The lab of chemical and biomolecular engineer Xue Sherry Gao discovered a way to further tap the therapeutic potential of proteolysis targeting chimeras (PROTACs), small molecules that are used as effective tools for treating cancer, immune disorders, viral infections and neurodegenerative diseases.

Gao and collaborators reengineered the PROTAC molecular infrastructure and showed it can be used to achieve chemically induced dimerization (CID), a mechanism by which two proteins bind together only in the presence of a specific third molecule known as an inducer. The research is described in a study published in the Journal of the American Chemical Society.

“The novelty of this is the extent of control that combining these two mechanisms gives us over inducing gene activation at desired locations in the body and for desired durations,” Gao said.

“Small molecules can act as a switch to turn gene expression on and off,” she said. “Temporal control is a result of the fact that small molecules are metabolized by living organisms. What this means is that you can schedule for a certain gene to be expressed for a certain amount of time.

“In terms of spatial control, we can deliver the system only to the organ or site of the body where it is needed,” Gao continued. “You don’t need to have the medication go through your whole body and generate unnecessary and harmful toxicity.”

The CID mechanism is a key part of many biological processes, and over the past two decades scientists have devised a host of ways to engineer it to serve medical, research and even manufacturing needs. The development highlights the growing impact of synthetic biology, which takes an engineering approach to biological systems, repurposing their mechanisms to harness new resources.

Sirolimus, formerly known as rapamycin. is an example of a molecule that can act as an inducer and form CID systems with multiple cell pathways in the body. Discovered in 1972 in soil bacteria on Easter Island, the compound has been used as an antitumor and immunosuppressant drug. More recently, it was touted as a potential anti-aging drug after researchers discovered it could interfere with a cellular pathway that activates lysosomes, organelles responsible for cleaning up damaged cells.

“CID systems are attractive tools because they enable precise control over molecular interactions, which in turn can activate or inhibit biological outcomes, such as, for example insulin production in a diabetic patient or tumor growth in a cancer patient,” Gao said.

“Right now there are only a limited number of functional and efficient CID systems,” she added. “I wanted to address this unmet need. I saw PROTACs, which are already being used with good results as therapies, as an opportunity to expand the CID toolbox.”

PROTACs work by targeting specific proteins, such as those found in a tumor, causing them to disintegrate. One side of the molecule binds to a targeted harmful protein, another side flags down a specific enzyme that initiates protein degradation and a third element connects the two sides together.

“You can think of this mechanism as similar to a smart missile that relies on a sensor to track its target,” Gao said. “The vocabulary is suggestive in this sense, too, since the protein you want to destroy is called a ‘target protein,’ and the part of the PROTAC system that binds to the target protein is called a ‘warhead.’ We are hijacking this system to control gene expression instead.”

The advantage of PROTACs over other drugs is that they can be effective in small doses and do not lead to the development of drug resistance. There are over 1,600 PROTAC small molecules approved for cancer therapy, acting on more than 100 human protein targets.

“PROTACs are very efficient and act with great specificity against oncogenic proteins, which are proteins encoded by certain activated or dysregulated genes that have a potential to cause cancer,” Gao said. “We wanted to harness that efficiency and precision and put it to work in a new way. We redesigned PROTAC from a protein-degradation system to a gene-activation system.

“Ultimately, I hope this will prove useful in the context of treating real diseases,” she continued. “The ability to regulate when and where genes are activated in the body could help solve a wide range of medical problems. My main goal with this project is to have a small molecule-controlled gene expression system, including the CRISPR genome editors.”

Gao is Rice’s T.N. Law Assistant Professor of Chemical and Biomolecular Engineering and an assistant professor of bioengineering and chemistry. The study was developed in collaboration with the Zheng Sun lab at Baylor College of Medicine.

The National Science Foundation (2143626), the Robert A. Welch Foundation (C-1952), the National Institutes of Health (HL157714, HL153320, DK111436, AG069966, ES027544), the John S. Dunn Foundation, the Clifford Elder White Graham Endowed Research Fund, the Cardiovascular Research Institute at Baylor College of Medicine, the Dan L. Duncan Comprehensive Cancer Center (P30CA125123), the Specialized Programs of Research Excellence (P50CA126752), the Gulf Coast Center for Precision Environmental Health (P30ES030285) and the Texas Medical Center Digestive Diseases Center (P30DK056338) supported the research.

Today’s biggest quantum computers still only have a few hundred “qubits,” the quantum equivalents of digital bits.

Now, researchers at MIT have proposed a new approach to making qubits and controlling them to read and write data. The method, which is theoretical at this stage, is based on measuring and controlling the spins of atomic nuclei, using beams of light from two lasers of slightly different colors. The findings are described in a paper published in the journal Physical Review X, written by MIT doctoral student Haowei Xu, professors Ju Li and Paola Cappellaro, and four others.

Nuclear spins have long been recognized as potential building blocks for quantum-based information processing and communications systems, and so have photons, the elementary particles that are discreet packets, or “quanta,” of electromagnetic radiation. But coaxing these two quantum objects to work together was difficult because atomic nuclei and photons barely interact, and their natural frequencies differ by six to nine orders of magnitude.

In the new process developed by the MIT team, the difference in the frequency of an incoming laser beam matches the transition frequencies of the nuclear spin, nudging the nuclear spin to flip a certain way.

“We have found a novel, powerful way to interface nuclear spins with optical photons from lasers,” says Cappellaro, a professor of nuclear science and engineering. “This novel coupling mechanism enables their control and measurement, which now makes using nuclear spins as qubits a much more promising endeavor.”

The process is completely tunable, the researchers say. For example, one of the lasers could be tuned to match the frequencies of existing telecom systems, thus turning the nuclear spins into quantum repeaters to enable long-distance- quantum communication.

Previous attempts to use light to affect nuclear spins were indirect, coupling instead to electron spins surrounding that nucleus, which in turn would affect the nucleus though magnetic interactions. But this requires the existence of nearby unpaired electron spins and leads to additional noise on the nuclear spins. For the new approach, the researchers took advantage of the fact that many nuclei have an electric quadrupole, which leads to an electric nuclear quadrupolar interaction with the environment. This interaction can be affected by light in order to change the state of the nucleus itself.

“Nuclear spin is usually pretty weakly interacting,” says Li. “But by using the fact that some nuclei have an electric quadrupole, we can induce this second-order, nonlinear optical effect that directly couples to the nuclear spin, without any intermediate electron spins. This allows us to directly manipulate the nuclear spin.”

Among other things, this can allow the precise identification and even mapping of isotopes of materials, while Raman spectroscopy, a well-established method based on analogous physics, can identify the chemistry and structure of the material, but not isotopes. This capability could have many applications, the researchers say.

As for quantum memory, typical devices presently being used or considered for quantum computing have coherence times — meaning the amount of time that stored information can be reliably kept intact — that tend to be measured in tiny fractions of a second. But with the nuclear spin system, the quantum coherence times are measured in hours.

Since optical photons are used for long-distance communications through fiber-optic networks, the ability to directly couple these photons to quantum memory or sensing devices could provide significant benefits in new communications systems, the team says. In addition, the effect could be used to provide an efficient way of translating one set of wavelengths to another. “We are thinking of using nuclear spins for the transduction of microwave photons and optical photons,” Xu says, adding that this can provide greater fidelity for such translation than other methods.

So far, the work is theoretical, so the next step is to implement the concept in actual laboratory devices, probably first of all in a spectroscopic system. “This may be a good candidate for the proof-of-principle experiment,” Xu says. After that, they will tackle quantum devices such as memory or transduction effects, he says.

The team also included Changhao Li, Guoqing Wang, Hua Wang, Hao Tang, and Ariel Barr, all at MIT.

At the Aspen Center for Physics in Colorado, Vayrynen discussed this issue with a colleague from the Weizmann Institute of Science in Israel, Dr. Yuval Oreg, who helped circumvent the obstacle. The team used this new understanding of their calculations to propose a quantum device that could be tested experimentally to succinctly realize emergent particles such as the Fibonacci anyon. They have published their findings, “Multichannel topological Kondo effect,” in Physical Review Letters on February 10, 2023.

Condensed matter theory is a field of physics that studies, for example, the properties of electronic quantum systems, with applications to technologies such as superconductors, transistors, or quantum computing devices. One of the challenges in this field is understanding the quantum mechanical behavior of many electrons, also known as the “many-body problem.” It is a problem because it can only be theoretically modeled in very limited cases. However, even in those limited cases, rich emergent phenomena such as collective excitations or fractionally charged emergent “quasi”-particles are known to emerge. These phenomena are a result of the complex interactions between electrons and can lead to the development of new materials and technologies.

“In our paper, we propose a quantum device that is simple enough to be theoretically modeled and tested experimentally in the future, yet also complex enough to display non-trivial emergent particles,” says Vayrynen. “Our results indicate that the proposed device can realize an emergent particle called a Fibonacci anyon that can be used as a building block of a quantum computer. The device is therefore a promising candidate for the development of quantum computing technology.”

This discovery could be used in future quantum computers in a way that allows one to make them more resistant to decoherence, a.k.a. noise.

According to their publication, the team introduced a physically motivated N-channel generalization of a topological Kondo model. Starting from the simplest case N = 2, they conjecture a stable intermediate coupling fixed point and evaluate the resulting low-temperature impurity entropy. The impurity entropy indicates that an emergent Fibonacci anyon can be realized in the N = 2 model.

According to Li, “a Fibonacci anyon is an emergent particle with the property that as you add more particles to the system, the number of quantum states grows like the Fibonacci sequence, 1, 2, 3, 5, 8, etc. In our system, a small quantum device is connected to conduction electron leads which will overly screen the device and can result in an emergent Fibonacci anyon.”

The team also gives a number of predictions that could be experimentally tested in future quantum devices.

“We evaluate the zero-temperature impurity entropy and conductance to obtain experimentally observable signatures of our results. In the large-N limit we evaluate the full cross over function describing the temperature-dependent conductance,” says Vayrynen.

This research is the first in a series that the Purdue team of Li and Vayrynen will work on. They collaborated with a senior scientist from Max Planck Institute for Solid State Research in Germany, Dr. Elio König, and posted a related work, “Topological Symplectic Kondo Effect,” in a preprint arXiv (2210.16614) on October 20, 2022.

This research was based on work supported by the Quantum Science Center, a U.S. Department of Energy National Quantum Information Science Research Center headquartered at DOE’s Oak Ridge National Laboratory. Dr. Yong Chen, the Karl Lark-Horovitz Professor of Physics and Astronomy and Professor of Electrical and Computer Engineering, is on the QSC’s Governance Advisory Board, and Purdue is one of the center’s core partners.