Electronic circuits are found in almost everything from smartphones to spacecraft and are useful in a variety of computational problems from simple addition to determining the trajectories of interplanetary satellites. At Caltech, a group of researchers led by Assistant Professor of Bioengineering Lulu Qian is working to create circuits using not the usual silicon transistors but strands of DNA.
The Qian group has made the technology of DNA circuits accessible to even novice researchers—including undergraduate students—using a software tool they developed called the Seesaw Compiler. Now, they have experimentally demonstrated that the tool can be used to quickly design DNA circuits that can then be built out of cheap “unpurified” DNA strands, following a systematic wet-lab procedure devised by Qian and colleagues.
A paper describing the work appears in the February 23 issue of Nature Communications.
Although DNA is best known as the molecule that encodes the genetic information of living things, they are also useful chemical building blocks. This is because the smaller molecules that make up a strand of DNA, called nucleotides, bind together only with very specific rules—an A nucleotide binds to a T, and a C nucleotide binds to a G. A strand of DNA is a sequence of nucleotides and can become a double strand if it binds with a sequence of complementary nucleotides.
DNA circuits are good at collecting information within a biochemical environment, processing the information locally and controlling the behavior of individual molecules. Circuits built out of DNA strands instead of silicon transistors can be used in completely different ways than electronic circuits. “A DNA circuit could add ‘smarts’ to chemicals, medicines, or materials by making their functions responsive to the changes in their environments,” Qian says. “Importantly, these adaptive functions can be programmed by humans.”
To build a DNA circuit that can, for example, compute the square root of a number between 0 and 16, researchers first have to carefully design a mixture of single and partially double-stranded DNA that can chemically recognize a set of DNA strands whose concentrations represent the value of the original number. Mixing these together triggers a cascade of zipping and unzipping reactions, each reaction releasing a specific DNA strand upon binding. Once the reactions are complete, the identities of the resulting DNA strands reveal the answer to the problem.
With the Seesaw Compiler, a researcher could tell a computer the desired function to be calculated and the computer would design the DNA sequences and mixtures needed. However, it was not clear how well these automatically designed DNA sequences and mixtures would work for building DNA circuits with new functions; for example, computing the rules that govern how a cell evolves by sensing neighboring cells, defined in a classic computational model called “cellular automata.”
“Constructing a circuit made of DNA has thus far been difficult for those who are not in this research area, because every circuit with a new function requires DNA strands with new sequences and there are no off-the-shelf DNA circuit components that can be purchased,” says Chris Thachuk, senior postdoctoral scholar in computing and mathematical sciences and second author on the paper. “Our circuit-design software is a step toward enabling researchers to just type in what they want to do or compute and having the software figure out all the DNA strands needed to perform the computation, together with simulations to predict the DNA circuit’s behavior in a test tube. Even though these DNA strands are still not off-the-shelf products, we have now shown that they do work well for new circuits with user-designed functions.”
“In the 1950s, only a few research labs that understood the physics of transistors could build early versions of electronic circuits and control their functions,” says Qian. “But today many software tools are available that use simple and human-friendly languages to design complex electronic circuits embedded in smart machines. Our software is kind of like that: it translates simple and human-friendly descriptions of computation to the design of complex DNA circuits.”
The Seesaw Compiler was put to the test in 2015 in a unique course at Caltech, taught by Qian and called “Design and Construction of Programmable Molecular Systems” (BE/CS 196 ab). “How do you evaluate the accessibility of a new technology? You give the technology to someone who is intellectually capable but has minimal prior background,” Qian says.
“The students in this class were undergrads and first-year graduate students majoring in computer science and bioengineering,” says Anupama Thubagere, a graduate student in biology and bioengineering and first author on the paper. “I started working with them as a head teaching assistant and together we soon discovered that using the Seesaw Compiler to design a DNA circuit was easy for everyone.”
However, building the designed circuit in the wet lab was not so simple. Thus, with continued efforts after the class, the group set out to develop a systematic wet-lab procedure that could guide researchers—even novices like undergraduate students—through the process of building DNA circuits. “Fortunately, we found a general solution to every challenge that we encountered, now making it easy for everyone to build their own DNA circuits,” Thubagere says.
The group showed that it was possible to use cheap, “unpurified” DNA strands in these circuits using the new process. This was only possible because steps in the systematic wet-lab procedure were designed to compensate for the lower synthesis quality of the DNA strands.
“We hope that this work will convince more computer scientists and researchers from other fields to join our community in developing increasingly powerful molecular machines and to explore a much wider range of applications that will eventually lead to the transformation of technology that has been promised by the invention of molecular computers,” Qian says.
Learn more: Computing with Biochemical Circuits Made Easy
KSU also holds classes at the Cobb Galleria Centre, Dalton State College, Appalachian Technical College and Dallas. Current enrollment is over 32,000 students.
Caltech has six academic divisions with strong emphases on science and engineering. Its 124-acre (50 ha) primary campus is located approximately 11 mi (18 km) northeast of downtown Los Angeles.
Although founded as a preparatory and vocational school by Amos G. Throop in 1891, the college attracted influential scientists such as George Ellery Hale, Arthur Amos Noyes, and Robert Andrews Millikan in the early 20th century. The vocational and preparatory schools were disbanded and spun off in 1910, and the college assumed its present name in 1921. In 1934, Caltech was elected to the Association of American Universities, and the antecedents of NASA’s Jet Propulsion Laboratory, which Caltech continues to manage and operate, were established between 1936 and 1943 under Theodore von Kármán.
Despite its small size, 32 Caltech alumni and faculty have won a total of 33 Nobel Prizes (Linus Pauling being the only individual in history to win two unshared prizes) and 70 have won the United States National Medal of Science or Technology. There are 112 faculty members who have been elected to the National Academies. In addition, numerous faculty members are associated with the Howard Hughes Medical Institute as well as NASA. Caltech managed $332 million in 2011 in sponsored research and $1.75 billion for its endowment in 2012. It also has a long standing rivalry with the Massachusetts Institute of Technology (MIT).
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A computer algorithm for analyzing time-lapse biological images could make it easier for scientists and clinicians to find and track multiple molecules in living organisms. The technique is faster, less expensive and more accurate than current methods — and it even works with cell phone images.
A new image analysis technique makes finding important biological molecules — including tell-tale signs of disease — and learning how they interact in living organisms much faster and far less expensive. Called Hyper-Spectral Phasor analysis, or HySP, it could even be useful for diagnosing and monitoring diseases using cell phone images.
Researchers use fluorescent imaging to locate proteins and other molecules in cells and tissues. It works by tagging the molecules with dyes that glow under certain kinds of light — the same principle behind so-called “black light” images.
Fluorescent imaging can help scientists understand which molecules are produced in large amounts in cancer or other diseases, information that may be useful in diagnosis or in identifying possible targets for therapeutic drugs.
Looking at just one or two molecules in cell or tissue samples is fairly straightforward. Unfortunately, it doesn’t provide a clear picture of how those molecules are behaving in the real world. For that, scientists need to expand their view.
“Biological research is moving toward complex systems that extend across multiple dimensions, the interaction of multiple elements over time,” said postdoctoral fellow Francesco Cutrale. He developed HySP with Scott Fraser
, Elizabeth Garrett Chair in Convergent Bioscience and Provost Professor of Biological Science. The work was done at USC’s Translational Imaging Center, a joint venture of USC Dornsife and USC Viterbi School of Engineering.
“By looking at multiple targets, or watching targets move over time, we can get a much better view of what’s actually happening within complex living systems,” Cutrale said.
Currently, researchers must look at different labels separately, then apply complicated techniques to layer them together and figure out how they relate to one another, a time-consuming and expensive process, Cutrale said. HySP can look at many different molecules in one pass.
“Imagine looking at 18 targets,” Cutrale said. “We can do that all at once, rather than having to perform 18 separate experiments and try to combine them later.”
In addition, the algorithm effectively filters through interference to discern the true signal, even if that signal is extremely weak — very much like finding the proverbial needle in a haystack. Recent technology from NASA’s Jet Propulsion Laboratory can also do this, but the equipment and process are both extremely expensive and time-consuming.
In research published Jan. 9 online by the scientific journal Nature Methods, Cutrale and Fraser, along with researchers from Keck School of Medicine, Caltech and the University of Cambridge in the United Kingdom, have used zebra fish to test and develop HySP. In this common laboratory model, the system works extremely well. But what about in people?
“In experimental models, we can use genetic manipulation to label molecules, but we can’t do that with people,” said Fraser. “In people, we have to use the intrinsic signals of those molecules.”
Those inherent signals, the natural fluorescence from biomolecules, normally gets in the way of imaging, Fraser said. However, using this new computer algorithm that can effectively find weak signals in a cluttered background, the team can pinpoint their targets in the body.
Different fluorescent light wavelengths reveal features of a zebra fish embryo. Photo courtesy of Francesco Cutrale.
The scientists hope to test the process in the next couple of years with the help of soldiers whose lungs have been damaged by chemicals and irritants they may have encountered in combat. The researchers will extend a light-emitting probe down into the soldiers’ lungs while the probe records images of the fluorescence in the surrounding tissues. They will then use HySP to create what amounts to a fluorescent map and compare it with that of healthy lung tissue to see if they can discern the damage. If so, they hope to further develop the technology so it may one day help these soldiers and other lung patients receive more targeted treatment.
It might also be possible one day for clinicians to use HySP to analyze cell phone pictures of skin lesions to determine if they are at risk of being cancerous, according to Fraser and Cutrale.
“We could determine if the lesions have changed color or shape over time,” Cutrale said. Clinicians could then examine the patient further to be certain of a diagnosis and respond appropriately.
Cutrale and Fraser see the technology as a giant leap forward for both research and medicine.
“Both scientists at the bench and scientists at the clinic will be able to perform their work faster and with greater confidence in the results,” Cutrale said. “Better, faster, cheaper. That’s the payoff here.”
Seeing deep into space requires large telescopes. The larger the telescope, the more light it collects, and the sharper the image it provides.
For example, NASA’s Kepler space observatory, with a mirror diameter of under one meter, is searching for exoplanets orbiting stars up to 3,000 light-years away. By contrast, the Hubble Space Telescope, with a 2.4-meter mirror, has studied stars more than 10 billion light-years away.
Now Caltech’s Sergio Pellegrino and colleagues are proposing a space observatory that would have a primary mirror with a diameter of 100 meters—40 times larger than Hubble’s. Space telescopes, which provide some of the clearest images of the universe, are typically limited in size due to the difficulty and expense of sending large items into space. Pellegrino’s team would circumvent that issue by shipping the mirror up as separate components that would be assembled, in space, by robots.
Their design calls for the use of more than 300 deployable truss modules that could be unfolded to form a scaffolding upon which a commensurate number of small mirror plates could be placed to create a large segmented mirror. The assembly of the scaffolding and the attachment of the many mirrors is a task well-suited to robots, Pellegrino and his colleagues say.
In their concept, a spider-like, six-armed “hexbot” would assemble the trusswork and then crawl across the structure to build the mirror atop it. It was modeled on the JPL RoboSimian system, which in 2015 completed the DARPA Robotics Challenge, a federal competition aimed at spurring the development of robots that could perform complicated tasks that would be dangerous for humans. The hexbot would run on electrical power from the telescope’s solar grid. It would use four of its arms to walk—with one leg moving at any given time, while the three others remain securely attached to the structure. The two remaining arms would be free to assemble the trusses and mirrors.
The team opted to pursue an ambitious 100-meter design. “We wanted to study how different kinds of architectures perform as the diameter is increased,” says Pellegrino, Joyce and Kent Kresa Professor of Aeronautics and Professor of Civil Engineering in Caltech’s Division of Engineering and Applied Science, and Jet Propulsion Laboratory Senior Research Scientist. “We found that far away from the Earth, a structurally connected telescope is much heavier than an architecture based on separate spacecraft for the primary mirror, the optics, and the instrumentation.”
The realization of such an assembly is still decades away. However, Pellegrino and his colleagues are already working on the various technologies that will be needed to make it possible.
The entire space observatory would be composed of the fully assembled mirror-and-truss structure and three other parts, flying in formation. An optics and instrumentation unit would be located about 400 meters from the mirror; a control unit, stationed about 400 meters beyond that, would align the system and keep it working properly; and a thin shade, roughly 20 meters in diameter, would shield the mirror from the sun to keep its temperature stable and consistent across its diameter.
The four-part assembly would be stationed at one of the sun–earth Lagrange points—locations between the sun and the earth where the pull of gravity from two bodies locks a satellite into orbit with them, allowing it to maintain a stable position. There, the space observatory could peer deep into space without drifting out of place.
Low-cost coating would disrupt the building retrofit market and potentially save billions in electricity
It’s estimated that 10 percent of all the energy used in buildings in the U.S. can be attributed to window performance, costing building owners about $50 billion annually, yet the high cost of replacing windows or retrofitting them with an energy efficient coating is a major deterrent. U.S. Dept. of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab) researchers are seeking to address this problem with creative chemistry—a polymer heat-reflective coating that can be painted on at one-tenth the cost.
“Instead of hiring expensive contractors, a homeowner could go to the local hardware store, buy the coating, and paint it on as a DIY retrofit—that’s the vision,” said Berkeley Lab scientist Raymond Weitekamp. “The coating will selectively reflect the infrared solar energy back to the sky while allowing visible light to pass through, which will drastically improve the energy efficiency of windows, particularly in warm climates and southern climates, where a significant fraction of energy usage goes to air conditioning.”
A team of Berkeley Lab scientists is receiving part of a $3.95 million award from the Department of Energy’s Advanced Research Projects Agency–Energy (ARPA-E) to develop this product. The multi-institutional team is led by researcher Garret Miyake at the University of Colorado Boulder, and also includes Caltech and Materia Inc.
There are retrofit window films on the market now that have spectral selectivity, but a professional contractor is needed to install them, a barrier for many building owners. A low-cost option could significantly expand adoption and result in potential annual energy savings of 35 billion kilowatt-hours, reducing carbon dioxide emissions by 24 billion kilograms per year, the equivalent of taking 5 million cars off the road.
The Berkeley Lab technology relies on a type of material called a bottlebrush polymer, which, as its name suggests, has one main rigid chain of molecules with bristles coming off the sides. This unusual molecular architecture lends it some unique properties, one being that it doesn’t entangle easily.
“Imagine spaghetti versus gummy worms,” Weitekamp explained. “Spaghetti can be tied up in knots. If you want to rearrange cooked spaghetti back to its uncooked alignment, you would have to put significant energy into unwinding it. But with gummy worms you can line them all up easily because they’re pretty rigid.”
As a graduate student at Caltech, Weitekamp worked on understanding and controlling how bottlebrush polymers self-assemble into nanostructures behaving as photonic crystals, which can selectively reflect light at different frequencies. Last year he came to Berkeley Lab as part of Cyclotron Road, a program for entrepreneurial researchers, to commercialize these coatings and other related polymer-based technologies. He has been working on the development of polymeric materials as a user at the Molecular Foundry, a DOE Office of Science User Facility at Berkeley Lab.
“We were very compelled by the potential impact of [Weitekamp’s] technology across a number of industries,” said Cyclotron Road director Ilan Gur. “His ideas aligned with the Foundry’s expertise in polymer chemistry and the window application fit squarely into Berkeley Lab’s existing strengths in buildings technology and energy analysis.”
For the ARPA-E award, Weitekamp is collaborating with Berkeley Lab’s Steve Selkowitz, a leading expert on building science and window technologies, and Arman Shehabi, an expert in analyzing energy use of buildings, to develop a cost-competitive and scalable product. Their target cost is $1.50 per square foot, one-tenth the current market cost for commercially installed energy efficient retrofit window coatings.
“ARPA-E invests in high-risk, high-reward projects,” Shehabi said. “The high reward in this project isn’t in the performance improvement. It’s transformative in how windows could be retrofitted—it’s something you can do yourself. The market need is very large, and there’s nothing low-cost out there that meets that need.”
Mathematical equations can make Internet communication via computer, mobile phone or satellite many times faster and more secure than today.
Results with software developed by researchers from Aalborg University in collaboration with the US universities the Massachusetts Institute of Technology (MIT) and California Institute of Technology (Caltech) are attracting attention in the international technology media.
A new study uses a four minute long mobile video as an example. The method used by the Danish and US researchers in the study resulted in the video being downloaded five times faster than state of the art technology. The video also streamed without interruptions. In comparison, the original video got stuck 13 times along the way.