Tag Archives: living computers

Transforming bacterial cells into living computers

If this were a movie instead of a press release, we’d have some ominous music playing over a scene in a pristine white lab. Instead, we have a November 13, 2022 Technion-Israel Institute of Technology press release (also on EurekAlert) where the writer tries to highlight the achievement while downplaying the sort of research (in synthetic biology) that could have people running for the exits,

Bringing together concepts from electrical engineering and bioengineering tools, Technion and MIT [Massachusetts Institute of Technology] scientists collaborated to produce cells engineered to compute sophisticated functions – “biocomputers” of sorts. Graduate students and researchers from Technion – Israel Institute of Technology Professor Ramez Daniel’s Laboratory for Synthetic Biology & Bioelectronics worked together with Professor Ron Weiss from the Massachusetts Institute of Technology to create genetic “devices” designed to perform computations like artificial neural circuits. Their results were recently published in Nature Communications.

The genetic material was inserted into the bacterial cell in the form of a plasmid: a relatively short DNA molecule that remains separate from the bacteria’s “natural” genome. Plasmids also exist in nature, and serve various functions. The research group designed the plasmid’s genetic sequence to function as a simple computer, or more specifically, a simple artificial neural network. This was done by means of several genes on the plasmid regulating each other’s activation and deactivation according to outside stimuli.

What does it mean that a cell is a circuit? How can a computer be biological?

At its most basic level, a computer consists of 0s and 1s, of switches. Operations are performed on these switches: summing them, picking the maximal or minimal value between them, etc. More advanced operations rely on the basic ones, allowing a computer to play chess or fly a rocket to the moon.

In the electronic computers we know, the 0/1 switches take the form of transistors. But our cells are also computers, of a different sort. There, the presence or absence of a molecule can act as a switch. Genes activate, trigger or suppress other genes, forming, modifying, or removing molecules. Synthetic biology aims (among other goals) to harness these processes, to synthesize the switches and program the genes that would make a bacterial cell perform complex tasks. Cells are naturally equipped to sense chemicals and to produce organic molecules. Being able to “computerize” these processes within the cell could have major implications for biomanufacturing and have multiple medical applications.

The Ph.D students (now doctors) Luna Rizik and Loai Danial, together with Dr. Mouna Habib, under the guidance of Prof. Ramez Daniel from the Faculty of Biomedical Engineering at the Technion, and in collaboration with Prof. Ron Weiss from the Synthetic Biology Center, MIT,  were inspired by how artificial neural networks function. They created synthetic computation circuits by combining existing genetic “parts,” or engineered genes, in novel ways, and implemented concepts from neuromorphic electronics into bacterial cells. The result was the creation of bacterial cells that can be trained using artificial intelligence algorithms.

The group were able to create flexible bacterial cells that can be dynamically reprogrammed to switch between reporting whether at least one of a test chemicals, or two, are present (that is, the cells were able to switch between performing the OR and the AND functions). Cells that can change their programming dynamically are capable of performing different operations under different conditions. (Indeed, our cells do this naturally.) Being able to create and control this process paves the way for more complex programming, making the engineered cells suitable for more advanced tasks. Artificial Intelligence algorithms allowed the scientists to produce the required genetic modifications to the bacterial cells at a significantly reduced time and cost.

Going further, the group made use of another natural property of living cells: they are capable of responding to gradients. Using artificial intelligence algorithms, the group succeeded in harnessing this natural ability to make an analog-to-digital converter – a cell capable of reporting whether the concentration of a particular molecule is “low”, “medium”, or “high.” Such a sensor could be used to deliver the correct dosage of medicaments, including cancer immunotherapy and diabetes drugs.

Of the researchers working on this study, Dr. Luna Rizik and Dr. Mouna Habib hail from the Department of Biomedical Engineering, while Dr. Loai Danial is from the Andrew and Erna Viterbi Faculty of Electrical Engineering. It is bringing the two fields together that allowed the group to make the progress they did in the field of synthetic biology.

This work was partially funded by the Neubauer Family Foundation, the Israel Science Foundation (ISF), European Union’s Horizon 2020 Research and Innovation Programme, the Technion’s Lorry I. Lokey interdisciplinary Center for Life Sciences and Engineering, and the [US Department of Defense] Defense Advanced Research Projects Agency [DARPA].

Here’s a link to and a citation for the paper,

Synthetic neuromorphic computing in living cells by Luna Rizik, Loai Danial, Mouna Habib, Ron Weiss & Ramez Daniel. Nature Communications volume 13, Article number: 5602 (2022) DOIL https://doi.org/10.1038/s41467-022-33288-8 Published: 24 September 2022

This paper is open access.

A 3D printed ‘living’ tattoo

MIT engineers have devised a 3-D printing technique that uses a new kind of ink made from genetically programmed living cells. Courtesy of the researchers [and MIT]

If that image isn’t enough, there’s also a video abstract (I don’t think I’ve seen one of these before) for the paper,

For those who’d still like to read the text, here’s more from a December 5, 2017 MIT (Massachusetts Institute of Technology) news release (also on EurekAlert),

MIT engineers have devised a 3-D printing technique that uses a new kind of ink made from genetically programmed living cells.

The cells are engineered to light up in response to a variety of stimuli. When mixed with a slurry of hydrogel and nutrients, the cells can be printed, layer by layer, to form three-dimensional, interactive structures and devices.

The team has then demonstrated its technique by printing a “living tattoo” — a thin, transparent patch patterned with live bacteria cells in the shape of a tree. Each branch of the tree is lined with cells sensitive to a different chemical or molecular compound. When the patch is adhered to skin that has been exposed to the same compounds, corresponding regions of the tree light up in response.

The researchers, led by Xuanhe Zhao, the Noyce Career Development Professor in MIT’s Department of Mechanical Engineering, and Timothy Lu, associate professor of biological engineering and of electrical engineering and computer science, say that their technique can be used to fabricate “active” materials for wearable sensors and interactive displays. Such materials can be patterned with live cells engineered to sense environmental chemicals and pollutants as well as changes in pH and temperature.

What’s more, the team developed a model to predict the interactions between cells within a given 3-D-printed structure, under a variety of conditions. The team says researchers can use the model as a guide in designing responsive living materials.

Zhao, Lu, and their colleagues have published their results today [December 5, 2017] in the journal Advanced Materials. The paper’s co-authors are graduate students Xinyue Liu, Hyunwoo Yuk, Shaoting Lin, German Alberto Parada, Tzu-Chieh Tang, Eléonore Tham, and postdoc Cesar de la Fuente-Nunez.

A hardy alternative

In recent years, scientists have explored a variety of responsive materials as the basis for 3D-printed inks. For instance, scientists have used inks made from temperature-sensitive polymers to print heat-responsive shape-shifting objects. Others have printed photoactivated structures from polymers that shrink and stretch in response to light.

Zhao’s team, working with bioengineers in Lu’s lab, realized that live cells might also serve as responsive materials for 3D-printed inks, particularly as they can be genetically engineered to respond to a variety of stimuli. The researchers are not the first to consider 3-D printing genetically engineered cells; others have attempted to do so using live mammalian cells, but with little success.

“It turns out those cells were dying during the printing process, because mammalian cells are basically lipid bilayer balloons,” Yuk says. “They are too weak, and they easily rupture.”

Instead, the team identified a hardier cell type in bacteria. Bacterial cells have tough cell walls that are able to survive relatively harsh conditions, such as the forces applied to ink as it is pushed through a printer’s nozzle. Furthermore, bacteria, unlike mammalian cells, are compatible with most hydrogels — gel-like materials that are made from a mix of mostly water and a bit of polymer. The group found that hydrogels can provide an aqueous environment that can support living bacteria.

The researchers carried out a screening test to identify the type of hydrogel that would best host bacterial cells. After an extensive search, a hydrogel with pluronic acid was found to be the most compatible material. The hydrogel also exhibited an ideal consistency for 3-D printing.

“This hydrogel has ideal flow characteristics for printing through a nozzle,” Zhao says. “It’s like squeezing out toothpaste. You need [the ink] to flow out of a nozzle like toothpaste, and it can maintain its shape after it’s printed.”

From tattoos to living computers

Lu provided the team with bacterial cells engineered to light up in response to a variety of chemical stimuli. The researchers then came up with a recipe for their 3-D ink, using a combination of bacteria, hydrogel, and nutrients to sustain the cells and maintain their functionality.

“We found this new ink formula works very well and can print at a high resolution of about 30 micrometers per feature,” Zhao says. “That means each line we print contains only a few cells. We can also print relatively large-scale structures, measuring several centimeters.”

They printed the ink using a custom 3-D printer that they built using standard elements combined with fixtures they machined themselves. To demonstrate the technique, the team printed a pattern of hydrogel with cells in the shape of a tree on an elastomer layer. After printing, they solidified, or cured, the patch by exposing it to ultraviolet radiation. They then adhere the transparent elastomer layer with the living patterns on it, to skin.

To test the patch, the researchers smeared several chemical compounds onto the back of a test subject’s hand, then pressed the hydrogel patch over the exposed skin. Over several hours, branches of the patch’s tree lit up when bacteria sensed their corresponding chemical stimuli.

The researchers also engineered bacteria to communicate with each other; for instance they programmed some cells to light up only when they receive a certain signal from another cell. To test this type of communication in a 3-D structure, they printed a thin sheet of hydrogel filaments with “input,” or signal-producing bacteria and chemicals, overlaid with another layer of filaments of an “output,” or signal-receiving bacteria. They found the output filaments lit up only when they overlapped and received input signals from corresponding bacteria .

Yuk says in the future, researchers may use the team’s technique to print “living computers” — structures with multiple types of cells that communicate with each other, passing signals back and forth, much like transistors on a microchip.

“This is very future work, but we expect to be able to print living computational platforms that could be wearable,” Yuk says.

For more near-term applications, the researchers are aiming to fabricate customized sensors, in the form of flexible patches and stickers that could be engineered to detect a variety of chemical and molecular compounds. They also envision their technique may be used to manufacture drug capsules and surgical implants, containing cells engineered produce compounds such as glucose, to be released therapeutically over time.

“We can use bacterial cells like workers in a 3-D factory,” Liu says. “They can be engineered to produce drugs within a 3-D scaffold, and applications should not be confined to epidermal devices. As long as the fabrication method and approach are viable, applications such as implants and ingestibles should be possible.”

Here’s a link to and a citation for the paper,

3D Printing of Living Responsive Materials and Devices by Xinyue Liu, Hyunwoo Yuk, Shaoting Lin, German Alberto Parada, Tzu-Chieh Tang, Eléonore Tham, Cesar de la Fuente-Nunez, Timothy K. Lu, and Xuanhe Zhao. Advanced Materials DOI: 10.1002/adma.201704821 Version of Record online: 5 DEC 2017

© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.