Synthetic Biology and Conservation Biology Meet

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Synthetic Biology and Conservation Biology Meet

Scientists Use 3-D Printer to Speed Human Embryonic Stem Cell Research

Image of human embryo stem cell droplets courtesy of Will Shu/Biofabrication

scientificamerican

By Larry Greenemeier

Every week, it seems, there’s a new breakthrough in 3-D printing that promises us the ability to (eventually) fabricate some new thing in one of those glass-walled wonder boxes. Such things have included everything from spare parts for the International Space Station above to the beef on our dinner plates to the organs inside our bodies. Although this last idea of fabricating body parts may seem the most fanciful, a team of scientists is reporting a breakthrough in 3-D printing using human embryonic stem cells that could purportedly lead to life-like bioengineered tissue and, eventually, artificial organs tailor-made for specific patients.
Researchers have been able to engineer tissue samples in the past by combining artificial scaffold-like structures and animal cells. Depositing human embryonic stem cells in cultures using a 3-D printer offers some advantages. In particular, the cells can be positioned in droplets of uniform size cheaper, faster and more easily than using manual methods. This uniformity is important for researchers trying to generate specific cell types.

Image of 3-D cell printer courtesy of Colin Hattersley

Whereas human embryonic stem cells have proved too fragile to print in the past, scientists at Scotland’s Heriot-Watt University and Roslin Cellab, a stem cell technology company, say they have developed a new technique that allowed them to deposit droplets of a consistent size containing living cells that survived the process and maintained their ability to develop into different types of mature cells. The research will be published Tuesday in the journal Biofabrication.
In the 3-D printing process, generally a nozzle resembling an inkjet deposits thin layers of resin or a polymer that hardens—either naturally or after being sintered by a laser—into a particular structure. So-called “bioprinters” naturally use cells rather than plastics to create organic structures. However, this technique can damage the printed cells, so the Heriot-Watt and Roslin Cellab scientists developed a printing system driven by pneumatic pressure and controlled by the opening and closing of a microvalve. The researchers could precisely control the amount of cells dispensed by changing the nozzle diameter, the inlet air pressure or the opening time of the valve.

The scientists acknowledge that other researchers have in the past printed mouse embryonic stem cells and even certain types of human stem cells. Human embryonic stem cells, although more sensitive to physical manipulation, can generate a wider variety of specific cell types than other forms of human stem cells. In addition, any tissue formed would yield better models of human biology than those formed from mouse cells.
The use of embryonic stem cells has been a source of controversy particularly in the United States. Last month the US Supreme Court ended an effort to shut down government support of human embryonic stem cell research by refusing to hear a case that challenged the legality of funding for the work by the National Institutes of Health (NIH). This means NIH-funded researchers can continue to work with the 195 new human embryonic stem cell lines the federal government has made available to them.
Despite the success reported by the Scottish scientists, 3-D-printed organs are still decades away from reality. Unlike the skin and muscle tissue that some researchers have successfully fabricated in the lab, solid organs such as the liver, kidney and heart require complex vascular structures that allow them to absorb nutrients and discard waste. Researchers at the University of Pennsylvania’s Tissue Microfabrication Laboratory, the Wake Forest Institute for Regenerative Medicine and elsewhere are developing methods for bioengineering functional vessels that could someday be used to ferry blood around 3-D-printed organs.
A more immediate benefit of 3-D printing embryonic stem cells might be the ability to make tissue samples that could be used to accurately test drug compounds for toxicity in humans, without the need for animal testing, according to the researchers.

Scientists Use 3-D Printer to Speed Human Embryonic Stem Cell Research

Scientists use urine to make stem cells

ReutersVideo

Scientists use urine to make stem cells

Woman with quadriplegia feeds herself chocolate using mind-controlled robot arm

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Jan Scheuermann, who has quadriplegia, brings a chocolate bar to her mouth using a robot arm she is guiding with her thoughts, while researcher Elke Brown, M.D., watches in the background (credit: UPMC)

Reaching out to “high five” someone, grasping and moving objects of different shapes and sizes, feeding herself dark chocolate.

For Jan Scheuermann and a team of researchers from the University of Pittsburgh School of Medicine and UPMC, accomplishing these seemingly ordinary tasks demonstrated for the first time that a person with longstanding quadriplegia can maneuver a mind-controlled, human-like robot arm in seven dimensions (7D) to consistently perform many of the natural and complex motions of everyday life.

In a study published in the online version of The Lancet, the researchers described the brain-computer interface (BCI) technology and training programs that allowed Ms. Scheuermann, 53, to intentionally move an arm, turn and bend a wrist, and close a hand for the first time in nine years.

Less than a year after she told the research team, “I’m going to feed myself chocolate before this is over,” Ms. Scheuermann savored its taste and announced as they applauded her feat, “One small nibble for a woman, one giant bite for BCI.”

“This is a spectacular leap toward greater function and independence for people who are unable to move their own arms,” agreed senior investigator Andrew B. Schwartz, Ph.D., professor, Department of Neurobiology, Pitt School of Medicine. “This technology, which interprets brain signals to guide a robot arm, has enormous potential that we are continuing to explore. Our study has shown us that it is technically feasible to restore ability; the participants have told us that BCI gives them hope for the future.”

On Feb. 10, 2012, after screening tests to confirm that she was eligible for the study, co-investigator and UPMC neurosurgeon Elizabeth Tyler-Kabara, M.D., Ph.D., assistant professor, Department of Neurological Surgery, Pitt School of Medicine, placed two quarter-inch square electrode grids with 96 tiny contact points each in the regions of Ms. Scheuermann’s brain that would normally control right arm and hand movement.

The electrode points pick up signals from individual neurons and computer algorithms are used to identify the firing patterns associated with particular observed or imagined movements, such as raising or lowering the arm, or turning the wrist, explained lead investigator Jennifer Collinger, Ph.D., assistant professor, Department of Physical Medicine and Rehabilitation (PM&R), and research scientist for the VA Pittsburgh Healthcare System. That intent to move is then translated into actual movement of the robot arm, which was developed by Johns Hopkins University’s Applied Physics Lab.

Two days after the operation, the team hooked up the two terminals that protrude from Ms. Scheuermann’s skull to the computer. “We could actually see the neurons fire on the computer screen when she thought about closing her hand,” Dr. Collinger said. “When she stopped, they stopped firing. So we thought, ‘This is really going to work.’”

7D control

How the neuroprosthetic system works. Two silicon-substrate microelectrode arrays surgically implanted in the motor cortex (upper right) allow recordings of ensemble neuronal activity, which are then translated into intended movement commands. This brain-derived information is conveyed to a shared controller that integrates the participant’s intent, robotic position feedback, and task-dependent constraints. Using this bioinspired brain-machine interface, the paralyzed woman could manipulate objects of various shapes and sizes in a 3D workspace. (Credit: Jennifer L Collinger et al./The Lancet)

Within a week, Ms. Scheuermann could reach in and out, left and right, and up and down with the arm, which she named Hector, giving her 3-dimensional control that had her high-fiving with the researchers. “What we did in the first week they thought we’d be stuck on for a month,” she noted.

Before three months had passed, she also could flex the wrist back and forth, move it from side to side and rotate it clockwise and counter-clockwise, as well as grip objects, adding up to what scientists call 7D control.

In a study task called the Action Research Arm Test, Ms. Scheuermann guided the arm from a position four inches above a table to pick up blocks and tubes of different sizes, a ball and a stone and put them down on a nearby tray. She also picked up cones from one base to restack them on another a foot away, another task requiring grasping, transporting and positioning of objects with precision.

“Our findings indicate that by a variety of measures, she was able to improve her performance consistently over many days,” Dr. Schwartz explained. “The training methods and algorithms that we used in monkey models of this technology also worked for Jan, suggesting that it’s possible for people with long-term paralysis to recover natural, intuitive command signals to orient a prosthetic hand and arm to allow meaningful interaction with the environment.”

Electrocortigraphy (ECoG) study

In a separate study, researchers also continue to study BCI technology that uses an electrocortigraphy (ECoG) grid, which sits on the surface of the brain rather than slightly penetrates the tissue as in the case of the grids used for Ms. Scheuermann.

In both studies, “we’re recording electrical activity in the brain, and the goal is to try to decode what that activity means and then use that code to control an arm,” said senior investigator Michael Boninger, M.D., professor and chair, PM&R, and director of UPMC Rehabilitation Institute. “We are learning so much about how the brain controls motor activity, thanks to the hard work and dedication of our trial participants. Perhaps in five to 10 years, we will have a device that can be used in the day-to-day lives of people who are not able to use their own arms.”

The next step for BCI technology will likely use a two-way electrode system that can not only capture the intention to move, but in addition, will stimulate the brain to generate sensation, potentially allowing a user to adjust grip strength to firmly grasp a doorknob or gently cradle an egg.

After that, “we’re hoping this can become a fully implanted, wireless system that people can actually use in their homes without our supervision,” Dr. Collinger said. “It might even be possible to combine brain control with a device that directly stimulates muscles to restore movement of the individual’s own limb.”

For now, Ms. Scheuermann is expected to continue to put the BCI technology through its paces for two more months, and then the implants will be removed in another operation.

“This is the ride of my life,” she said. “This is the rollercoaster. This is skydiving. It’s just fabulous, and I’m enjoying every second of it.”

The BCI projects are funded by the Defense Advanced Research Projects Agency, National Institutes of Health, the U.S. Department of Veteran’s Affairs, the UPMC Rehabilitation Institute and the University of Pittsburgh Clinical and Translational Science Institute.

For more information about participating in the trials, call 412-383-1355.

How this compares to previous studies

The results of previous work have shown that neural activity can be recorded from the motor cortex and translated to movement of an external device or the individual’s own muscles, the authors say. However, until now, the results of human studies have not shown whether the natural and complex movements can be done consistently for different tasks.

“Here, we have shown that a person with chronic tetraplegia can do complex and coordinated movements freely in seven-dimensional space consistently over several weeks of testing. This study is different from previous studies in which investigators had little control in translation dimensions, used staged control schemes, or had insufficient workspace to complete very structured tasks.

“Increasing dimensional control allows our participant to fully explore the workspace by placing the hand in the desired three-dimensional location and orienting the palm in three dimensions. This study is the first time that performance has been quantified with functional clinical assessments. Although in most human studies only a few days of performance data were reported, we have shown that the participant learned to improve her performance consistently over many days using different metrics.

“By using training methods and algorithms validated in non-human primate work, individuals with long-term paralysis can recover the natural and intuitive command signals for hand placement, orientation, and reaching to move freely in space and interact with the environment.”

Woman with quadriplegia feeds herself chocolate using mind-controlled robot arm

Rise of the Molecular Machines

Foresight Institute/—James Lewis, PhD

The RSC web site features an article on molecular machines written by Josh Howgego that gives a very good brief introduction to the topic: Rise of the molecular machines. A downloadable PDF of the article as it originally appeared in Education in Chemistry provides better images of the figures than does the HTML version. The article explains how chemists have worked to mimic the function of biological molecular machine like muscles, by using intermolecular forces to control movements of mechanically interlocked molecules. The first example given is from the work of Fraser Stoddart, winner of the 2007 Feynman Prizes in Nanotechnology for Experimental work and Co-Chair of the January 2013 Foresight Technical Conference: Illuminating Atomic Precision, which will feature a session on “Molecular Machines and Non-Equilibrium Processes,” which Prof. Stoddart will chair. The article goes on to explain that harnessing simple molecular shuttles of the type pioneered by Stoddart to do real work like muscles has proved difficult, and cites as a prototype solution a molecular machine that works in a different way: a walker that sequentially makes and breaks different types of covalent bonds, developed by David Leigh, winner of the 2007 Feynman Prizes in Nanotechnology in the Theory category. The article finishes with a description of a nanocar developed by Ben Feringa that uses electricity to move across a metal surface by rotating paddle-like wheels.

Rise of the Molecular Machines

New genetic clues to 4 types of breast cancer found

NBC/

NEW YORK — Scientists reported Sunday that they have completed a major analysis of the genetics of breast cancer, finding four major classes of the disease. They hope their work will lead to more effective treatments, perhaps with some drugs already in use.

The new finding offers hints that one type of breast cancer might be vulnerable to drugs that already work against ovarian cancer.

The study, published online Sunday by the journal Nature, is the latest example of research into the biological details of tumors, rather than focusing primarily on where cancer arises in the body.

The hope is that such research can reveal cancer's genetic weaknesses for better drug targeting.

"With this study, we're one giant step closer to understanding the genetic origins of the four major subtypes of breast cancer," Dr. Matthew Ellis of the Washington University School of Medicine said in a statement. He is a co-leader of the research.

"Now we can investigate which drugs work best for patients based on the genetic profiles of their tumors," he said.

The researchers analyzed DNA of breast cancer tumors from 825 patients, looking for abnormalities. Altogether, they reported, breast cancers appear to fall into four main classes when viewed in this way.

One class showed similarities to ovarian cancers, suggesting it may be driven by similar biological developments.

"It's clear they are genetically more similar to ovarian tumors than to other breast cancers," Ellis said. "Whether they can be treated the same way is an intriguing possibility that needs to be explored."

The report is the latest from the Cancer Genome Atlas, a federally funded project that has produced similar analyses for brain, colorectal, lung, and ovarian cancers.

New genetic clues to 4 types of breast cancer found

New DNA project shows us living beyond our genes

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