Tag Archives: Bozhi Tian

The roles mathematics and light play in cellular communication

These are two entirely different types of research but taken together they help build a picture about how the cells in our bodies function.

Cells and light

An April 30, 2018 news item on phys.org describes work on controlling biology with light,

Over the past five years, University of Chicago chemist Bozhi Tian has been figuring out how to control biology with light.

A longterm science goal is devices to serve as the interface between researcher and body—both as a way to understand how cells talk among each other and within themselves, and eventually, as a treatment for brain or nervous system disorders [emphasis mine] by stimulating nerves to fire or limbs to move. Silicon—a versatile, biocompatible material used in both solar panels and surgical implants—is a natural choice.

In a paper published April 30 in Nature Biomedical Engineering, Tian’s team laid out a system of design principles for working with silicon to control biology at three levels—from individual organelles inside cells to tissues to entire limbs. The group has demonstrated each in cells or mice models, including the first time anyone has used light to control behavior without genetic modification.

“We want this to serve as a map, where you can decide which problem you would like to study and immediately find the right material and method to address it,” said Tian, an assistant professor in the Department of Chemistry.

Researchers built this thin layer of silicon lace to modulate neural signals when activated by light. Courtesy of Yuanwen Jiang and Bozhi Tian

An April 30, 2018 University of Chicago news release by Louise Lerner, which originated the news item, describes the work in greater detail,

The scientists’ map lays out best methods to craft silicon devices depending on both the intended task and the scale—ranging from inside a cell to a whole animal.

For example, to affect individual brain cells, silicon can be crafted to respond to light by emitting a tiny ionic current, which encourages neurons to fire. But in order to stimulate limbs, scientists need a system whose signals can travel farther and are stronger—such as a gold-coated silicon material in which light triggers a chemical reaction.

The mechanical properties of the implant are important, too. Say researchers would like to work with a larger piece of the brain, like the cortex, to control motor movement. The brain is a soft, squishy substance, so they’ll need a material that’s similarly soft and flexible, but can bind tightly against the surface. They’d want thin and lacy silicon, say the design principles.

The team favors this method because it doesn’t require genetic modification or a power supply wired in, since the silicon can be fashioned into what are essentially tiny solar panels. (Many other forms of monitoring or interacting with the brain need to have a power supply, and keeping a wire running into a patient is an infection risk.)

They tested the concept in mice and found they could stimulate limb movements by shining light on brain implants. Previous research tested the concept in neurons.

“We don’t have answers to a number of intrinsic questions about biology, such as whether individual mitochondria communicate remotely through bioelectric signals,” said Yuanwen Jiang, the first author on the paper, then a graduate student at UChicago and now a postdoctoral researcher at Stanford. “This set of tools could address such questions as well as pointing the way to potential solutions for nervous system disorders.”

Other UChicago authors were Assoc. Profs. Chin-Tu Chen and Chien-Min Kao, Asst. Prof Xiaoyang, postdoctoral researchers Jaeseok Yi, Yin Fang, Xiang Gao, Jiping Yue, Hsiu-Ming Tsai, Bing Liu and Yin Fang, graduate students Kelliann Koehler, Vishnu Nair, and Edward Sudzilovsky, and undergraduate student George Freyermuth.

Other researchers on the paper hailed from Northwestern University, the University of Illinois at Chicago and Hong Kong Polytechnic University.

The researchers have also made this video illustrating their work,

via Gfycat Tiny silicon nanowires (in blue), activated by light, trigger activity in neurons. (Courtesy Yuanwen Jiang and Bozhi Tian)

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

Rational design of silicon structures for optically controlled multiscale biointerfaces by Yuanwen Jiang, Xiaojian Li, Bing Liu, Jaeseok Yi, Yin Fang, Fengyuan Shi, Xiang Gao, Edward Sudzilovsky, Ramya Parameswaran, Kelliann Koehler, Vishnu Nair, Jiping Yue, KuangHua Guo, Yin Fang, Hsiu-Ming Tsai, George Freyermuth, Raymond C. S. Wong, Chien-Min Kao, Chin-Tu Chen, Alan W. Nicholls, Xiaoyang Wu, Gordon M. G. Shepherd, & Bozhi Tian. Nature Biomedical Engineering (2018) doi:10.1038/s41551-018-0230-1 Published: 30 April 2018

This paper is behind a paywall.

Mathematics and how living cells ‘think’

This May 2, 2018 Queensland University of Technology (QUT; Australia) press release is also on EurekAlert,

How does the ‘brain’ of a living cell work, allowing an organism to function and thrive in changing and unfavourable environments?

Queensland University of Technology (QUT) researcher Dr Robyn Araujo has developed new mathematics to solve a longstanding mystery of how the incredibly complex biological networks within cells can adapt and reset themselves after exposure to a new stimulus.

Her findings, published in Nature Communications, provide a new level of understanding of cellular communication and cellular ‘cognition’, and have potential application in a variety of areas, including new targeted cancer therapies and drug resistance.

Dr Araujo, a lecturer in applied and computational mathematics in QUT’s Science and Engineering Faculty, said that while we know a great deal about gene sequences, we have had extremely limited insight into how the proteins encoded by these genes work together as an integrated network – until now.

“Proteins form unfathomably complex networks of chemical reactions that allow cells to communicate and to ‘think’ – essentially giving the cell a ‘cognitive’ ability, or a ‘brain’,” she said. “It has been a longstanding mystery in science how this cellular ‘brain’ works.

“We could never hope to measure the full complexity of cellular networks – the networks are simply too large and interconnected and their component proteins are too variable.

“But mathematics provides a tool that allows us to explore how these networks might be constructed in order to perform as they do.

“My research is giving us a new way to look at unravelling network complexity in nature.”

Dr Araujo’s work has focused on the widely observed function called perfect adaptation – the ability of a network to reset itself after it has been exposed to a new stimulus.

“An example of perfect adaptation is our sense of smell,” she said. “When exposed to an odour we will smell it initially but after a while it seems to us that the odour has disappeared, even though the chemical, the stimulus, is still present.

“Our sense of smell has exhibited perfect adaptation. This process allows it to remain sensitive to further changes in our environment so that we can detect both very feint and very strong odours.

“This kind of adaptation is essentially what takes place inside living cells all the time. Cells are exposed to signals – hormones, growth factors, and other chemicals – and their proteins will tend to react and respond initially, but then settle down to pre-stimulus levels of activity even though the stimulus is still there.

“I studied all the possible ways a network can be constructed and found that to be capable of this perfect adaptation in a robust way, a network has to satisfy an extremely rigid set of mathematical principles. There are a surprisingly limited number of ways a network could be constructed to perform perfect adaptation.

“Essentially we are now discovering the needles in the haystack in terms of the network constructions that can actually exist in nature.

“It is early days, but this opens the door to being able to modify cell networks with drugs and do it in a more robust and rigorous way. Cancer therapy is a potential area of application, and insights into how proteins work at a cellular level is key.”

Dr Araujo said the published study was the result of more than “five years of relentless effort to solve this incredibly deep mathematical problem”. She began research in this field while at George Mason University in Virginia in the US.

Her mentor at the university’s College of Science and co-author of the Nature Communications paper, Professor Lance Liotta, said the “amazing and surprising” outcome of Dr Araujo’s study is applicable to any living organism or biochemical network of any size.

“The study is a wonderful example of how mathematics can have a profound impact on society and Dr Araujo’s results will provide a set of completely fresh approaches for scientists in a variety of fields,” he said.

“For example, in strategies to overcome cancer drug resistance – why do tumours frequently adapt and grow back after treatment?

“It could also help understanding of how our hormone system, our immune defences, perfectly adapt to frequent challenges and keep us well, and it has future implications for creating new hypotheses about drug addiction and brain neuron signalling adaptation.”

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

The topological requirements for robust perfect adaptation in networks of any size by Robyn P. Araujo & Lance A. Liotta. Nature Communicationsvolume 9, Article number: 1757 (2018) doi:10.1038/s41467-018-04151-6 Published: 01 May 2018

This paper is open access.

Phagocytosis for a bioelectronic future

The process by which a cell engulfs matter is known as phagocytosis. One of the best known examples of failed phagocytosis is that of asbestos fibres in the lungs where lung cells have attempted to engulf a fibre that’s just too big and ends up piercing the cell. When enough of the cells are pierced, the person is diagnosed with mesothelioma.

This particular example of phagocytosis is a happier one according to a Dec. 16, 2016 article by Meghan Rosen for ScienceNews,

Human cells can snack on silicon.

Cells grown in the lab devour nano-sized wires of silicon through an engulfing process known as phagocytosis, scientists report December 16 in Science Advances.

Silicon-infused cells could merge electronics with biology, says John Zimmerman, a biophysicist now at Harvard University. “It’s still very early days,” he adds, but “the idea is to get traditional electronic devices working inside of cells.” Such hybrid devices could one day help control cellular behavior, or even replace electronics used for deep brain stimulation, he says.

Scientists have been trying to load electronic parts inside cells for years. One way is to zap holes in cells with electricity, which lets big stuff, like silicon nanowires linked to bulky materials, slip in. Zimmerman, then at the University of Chicago, and colleagues were looking for a simpler technique, something that would let tiny nanowires in easily and could potentially allow them to travel through a person’s bloodstream — like a drug.

A Dec. 22, 2016 University of Chicago news release by Matt Wood provides more detail,

“You can treat it as a non-genetic, synthetic biology platform,” said Bozhi Tian, PhD, assistant professor of chemistry and senior author of the new study. “Traditionally in biology we use genetic engineering and modify genetic parts. Now we can use silicon parts, and silicon can be internalized. You can target those silicon parts to specific parts of the cell and modulate that behavior with light.”

In the new study, Tian and his team show how cells consume or internalize the nanowires through phagocytosis, the same process they use to engulf and ingest nutrients and other particles in their environment. The nanowires are simply added to cell media, the liquid solution the cells live in, the same way you might administer a drug, and the cells take it from there. Eventually, the goal would be to inject them into the bloodstream or package them into a pill.

Once inside, the nanowires can interact directly with individual parts of the cell, organelles like the mitochondria, nucleus and cytoskeletal filaments. Researchers can then stimulate the nanowires with light to see how individual components of the cell respond, or even change the behavior of the cell. They can last up to two weeks inside the cell before biodegrading.

Seeing how individual parts of a cell respond to stimulation could give researchers insight into how medical treatments that use electrical stimulation work at a more detailed level. For instance, deep brain stimulation helps treat tremors from movement disorders like Parkinson’s disease by sending electrical signals to areas of the brain. Doctors know it works at the level of tissues and brain structures, but seeing how individual components of nerve cells react to these signals could help fine tune and improve the treatment.

The experiments in the study used umbilical vascular endothelial cells, which make up blood vessel linings in the umbilical cord. These cells readily took up the nanowires, but others, like cardiac muscle cells, did not. Knowing that some cells consume the wires and some don’t could also prove useful in experimental settings and give researchers more ways to target specific cell types.

Tian and his team manufactures the nanowires in their lab with a chemical vapor deposition system that grows the silicon structures to different specifications. They can adjust size, shape, and electrical properties as needed, or even add defects on purpose for testing. They can also make wires with porous surfaces that could deliver drugs or genetic material to the cells. The process gives them a variety of ways to manipulate the properties of the nanowires for research.

Seeing how individual parts of a cell respond to stimulation could give researchers insight into how medical treatments that use electrical stimulation work at a more detailed level. For instance, deep brain stimulation helps treat tremors from movement disorders like Parkinson’s disease by sending electrical signals to areas of the brain. Doctors know it works at the level of tissues and brain structures, but seeing how individual components of nerve cells react to these signals could help fine tune and improve the treatment.

The experiments in the study used umbilical vascular endothelial cells, which make up blood vessel linings in the umbilical cord. These cells readily took up the nanowires, but others, like cardiac muscle cells, did not. Knowing that some cells consume the wires and some don’t could also prove useful in experimental settings and give researchers more ways to target specific cell types.

Tian and his team manufactures the nanowires in their lab with a chemical vapor deposition system that grows the silicon structures to different specifications. They can adjust size, shape, and electrical properties as needed, or even add defects on purpose for testing. They can also make wires with porous surfaces that could deliver drugs or genetic material to the cells. The process gives them a variety of ways to manipulate the properties of the nanowires for research.

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

Cellular uptake and dynamics of unlabeled freestanding silicon nanowires by John F. Zimmerman, Ramya Parameswaran, Graeme Murray, Yucai Wang, Michael Burke, and Bozhi Tian. Science Advances  16 Dec 2016: Vol. 2, no. 12, e1601039 DOI: 10.1126/sciadv.1601039

This paper appears to be open access.

Small, soft, and electrically functional: an injectable biomaterial

This development could be looked at as a form of synthetic biology without the genetic engineering. From a July 1, 2016 news item on ScienceDaily,

Ideally, injectable or implantable medical devices should not only be small and electrically functional, they should be soft, like the body tissues with which they interact. Scientists from two UChicago labs set out to see if they could design a material with all three of those properties.

The material they came up with, published online June 27, 2016, in Nature Materials, forms the basis of an ingenious light-activated injectable device that could eventually be used to stimulate nerve cells and manipulate the behavior of muscles and organs.

“Most traditional materials for implants are very rigid and bulky, especially if you want to do electrical stimulation,” said Bozhi Tian, an assistant professor in chemistry whose lab collaborated with that of neuroscientist Francisco Bezanilla on the research.

The new material, in contrast, is soft and tiny — particles just a few micrometers in diameter (far less than the width of a human hair) that disperse easily in a saline solution so they can be injected. The particles also degrade naturally inside the body after a few months, so no surgery would be needed to remove them.

A July 1, 2016 University of Chicago news release (also on EurekAlert) by , which originated the news item, provides more detail,

Each particle is built of two types of silicon that together form a structure full of nano-scale pores, like a tiny sponge. And like a sponge, it is squishy — a hundred to a thousand times less rigid than the familiar crystalline silicon used in transistors and solar cells. “It is comparable to the rigidity of the collagen fibers in our bodies,” said Yuanwen Jiang, Tian’s graduate student. “So we’re creating a material that matches the rigidity of real tissue.”

The material constitutes half of an electrical device that creates itself spontaneously when one of the silicon particles is injected into a cell culture, or, eventually, a human body. The particle attaches to a cell, making an interface with the cell’s plasma membrane. Those two elements together — cell membrane plus particle — form a unit that generates current when light is shined on the silicon particle.

“You don’t need to inject the entire device; you just need to inject one component,” João L. Carvalho-de-Souza , Bezanilla’s postdoc said. “This single particle connection with the cell membrane allows sufficient generation of current that could be used to stimulate the cell and change its activity. After you achieve your therapeutic goal, the material degrades naturally. And if you want to do therapy again, you do another injection.”

The scientists built the particles using a process they call nano-casting. They fabricate a silicon dioxide mold composed of tiny channels — “nano-wires” — about seven nanometers in diameter (less than 10,000 times smaller than the width of a human hair) connected by much smaller “micro-bridges.” Into the mold they inject silane gas, which fills the pores and channels and decomposes into silicon.

And this is where things get particularly cunning. The scientists exploit the fact the smaller an object is, the more the atoms on its surface dominate its reactions to what is around it. The micro-bridges are minute, so most of their atoms are on the surface. These interact with oxygen that is present in the silicon dioxide mold, creating micro-bridges made of oxidized silicon gleaned from materials at hand. The much larger nano-wires have proportionately fewer surface atoms, are much less interactive, and remain mostly pure silicon. [I have a note regarding ‘micro’ and ‘nano’ later in this posting.]

“This is the beauty of nanoscience,” Jiang said. “It allows you to engineer chemical compositions just by manipulating the size of things.”

Web-like nanostructure

Finally, the mold is dissolved. What remains is a web-like structure of silicon nano-wires connected by micro-bridges of oxidized silicon that can absorb water and help increase the structure’s softness. The pure silicon retains its ability to absorb light.

Transmission electron microscopy image shows an ordered nanowire array. The 100-nanometer scale bar is 1,000 times narrower than a hair. Courtesy of Tian Lab

Transmission electron microscopy image shows an ordered nanowire array. The 100-nanometer scale bar is 1,000 times narrower than a hair. Courtesy of
Tian Lab

The scientists have added the particles onto neurons in culture in the lab, shone light on the particles, and seen current flow into the neurons which activates the cells. The next step is to see what happens in living animals. They are particularly interested in stimulating nerves in the peripheral nervous system that connect to organs. These nerves are relatively close to the surface of the body, so near-infra-red wavelength light can reach them through the skin.

Tian imagines using the light-activated devices to engineer human tissue and create artificial organs to replace damaged ones. Currently, scientists can make engineered organs with the correct form but not the ideal function.

To get a lab-built organ to function properly, they will need to be able to manipulate individual cells in the engineered tissue. The injectable device would allow a scientist to do that, tweaking an individual cell using a tightly focused beam of light like a mechanic reaching into an engine and turning a single bolt. The possibility of doing this kind of synthetic biology without genetic engineering [emphasis mine] is enticing.

“No one wants their genetics to be altered,” Tian said. “It can be risky. There’s a need for a non-genetic system that can still manipulate cell behavior. This could be that kind of system.”

Tian’s graduate student Yuanwen Jiang did the material development and characterization on the project. The biological part of the collaboration was done in the lab of Francisco Bezanilla, the Lillian Eichelberger Cannon Professor of Biochemistry and Molecular Biology, by postdoc João L. Carvalho-de-Souza. They were, said Tian, the “heroes” of the work.

I was a little puzzled about the use of the word ‘micro’ in a context suggesting it was smaller than something measured at the nanoscale. Dr. Tian very kindly cleared up my confusion with this response in a July 4, 2016 email,

In fact, the definition of ‘micro’ and ’nano’ have been quite ambiguous in literature. For example, microporous materials (e.g., zeolite) usually refer to materials with pore sizes of less than 2 nm — this is defined based on IUPAC [International Union of Pure and Applied Chemistry] definition (http://goldbook.iupac.org/M03853.html). We used ‘micro-bridges’ because they come from the ‘micropores’ in the original template.

Thank you Dr. Tian for that very clear reply and Steve Koppes for forwarding my request to Dr. Tian!

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

Heterogeneous silicon mesostructures for lipid-supported bioelectric interfaces by Yuanwen Jiang, João L. Carvalho-de-Souza, Raymond C. S. Wong, Zhiqiang Luo, Dieter Isheim, Xiaobing Zuo, Alan W. Nicholls, Il Woong Jung, Jiping Yue, Di-Jia Liu, Yucai Wang, Vincent De Andrade, Xianghui Xiao, Luizetta Navrazhnykh, Dara E. Weiss, Xiaoyang Wu, David N. Seidman, Francisco Bezanilla, & Bozhi Tian. Nature Materials (2016)  doi:10.1038/nmat4673 Published online 27 June 2016

This paper is behind a paywall.

I gather animal testing will be the next step as they continue to develop this exciting technology. Good luck!

The body as an electronic device—adding electronics to biological tissue

What makes this particular combination of electronic s  and living tissue special is t that it was achieved in 3-D rather than 2-D.  From the Boston Children’s Hospital Aug. 26, 2012 news release on EurekAlert,

A multi-institutional research team has developed a method for embedding networks of biocompatible nanoscale wires within engineered tissues. These networks—which mark the first time that electronics and tissue have been truly merged in 3D—allow direct tissue sensing and potentially stimulation, a potential boon for development of engineered tissues that incorporate capabilities for monitoring and stimulation, and of devices for screening new drugs.

The Aug. 27, 2012 news item on Nanowerk provides more detail about integration of the cells and electronics,

Until now, the only cellular platforms that incorporated electronic sensors consisted of flat layers of cells grown on planar metal electrodes or transistors. Those two-dimensional systems do not accurately replicate natural tissue, so the research team set out to design a 3-D scaffold that could monitor electrical activity, allowing them to see how cells inside the structure would respond to specific drugs.

The researchers built their new scaffold out of epoxy, a nontoxic material that can take on a porous, 3-D structure. Silicon nanowires embedded in the scaffold carry electrical signals to and from cells grown within the structure.

“The scaffold is not just a mechanical support for cells, it contains multiple sensors. We seed cells into the scaffold and eventually it becomes a 3-D engineered tissue,” Tian says [Bozhi Tian, a former postdoc at MIT {Massachusetts Institute of Technology} and Children’s Hospital and a lead author of the paper ].

The team chose silicon nanowires for electronic sensors because they are small, stable, can be safely implanted into living tissue and are more electrically sensitive than metal electrodes. The nanowires, which range in diameter from 30 to 80 nanometers (about 1,000 times smaller than a human hair), can detect voltages less than one-thousandth of a watt, which is the level of electricity that might be seen in a cell.

Here’s more about why the researchers want to integrate living tissue and electronics, from the Harvard University Aug. 26, 2012 news release on EurekAlert,

“The current methods we have for monitoring or interacting with living systems are limited,” said Lieber [Charles M. Lieber, the Mark Hyman, Jr. Professor of Chemistry at Harvard and one of the study’s team leaders]. “We can use electrodes to measure activity in cells or tissue, but that damages them. With this technology, for the first time, we can work at the same scale as the unit of biological system without interrupting it. Ultimately, this is about merging tissue with electronics in a way that it becomes difficult to determine where the tissue ends and the electronics begin.”

The research addresses a concern that has long been associated with work on bioengineered tissue – how to create systems capable of sensing chemical or electrical changes in the tissue after it has been grown and implanted. The system might also represent a solution to researchers’ struggles in developing methods to directly stimulate engineered tissues and measure cellular reactions.

“In the body, the autonomic nervous system keeps track of pH, chemistry, oxygen and other factors, and triggers responses as needed,” Kohane [Daniel Kohane, a Harvard Medical School professor in the Department of Anesthesia at Children’s Hospital Boston and a team leader] explained. “We need to be able to mimic the kind of intrinsic feedback loops the body has evolved in order to maintain fine control at the cellular and tissue level.”

Here’s a citation and a link to the paper (which is behind a paywall),

Macroporous nanowire nanoelectronic scaffolds for synthetic tissues by Bozhi Tian, Jia Lin, Tal Dvir, Lihua Jin, Jonathan H. Tsui, Quan  Qing, Zhigang Suo, Robert Langer, Daniel S. Kohane, and Charles M. Lieber in Nature Materials (2012) doi:10.1038/nmat3404 Published onlin26 August 2012.

This is the image MIT included with its Aug 27, 2012 news release (which originated the news item on Nanowerk),

A 3-D reconstructed confocal fluorescence micrograph of a tissue scaffold.
Image: Charles M. Lieber and Daniel S. Kohane.

At this point they’re discussing therapeutic possibilities but I expect that ‘enhancement’ is also being considered although not mentioned for public consumption.