional synthesis methods for higher n value 2D perovskites generate uneven crystal growth, which impacts the material’s performance reliability.

“In traditional methods of 2D perovskite synthesis, you get crystals with mixed phases due to the lack of control over crystallization kinetics, which is basically the dynamic interplay between temperature and time,” Hou said. “We designed a way to slow down the crystallization and tune each kinetics parameter gradually to hit the sweet spot for phase-pure synthesis.”

In addition to designing a synthesis method that can achieve a gradual n value increase in 2D halide perovskites, the researchers also created a map ⎯ or phase diagram ⎯ of the process through characterization, optical spectroscopy and machine learning.

“This work pushes the boundaries of higher quantum well 2D perovskites synthesis, making them a viable and stable option for a variety of applications,” Hou said.

“We have developed a new method to improve the purity of the crystals and resolved a long-standing question in the field on how to approach high n value, phase-pure crystal synthesis,” said Mohite, an associate professor of chemical and biomolecular engineering and materials science and nanoengineering whose lab has pioneered various methods of improving halide perovskite semiconductor quality and performance, from calibrating the initial stage of crystallization to fine-tuning solvent design.

“This research breakthrough is critical for the synthesis of 2D perovskites, which hold the key to achieving commercially relevant stability for solar cells and for many other optoelectronic device applications and fundamental light matter interactions,” Mohite added.

Semiconductors — most notably, silicon — underpin the computers, cellphones, and other electronic devices that power our daily lives, including the device on which you are reading this article. As ubiquitous as semiconductors have become, they come with limitations. The atomic structure of any material vibrates, which creates quantum particles called phonons. Phonons in turn cause the particles — either electrons or electron-hole pairs called excitons — that carry energy and information around electronic devices to scatter in a matter of nanometers and femtoseconds. This means that energy is lost in the form of heat, and that information transfer has a speed limit.

The search is on for better options. Writing in Science, a team of chemists at Columbia University led by Jack Tulyag, a PhD student working with chemistry professor Milan Delor, describes the fastest and most efficient semiconductor yet: a superatomic material called Re₆Se₈Cl₂.

Rather than scattering when they come into contact with phonons, excitons in Re₆Se₈Cl₂ actually bind with phonons to create new quasiparticles called acoustic exciton-polarons. Although polarons are found in many materials, those in Re₆Se₈Cl₂ have a special property: they are capable of ballistic, or scatter-free, flow. This ballistic behavior could mean faster and more efficient devices one day.

In experiments run by the team, acoustic exciton-polarons in Re₆Se₈Cl₂ moved fast — twice as fast as electrons in silicon — and crossed several microns of the sample in less than a nanosecond. Given that polarons can last for about 11 nanoseconds, the team thinks the exciton-polarons could cover more than 25 micrometers at a time. And because these quasiparticles are controlled by light rather than an electrical current and gating, processing speeds in theoretical devices have the potential to reach femtoseconds — six orders of magnitude faster than the nanoseconds achievable in current Gigahertz electronics. All at room temperature.

“In terms of energy transport, Re₆Se₈Cl₂ is the best semiconductor that we know of, at least so far,” Delor said.

A Quantum Version of the Tortoise and the Hare

Re₆Se₈Cl₂ is a superatomic semiconductor created in the lab of collaborator Xavier Roy. Superatoms are clusters of atoms bound together that behave like one big atom, but with different properties than the elements used to build them. Synthesizing superatoms is a specialty of the Roy lab, and they are a main focus of Columbia’s NSF-funded Material Research Science and Engineering Center on Precision Assembled Quantum Materials. Delor is interested in controlling and manipulating the transport of energy through superatoms and other unique materials developed at Columbia. To do this, the team builds super-resolution imaging tools that can capture particles moving at ultrasmall, ultrafast scales.

When Tulyag first brought Re₆Se₈Cl₂ into the lab, it wasn’t to search for a new and improved semiconductor — it was to test the resolution of the lab’s microscopes with a material that, in principle, shouldn’t have conducted much of anything. “It was the opposite of what we expected,” said Delor. “Instead of the slow movement we expected, we saw the fastest thing we’ve ever seen.”

Tulyag and his peers in the Delor group spent the next two years working to pinpoint why Re₆Se₈Cl₂ showed such remarkable behavior, including developing an advanced microscope with extreme spatial and temporal resolution that can directly image polarons as they form and move through the material. Theoretical chemist Petra Shih, a PhD student working in Timothy Berkelbach’s group, also developed a quantum mechanical model that provides an explanation for the observations.

The new quasiparticles are fast, but, counterintuitively, they accomplish that speed by pacing themselves — a bit like the story of the tortoise and the hare, Delor explained. What makes silicon a desirable semiconductor is that electrons can move through it very quickly, but like the proverbial hare, they bounce around too much and don’t actually make it very far, very fast in the end. Excitons in Re₆Se₈Cl₂ are, comparatively, very slow, but it’s precisely because they are so slow that they are able to meet and pair up with equally slow-moving acoustic phonons. The resulting quasiparticles are “heavy” and, like the tortoise, advance slowly but steadily along. Unimpeded by other phonons along the way, acoustic exciton-polarons in Re₆Se₈Cl₂ ultimately move faster than electrons in silicon.

The Semiconductor Search Continues

Like many of the emerging quantum materials being explored at Columbia, Re₆Se₈Cl₂ can be peeled into atom-thin sheets, a feature that means they can potentially be combined with other similar materials in the search for additional unique properties. Re₆Se₈Cl_2, however, is unlikely to ever make its way into a commercial product — the first element in the molecule, Rhenium, is one of the rarest on earth and extremely expensive as a result.

But with the new theory from the Berkelbach group in hand along with the advanced imaging technique that Tulyag and the Delor group developed to directly track the formation and movement of polarons in the first place, the team is ready to see if there are other superatomic contenders capable of beating Re₆Se₈Cl_2′‘s speed record.

“This is the only material that anyone has seen sustained room-temperature ballistic exciton transport in. But we can now start to predict what other materials might be capable of this behavior that we just haven’t considered before,” said Delor. “There is a whole family of superatomic and other 2D semiconductor materials out there with properties favorable for acoustic polaron formation.”