Scientists discover a new way of sharing genetic information in a common ocean microbe

From the tropics to the poles, from the sea surface to hundreds of feet below, the world’s oceans are teeming with one of the tiniest of organisms: a type of bacteria called Prochlorococcus, which despite their minute size are collectively responsible for a sizable portion of the oceans’ oxygen production. But the remarkable ability of these diminutive organisms to diversify and adapt to such profoundly different environments has remained something of a mystery.

Now, new research reveals that these tiny bacteria exchange genetic information with one another, even when widely separated, by a previously undocumented mechanism. This enables them to transmit whole blocks of genes, such as those conferring the ability to metabolize a particular kind of nutrient or to defend themselves from viruses, even in regions where their population in the water is relatively sparse.

The findings describe a new class of genetic agents involved in horizontal gene transfer, in which genetic information is passed directly between organisms — whether of the same or different species — through means other than lineal descent. The researchers have dubbed the agents that carry out this transfer “tycheposons,” which are sequences of DNA that can include several entire genes as well as surrounding sequences, and can spontaneously separate out from the surrounding DNA. Then, they can be transported to other organisms by one or another possible carrier system including tiny bubbles known as vesicles that cells can produce from their own membranes.

The research, which included studying hundreds of Prochlorococcus genomes from different ecosystems around the world, as well as lab-grown samples of different variants, and even evolutionary processes carried out and observed in the lab, is reported today in the journal Cell, in a paper by former MIT postdocs Thomas Hackl and Raphaël Laurenceau, visiting postdoc Markus Ankenbrand, Institute Professor Sallie “Penny” Chisholm, and 16 others at MIT and other institutions.

Chisholm, who played a role in the discovery of these ubiquitous organisms in 1988, says of the new findings, “We’re very excited about it because it’s a new horizontal gene-transfer agent for bacteria, and it explains a lot of the patterns that we see in Prochlorococcus in the wild, the incredible diversity.” Now thought to be the world’s most abundant photosynthetic organism, the tiny variants of what are known as cyanobacteria are also the smallest of all photosynthesizers.

Hackl, who is now at the University of Groningen in the Netherlands, says the work began by studying the 623 reported genome sequences of different species of Prochlorococcus from different regions, trying to figure out how they were able to so readily lose or gain particular functions despite their apparent lack of any of the known systems that promote/boost horizontal gene transfer, such as plasmids or viruses known as prophages.    

What Hackl, Laurenceau, and Ankenbrand investigated were “islands” of genetic material that seemed to be hotspots of variability and often contained genes that were associated with known key survival processes such as the ability to    assimilate essential, and often limiting, nutrients such as iron, or nitrogen, or phosphates. These islands contained genes that varied enormously between different species, but they always occurred in the same parts of the genome and sometimes were nearly identical even in widely different species — a strong indicator of horizontal transfer.

But the genomes showed none of the usual features associated with what are known as mobile genetic elements, so initially this remained a puzzle. It gradually became apparent that this system of gene transfer and diversification was different from any of the several other mechanisms that have been observed in other organisms, including in humans.

Hackl describes what they found as being something like a genetic LEGO set, with chunks of DNA bundled together in ways that could almost instantly confer the ability to adapt to a particular environment. For example, a species limited by the availability of particular nutrients could acquire genes necessary to enhance the uptake of that nutrient.       

The microbes appear to use a variety of mechanisms to transport these tycheposons (a name derived from the name of the Greek goddess Tyche, daughter of Oceanus). One is the use of membrane vesicles, little bubbles pouched off from the surface of a bacterial cell and released with tycheposons inside it. Another is by “hijacking” virus or phage infections and allowing them to carry the tycheposons along with their own infectious particles, called capsids. These are efficient solutions, Hackl says, “because in the open ocean, these cells rarely have cell-to-cell contacts, so it’s difficult for them to exchange genetic information without a vehicle.”

And sure enough, when capsids or vesicles collected from the open ocean were studied, “they’re actually quite enriched” in these genetic elements, Hackl says. The packets of useful genetic coding are “actually swimming around in these extracellular particles and potentially being able to be taken up by other cells.”

Chisholm says that “in the world of genomics, there’s a lot of different types of these elements” — sequences of DNA that are capable of being transferred from one genome to another. However, “this is a new type,” she says. Hackl adds that “it’s a distinct family of mobile genetic elements. It has similarities to others, but no really tight connections to any of them.”

While this study was specific to Prochlorococcus, Hackl says the team believes the phenomenon may be more generalized. They have already found similar genetic elements in other, unrelated marine bacteria, but have not yet analyzed these samples in detail. “Analogous elements have been described in other bacteria, and we now think that they may function similarly,” he says.

“It’s kind of a plug-and-play mechanism, where you can have pieces that you can play around with and make all these different combinations,” he says. “And with the enormous population size of Prochlorococcus, it can play around a lot, and try a lot of different combinations.”

Nathan Ahlgren, an assistant professor of biology at Clark University who was not associated with this research, says “The discovery of tycheposons is important and exciting because it provides a new mechanistic understanding of how Prochlorococcus are able to swap in and out new genes, and thus ecologically important traits. Tycheposons provide a new mechanistic explanation for how it’s done.” He says “they took a creative way to fish out and characterize these new genetic elements ‘hiding’ in the genomes of Prochlorococcus.”

He adds that genomic islands, the portions of the genome where these tycheposons were found, “are found in many bacteria, not just marine bacteria, so future work on tycheposons has wider implications for our understanding of the evolution of bacterial genomes.”

The team included researchers at MIT’s Department of Civil and Environmental Engineering, the University of Wuerzburg in Germany, the University of Hawaii at Manoa, Ohio State University, Oxford Nanopore Technologies in California, Bigelow Laboratory for Ocean Sciences in Maine, and Wellesley College. The work was supported by the Simons Foundation, the Gordon and Betty Moore Foundation, the U.S. Department of Energy, and the U.S. National Science Foundation.

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New quantum computing architecture could be used to connect large-scale devices

Quantum computers hold the promise of performing certain tasks that are intractable even on the world’s most powerful supercomputers. In the future, scientists anticipate using quantum computing to emulate materials systems, simulate quantum chemistry, and optimize hard tasks, with impacts potentially spanning finance to pharmaceuticals.

However, realizing this promise requires resilient and extensible hardware. One challenge in building a large-scale quantum computer is that researchers must find an effective way to interconnect quantum information nodes — smaller-scale processing nodes separated across a computer chip. Because quantum computers are fundamentally different from classical computers, conventional techniques used to communicate electronic information do not directly translate to quantum devices. However, one requirement is certain: Whether via a classical or a quantum interconnect, the carried information must be transmitted and received.    

To this end, MIT researchers have developed a quantum computing architecture that will enable extensible, high-fidelity communication between superconducting quantum processors. In work published today in Nature Physics, MIT researchers demonstrate step one, the deterministic emission of single photons — information carriers — in a user-specified direction. Their method ensures quantum information flows in the correct direction more than 96 percent of the time.

Linking several of these modules enables a larger network of quantum processors that are interconnected with one another, no matter their physical separation on a computer chip.

“Quantum interconnects are a crucial step toward modular implementations of larger-scale machines built from smaller individual components,” says Bharath Kannan PhD ’22, co-lead author of a research paper describing this technique.

“The ability to communicate between smaller subsystems will enable a modular architecture for quantum processors, and this may be a simpler way of scaling to larger system sizes compared to the brute-force approach of using a single large and complicated chip,” Kannan adds.

Kannan wrote the paper with co-lead author Aziza Almanakly, an electrical engineering and computer science graduate student in the Engineering Quantum Systems group of the Research Laboratory of Electronics (RLE) at MIT. The senior author is William D. Oliver, an MIT professor of electrical engineering and computer science and of physics, an MIT Lincoln Laboratory Fellow, director of the Center for Quantum Engineering, and associate director of RLE.

Moving quantum information

In a conventional classical computer, various components perform different functions, such as memory, computation, etc. Electronic information, encoded and stored as bits (which take the value of 1s or 0s), is shuttled between these components using interconnects, which are wires that move electrons around on a computer processor.

But quantum information is more complex. Instead of only holding a value of 0 or 1, quantum information can also be both 0 and 1 simultaneously (a phenomenon known as superposition). Also, quantum information can be carried by particles of light, called photons. These added complexities make quantum information fragile, and it can’t be transported simply using conventional protocols.

A quantum network links processing nodes using photons that travel through special interconnects known as waveguides. A waveguide can either be unidirectional, and move a photon only to the left or to the right, or it can be bidirectional.

Most existing architectures use unidirectional waveguides, which are easier to implement since the direction in which photons travel is easily established. But since each waveguide only moves photons in one direction, more waveguides become necessary as the quantum network expands, which makes this approach difficult to scale. In addition, unidirectional waveguides usually incorporate additional components to enforce the directionality, which introduces communication errors.

“We can get rid of these lossy components if we have a waveguide that can support propagation in both the left and right directions, and a means to choose the direction at will. This ‘directional transmission’ is what we demonstrated, and it is the first step toward bidirectional communication with much higher fidelities,” says Kannan.

Using their architecture, multiple processing modules can be strung along one waveguide. A remarkable feature the architecture design is that the same module can be used as both a transmitter and a receiver, he says. And photons can be sent and captured by any two modules along a common waveguide.

“We have just one physical connection that can have any number of modules along the way. This is what makes it scalable. Having demonstrated directional photon emission from one module, we are now working on capturing that photon downstream at a second module,” Almanakly adds.

Leveraging quantum properties

To accomplish this, the researchers built a module comprising four qubits.

Qubits are the building blocks of quantum computers, and are used to store and process quantum information. But qubits can also be used as photon emitters. Adding energy to a qubit causes the qubit to become excited, and then when it de-excites, the qubit will emit the energy in the form of a photon.

However, simply connecting one qubit to a waveguide does not ensure directionality. A single qubit emits a photon, but whether it travels to the left or to the right is completely random. To circumvent this problem, the researchers utilize two qubits and a property known as quantum interference to ensure the emitted photon travels in the correct direction.

The technique involves preparing the two qubits in an entangled state of single excitation called a Bell state. This quantum-mechanical state comprises two aspects: the left qubit being excited and the right qubit being excited. Both aspects exist simultaneously, but which qubit is excited at a given time is unknown.

When the qubits are in this entangled Bell state, the photon is effectively emitted to the waveguide at the two qubit locations simultaneously, and these two “emission paths” interfere with each other. Depending on the relative phase within the Bell state, the resulting photon emission must travel to the left or to the right. By preparing the Bell state with the correct phase, the researchers choose the direction in which the photon travels through the waveguide.

They can use this same technique, but in reverse, to receive the photon at another module.

“The photon has a certain frequency, a certain energy, and you can prepare a module to receive it by tuning it to the same frequency. If they are not at the same frequency, then the photon will just pass by. It’s analogous to tuning a radio to a particular station. If we choose the right radio frequency, we’ll pick up the music transmitted at that frequency,” Almanakly says.

The researchers found that their technique achieved more than 96 percent fidelity — this means that if they intended to emit a photon to the right, 96 percent of the time it went to the right.

Now that they have used this technique to effectively emit photons in a specific direction, the researchers want to connect multiple modules and use the process to emit and absorb photons. This would be a major step toward the development of a modular architecture that combines many smaller-scale processors into one larger-scale, and more powerful, quantum processor.

“The work demonstrates an on-demand quantum emitter, in which the interference of the emitted photon from an entangled state defines the direction, beautifully manifesting the power of waveguide quantum electrodynamics,” says Yasunobu Nakamura, director of the RIKEN Center for Quantum Computing, who was not involved with this research. “It can be used as a fully programmable quantum node that can emit/absorb/pass/store quantum information on a quantum network and as an interface for a bus connecting multiple quantum computer chips.”

The research is funded, in part, by the AWS Center for Quantum Computing, the U.S. Army Research Office, the U.S. Department of Energy Office of Science National Quantum Information Science Research Centers, the Co-design Center for Quantum Advantage, and the U.S. Department of Defense.

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Ian Hutchinson: A lifetime probing plasma, on Earth and in space

Ordinary folks gazing at the night sky can readily spot Earth’s close neighbors and the light of distant stars. But when Ian Hutchinson scans the cosmos, he takes in a great deal more. There is, for instance, the constant rush of plasma — highly charged ionized gases — from the sun. As this plasma flows by solid bodies such as the moon, it interacts with them electromagnetically, sometimes generating a phenomenon called an electron hole — a perturbation in the gaseous solar tide that forms a solitary, long-lived wave. Hutchinson, a professor in the MIT Department of Nuclear Science and Engineering (NSE), knows they exist because he found a way to measure them.

“When I look up at the moon with my sweetheart, my wife of 48 years, I imagine that streaming from its dark side are electron holes that my students and I predicted, and that we then discovered,” he says. “It’s quite sentimental to me.”

Hutchinson’s studies of these wave phenomena, summed up in a paper, “Electron holes in phase space: What they are and why they matter,” recently earned the 2022 Ronald C. Davidson Award for Plasma Physics presented by the American Physical Society’s Division of Plasma Physics.

Measuring perturbations in plasma

Hutchinson’s exploration of electron holes was sparked by his work over many decades in fusion energy, another branch of plasma physics. He has made many contributions to the design, operation, and experimental investigation of tokamaks — a toroidal magnetic confinement device — intended to replicate and harness the fiery thermonuclear reactions in the plasma of stars for carbon-free energy on Earth. Hutchinson took a particular interest in how to measure the plasma, notably the flow at the edges of tokamaks.

Heat generated from fusion reactions may escape magnetic confinement and build up along these edges, leading to potential temperature spikes that impact the performance of the confinement device. Hutchinson discovered how to interpret signals from small probes to measure and track plasma velocity at the tokamak’s edge.

“My theoretical work also showed that these probes quite likely induce electron holes,” he says. But proving this contention required experiments at resolutions in time and space beyond what tokamaks allow. That’s when Hutchinson had an important insight.

“I realized that the phenomena we were trying to investigate can actually be measured with exquisite accuracy by satellites that travel through plasma surrounding Earth and other solid bodies,” he says. Although plasmas in space are at a much larger scale than the plasmas generated in the laboratory, measurements of these gases by a satellite is analogous “to a situation where we fly a tiny micron-sized spacecraft through the wakes of probes at the edge of tokamaks,” says Hutchinson.

Using satellite data provided by NASA, Hutchinson set about analyzing solar plasma as it whips by the moon. “We predicted instabilities and the generation of electron holes,” he recounts. “Our theory passed with flying colors: We saw lots of holes in the wake of the moon, and few elsewhere.”

Developing tokamaks

Hutchinson grew up in the English midlands and attended Cambridge University, where he became “intrigued by plasma physics in a course taught by an entertaining and effective teacher,” he says.

Hutchinson headed for doctoral studies at Australian National University on fellowship. The experience afforded him his first opportunity for research on plasma confinement. “There I was at the ends of the Earth, and I was one of very few scientists worldwide with a tokamak almost to myself,” he says. “It was a device that had risen to the top of everyone’s agenda in fusion research as something we really needed to understand.”

His dissertation, which examined instabilities in plasma, and his hands-on experience with the device, brought him to the attention of Ronald Parker SM ’63, PhD ’67, now emeritus professor of nuclear science and engineering and electrical engineering and computer science, who was building MIT’s Alcator tokamak program.

In 1976, Hutchinson joined this group, spending three years as a research scientist. After an interval in Britain, he returned to MIT with a faculty position in NSE, and soon, a leadership role in developing the next phase of the Institute’s fusion experiment, the Alcator-C Mod tokamak.

“This was a major development of the high-magnetic field approach to fusion,” says Hutchinson. Powerful magnets are essential for containing the superhot plasma; the MIT group developed an experiment with a magnetic field more than 150,000 times the strength of the Earth’s magnetic field. “We were in the business of determining whether tokamaks had sufficiently good confinement to function as fusion reactors,” he says.

Hutchinson oversaw the nearly six-year construction of the device, which was funded by the U.S. Department of Energy. He then led its operation starting in 1993, creating a national facility for experiments that drew scientists and students from around the world. At the time, it was the largest research group on campus at MIT.

In their studies, scientists employed novel heating and sustainment techniques using radio waves and microwaves. They also discovered new methods for performing diagnostics inside the tokamak. “Alcator C-Mod demonstrated excellent confinement in a more compact and cost-effective device,” says Hutchinson. “It was unique in the world.”

Hutchinson is proud of Alcator C-Mod’s technological achievements, including its record for highest plasma pressure for a magnetic confinement device. But this large-scale project holds even greater significance for him. “Alcator C-Mod helped beat a new path in fusion research, and has become the basis for the SPARC tokamak now under construction,” he says.

SPARC is a compact, high-magnetic field fusion energy device under development through a collaboration between MIT’s Plasma Science and Fusion Center and startup Commonwealth Fusions Systems. Its goal is to demonstrate net energy gain from fusion, prove the viability of fusion as a source of carbon-free energy, and tip the scales in the race against climate change. A number of SPARC’s leaders are students Hutchinson taught. “This is a source of considerable satisfaction,” he says. “Some of their down-to-Earth realism comes from me, and perhaps some of their aspirations have been molded by their work with me.” 

A new phase

After leading Alcator C-Mod for 15 years and generating hundreds of journal articles, Hutchinson served as NSE's department head from 2003 to 2009. He wrote the standard textbook on measuring plasmas, and has more recently written “A Student’s Guide to Numerical Methods” (2015), which evolved from a course he taught to introduce graduate students to computational problem-solving in physics and engineering.

After this, his 40th year on the MIT faculty, Hutchinson will be stepping back from teaching. “It’s important for new generations of students to be taught by people at the pinnacle of their mental and intellectual capacity, and when you reach my age, you’re aware of the fact that you’re slowing down,” he says.

Hutchinson’s at no loss for ways to spend his time. As a devout Christian, he speaks and writes about the relationship between religion and science, trying to help skeptics on both sides find common ground. He sings in two choral groups, and is very busy grandparenting four grandsons. For a complete change of pace, Hutchinson goes fly fishing.

But he still has plans to explore new frontiers in plasma physics. “I’m gratified to say I still do important research,” he says. “I’ve solved most of the problems in electron holes, and now I need to say something about ion holes!”

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Strengthening electron-triggered light emission

The way electrons interact with photons of light is a key part of many modern technologies, from lasers to solar panels to LEDs. But the interaction is inherently a weak one because of a major mismatch in scale: A wavelength of visible light is about 1,000 times larger than an electron, so the way the two things affect each other is limited by that disparity.

Now, researchers at MIT and elsewhere have come up with an innovative way to make much stronger interactions between photons and electrons possible, in the process producing a hundredfold increase in the emission of light from a phenomenon called Smith-Purcell radiation. The finding has potential implications for both commercial applications and fundamental scientific research, although it will require more years of research to make it practical.

The findings are reported today in the journal Nature, in a paper by MIT postdocs Yi Yang (now an assistant professor at the University of Hong Kong) and Charles Roques-Carmes, MIT professors Marin Soljačić and John Joannopoulos, and five others at MIT, Harvard University, and Technion-Israel Institute of Technology.

In a combination of computer simulations and laboratory experiments, the team found that using a beam of electrons in combination with a specially designed photonic crystal — a slab of silicon on an insulator, etched with an array of nanometer-scale holes — they could theoretically predict stronger emission by many orders of magnitude than would ordinarily be possible in conventional Smith-Purcell radiation. They also experimentally recorded a one hundredfold increase in radiation in their proof-of-concept measurements.

Unlike other approaches to producing sources of light or other electromagnetic radiation, the free-electron-based method is fully tunable — it can produce emissions of any desired wavelength, simply by adjusting the size of the photonic structure and the speed of the electrons. This may make it especially valuable for making sources of emission at wavelengths that are difficult to produce efficiently, including terahertz waves, ultraviolet light, and X-rays.

The team has so far demonstrated the hundredfold enhancement in emission using a repurposed electron microscope to function as an electron beam source. But they say that the basic principle involved could potentially enable far greater enhancements using devices specifically adapted for this function.

The approach is based on a concept called flatbands, which have been widely explored in recent years for condensed matter physics and photonics but have never been applied to affecting the basic interaction of photons and free electrons. The underlying principle involves the transfer of momentum from the electron to a group of photons, or vice versa. Whereas conventional light-electron interactions rely on producing light at a single angle, the photonic crystal is tuned in such a way that it enables the production of a whole range of angles.

The same process could also be used in the opposite direction, using resonant light waves to propel electrons, increasing their velocity in a way that could potentially be harnessed to build miniaturized particle accelerators on a chip. These might ultimately be able to perform some functions that currently require giant underground tunnels, such as the 30-kilometer-wide Large Hadron Collider in Switzerland.

“If you could actually build electron accelerators on a chip,” Soljačić says, “you could make much more compact accelerators for some of the applications of interest, which would still produce very energetic electrons. That obviously would be huge. For many applications, you wouldn’t have to build these huge facilities.”

The new system could also potentially provide a highly controllable X-ray beam for radiotherapy purposes, Roques-Carmes says.

And the system could be used to generate multiple entangled photons, a quantum effect that could be useful in the creation of quantum-based computational and communications systems, the researchers say. “You can use electrons to couple many photons together, which is a considerably hard problem if using a purely optical approach,” says Yang. “That is one of the most exciting future directions of our work.”

Much work remains to translate these new findings into practical devices, Soljačić cautions. It may take some years to develop the necessary interfaces between the optical and electronic components and how to connect them on a single chip, and to develop the necessary on-chip electron source producing a continuous wavefront, among other challenges.

“The reason this is exciting,” Roques-Carmes adds, “is because this is quite a different type of source.” While most technologies for generating light are restricted to very specific ranges of color or wavelength, and “it’s usually difficult to move that emission frequency. Here it’s completely tunable. Simply by changing the velocity of the electrons, you can change the emission frequency. ... That excites us about the potential of these sources. Because they’re different, they offer new types of opportunities.”

But, Soljačić concludes, “in order for them to become truly competitive with other types of sources, I think it will require some more years of research. I would say that with some serious effort, in two to five years they might start competing in at least some areas of radiation.”

The research team also included Steven Kooi at MIT’s Institute for Soldier Nanotechnologies, Haoning Tang and Eric Mazur at Harvard University, Justin Beroz at MIT, and Ido Kaminer at Technion-Israel Institute of Technology. The work was supported by the U.S. Army Research Office through the Institute for Soldier Nanotechnologies, the U.S. Air Force Office of Scientific Research, and the U.S. Office of Naval Research.

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Uncovering how cells control their protein output

A typical bacterial genome contains more than 4,000 genes, which encode all of the proteins that the cells need to survive. How do cells know just how much of each protein they need for their everyday functions?

Gene-Wei Li, an MIT associate professor of biology, is trying to answer that question. A physicist by training, he uses genome-wide measurements and biophysical modeling to quantify cells’ protein production and discover how cells achieve such precise control of those quantities.

Using those techniques, Li has found that cells appear to strictly control the ratios of proteins that they produce, and that these ratios are consistent across cell types and across species.

“Coming from a physics background, it’s surprising to me that these cells have evolved to be really precise in making the right amount of their proteins,” Li says. “That observation was enabled by the fact that we are able to design measurements with a precision that matches what is actually happening in biology.”

From physics to biology

Li’s parents — his father, a marine biologist who teaches at a university in Taiwan, and his mother, a plant biologist who now runs a science camp for high school students — passed their affinity for science on to Li, who was born in San Diego while his parents were graduate students there.

The family returned to Taiwan when Li was 2 years old, and Li soon became interested in math and physics. In Taiwan, students choose their college major while still in high school, so he decided to study physics at National Tsinghua University.

While in college, Li was drawn to optical physics and spectroscopy. He went to Harvard University for graduate school, where after his first year, he started working in a lab that works on single-molecule imaging of biological systems.

“I realized there are a lot of really exciting fields at the boundary between disciplines. It’s something that we didn’t have in Taiwan, where the departments are very strict that physics is physics, and biology is biology,” Li says. “Biology is a lot messier than physics, and I had some hesitancy, but I was happy to see that biology does have rules that you can observe.”

For his PhD research, Li used single-molecule imaging to study proteins called transcription factors — specifically, how quickly they can bind to DNA and initiate the copying of DNA into RNA. Though he had never taken a class in biology, he began to learn more about it and decided to do a postdoc at the University of California at San Francisco, where he worked in the lab of Jonathan Weissman, a professor of cellular and molecular pharmacology.

Weissman, who is now a professor of biology at MIT, also trained as a physicist before turning to biology. In Weissman’s lab, Li developed techniques for studying gene expression in bacterial cells, using high-throughput DNA sequencing. In 2015, Li joined the faculty at MIT, where his lab began to work on tools that could be used to measure gene expression in cells.

When genes are expressed in cells, the DNA is first copied into RNA, which carries the genetic instructions to ribosomes, where proteins are assembled. Li’s lab has developed ways to measure protein synthesis rates in cells, along with the amount of RNA that is transcribed from different genes. Together, these tools can yield precise measurements of how much a particular gene is expressed in a given cell.

“We had the qualitative tools before, but now we can really have quantitative information and learn how much protein is made and how important those protein levels are to the cell,” Li says.

Precise control

Using these tools, Li and his students have discovered that different species of bacteria can have different strategies for making proteins. In E. coli, transcription of DNA and translation of RNA into proteins had long been known to be a coupled process, meaning that after RNA is produced, ribosomes immediately translate it into protein.

Many researchers assumed that this would be true for all bacteria, but in a 2020 study, Li found that Bacillus subtilis and hundreds of other bacterial species use a different strategy.

“A lot of other species have what we call runaway transcription, where the transcription happens really fast and the proteins don’t get made at the same time. And because of this uncoupling, these species have very different mechanisms of regulating their gene expression,” Li says.

Li’s lab has also found that across species, cells make the same proportions of certain proteins that work together. Many cellular processes, such as breaking down sugar and storing its energy as ATP, are coordinated by enzymes that perform a series of reactions in a specified sequence.

“Evolution, it turns out, gives us the same proportion of those enzymes, whether in E. coli or other bacteria or in eukaryotic cells,” Li says. “There are apparently rules and principles for designing these pathways that we didn't know of before.”

Mutations that cause too much or too little of a protein to be produced can cause a variety of human diseases. Li now plans to investigate how the genome encodes the rules governing the correct quantities of each protein, by measuring how changes to genetic and regulatory sequences affect gene expression at each step of the process — from initiation of transcription to protein assembly.

“The next level that we’re trying to focus on is: How is that information stored in the genome?” he says. “You can easily read off protein sequences from a genome, but it’s still impossible to tell how much protein is going to be made. That’s the next chapter.”

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Strengthening America’s manufacturing base

U.S. Under Secretary of Defense for Research and Engineering Heidi Shyu serves as the Department of Defense’s chief technology officer. In a recent talk at MIT, she spoke about the DoD’s initiatives to build a stronger U.S. manufacturing base and to tackle the country’s “toughest challenges.”

President Biden nominated Shyu as under secretary in April 2021, and three months later she stepped into the role. She is responsible for supporting research, development, and prototyping across the DoD. 

In her talk, which was part of the Manufacturing@MIT Distinguished Speaker Series, she touched on many areas, including funding startups “so good ideas don’t languish,” training a manufacturing workforce, strengthening U.S. supply chains, preparing for climate change, preventing intellectual property theft, supporting “leap-ahead” technologies, and rebuilding America’s semiconductor industry.

She described the recently announced DoD Office of Strategic Capital (OSC), which will provide capital to help innovative companies go from promising prototypes to scaled production, and will team with DoD agencies and the private sector. Through this approach, she said OSC will seek to prevent promising prototypes from ending up in a “Valley of Death” that lies between innovation and bringing new products to market. She explained that the DoD wants to do more to help young companies jump-start their operations. “The government needs to embrace strategic public investment as a key tool to achieving our full economic potential,” she said.

The under secretary is also leading a call for proposals for nine microelectronics regional hubs across the United States as part of $2 billion in CHIPS Act funding that the DoD will distribute. She described the value of connecting regional startups, larger companies, and universities to spur innovation: “We will be standing up multiple regional hubs that can leverage innovative research from universities to help develop the next generation of chips.”

Smaller businesses and startups, Shyu said, often do not know how to navigate the DoD. “I’m sure many of you will develop novel ideas in your research here and decide to spin off a technology into a startup company,” she said. “So how you do you connect to the DoD? That’s a daunting task!” She said she is determined to help fix this, by relaunching the site cto.innovation.mil, so companies and researchers find the right contacts in the DoD. 

Shyu said another priority was strengthening the U.S. workforce. For instance, this year her office funded 482 Smart Scholars, and plans to increase that number. Smart Scholars receive free university tuition. When they graduate, they then commit to working for the DoD for the number of years the DoD covered their tuition. 

MIT has led a number of workforce programs with the DoD’s Manufacturing Technology Office, including standing up the manufacturing careers platform buildyourfuture.us. MIT is also closely tied to the nine DoD manufacturing innovation institutes that Shyu’s office oversees.

After the talk, Shyu visited labs across campus. MIT Lincoln Laboratory’s Eric Evans and Bob Shin joined Under Secretary Shyu to hear from Lisa Kelley, Joel Grimm, and Scott VanBroeken about student projects at MIT Beaver Works and about Beaver Works’ summer institute for high school students. Professor Vladimir Bulovic guided her through MIT.nano and described MIT’s fabrication and characterization capabilities. She also visited Professor Zack Cordero’s lab in the Department of Aeronautics and Astronautics, Professor Klav Jensen’s in the Department of Chemical Engineering, and Professor Chris Voigt’s lab in the Department of Biological Engineering — all of whom presented a wide range of research programs that the DoD has supported.

The Manufacturing@MIT working group hosted Shyu’s visit as part of its new Distinguished Speaker Series. The series launched in Fall 2022, and its first speaker was Pennsylvania Governor Tom Wolf.

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Self-assembling proteins can store cellular “memories”

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.

This technique could help shed light on the steps that underlie processes such as memory formation, response to drug treatment, and gene expression.

“There are a lot of changes that happen at organ or body scale, over hours to weeks, which cannot be tracked over time,” says Edward Boyden, the Y. Eva Tan Professor in Neurotechnology, a professor of biological engineering and brain and cognitive sciences at MIT, a Howard Hughes Medical Institute investigator, and a member of MIT’s McGovern Institute for Brain Research and Koch Institute for Integrative Cancer Research.

If the technique could be extended to work over longer time periods, it could also be used to study processes such as aging and disease progression, the researchers say.

Boyden is the senior author of the study, which appears today in Nature Biotechnology. Changyang Linghu, a former J. Douglas Tan Postdoctoral Fellow at the McGovern Institute, who is now an assistant professor at the University of Michigan, is the lead author of the paper.

Cellular history

Biological systems such as organs contain many different kinds of cells, all of which have distinctive functions. One way to study these functions is to image proteins, RNA, or other molecules inside the cells, which provide hints to what the cells are doing. However, most methods for doing this offer only a glimpse of a single moment in time, or don’t work well with very large populations of cells.

“Biological systems are often composed of a large number of different types of cells. For example, the human brain has 86 billion cells,” Linghu says. “To understand those kinds of biological systems, we need to observe physiological events over time in these large cell populations.”

To achieve that, the research team came up with the idea of recording cellular events as a series of protein subunits that are continuously added to a chain. To create their chains, the researchers used engineered protein subunits, not normally found in living cells, that can self-assemble into long filaments.

The researchers designed a genetically encoded system in which one of these subunits is continuously produced inside cells, while the other is generated only when a specific event occurs. Each subunit also contains a very short peptide called an epitope tag — in this case, the researchers chose tags called HA and V5. Each of these tags can bind to a different fluorescent antibody, making it easy to visualize the tags later on and determine the sequence of the protein subunits.

For this study, the researchers made production of the V5-containing subunit contingent on the activation of a gene called c-fos, which is involved in encoding new memories. HA-tagged subunits make up most of the chain, but whenever the V5 tag shows up in the chain, that means that c-fos was activated during that time.

“We’re hoping to use this kind of protein self-assembly to record activity in every single cell,” Linghu says. “It’s not only a snapshot in time, but also records past history, just like how tree rings can permanently store information over time as the wood grows.”

Recording events

In this study, the researchers first used their system to record activation of c-fos in neurons growing in a lab dish. The c-fos gene was activated by chemically induced activation of the neurons, which caused the V5 subunit to be added to the protein chain.

To explore whether this approach could work in the brains of animals, the researchers programmed brain cells of mice to generate protein chains that would reveal when the animals were exposed to a particular drug. Later, the researchers were able to detect that exposure by preserving the tissue and analyzing it with a light microscope.

The researchers designed their system to be modular, so that different epitope tags can be swapped in, or different types of cellular events can be detected, including, in principle, cell division or activation of enzymes called protein kinases, which help control many cellular pathways.

The researchers also hope to extend the recording period that they can achieve. In this study, they recorded events for several days before imaging the tissue. There is a tradeoff between the amount of time that can be recorded and the time resolution, or frequency of event recording, because the length of the protein chain is limited by the size of the cell.

“The total amount of information it could store is fixed, but we could in principle slow down or increase the speed of the growth of the chain,” Linghu says. “If we want to record for a longer time, we could slow down the synthesis so that it will reach the size of the cell within, let’s say two weeks. In that way we could record longer, but with less time resolution.”

The researchers are also working on engineering the system so that it can record multiple types of events in the same chain, by increasing the number of different subunits that can be incorporated.

The research was funded by the Hock E. Tan and K. Lisa Yang Center for Autism Research, John Doerr, the National Institutes of Health, the National Science Foundation, the U.S. Army Research Office, and the Howard Hughes Medical Institute.

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