Cornell Engineers Solve a Biological Mystery and Boost Artificial Intelligence

By simulating 25,000 generations of evolution within computers, Cornell University engineering and robotics researchers have discovered why biological networks tend to be organized as modules – a finding that will lead to a deeper understanding of the evolution of complexity.

The new insight also will help evolve artificial intelligence, so robot brains can acquire the grace and cunning of animals.

From brains to gene regulatory networks, many biological entities are organized into modules – dense clusters of interconnected parts within a complex network. For decades biologists have wanted to know why humans, bacteria and other organisms evolved in a modular fashion. Like engineers, nature builds things modularly by building and combining distinct parts, but that does not explain how such modularity evolved in the first place. Renowned biologists Richard Dawkins, Günter P. Wagner, and the late Stephen Jay Gould identified the question of modularity as central to the debate over “the evolution of complexity.”

For years, the prevailing assumption was simply that modules evolved because entities that were modular could respond to change more quickly, and therefore had an adaptive advantage over their non-modular competitors. But that may not be enough to explain the origin of the phenomena.

The team discovered that evolution produces modules not because they produce more adaptable designs, but because modular designs have fewer and shorter network connections, which are costly to build and maintain. As it turned out, it was enough to include a “cost of wiring” to make evolution favor modular architectures.

This theory is detailed in “The Evolutionary Origins of Modularity,” published today in the Proceedings of the Royal Society by Hod Lipson, Cornell associate professor of mechanical and aerospace engineering; Jean-Baptiste Mouret, a robotics and computer science professor at Université Pierre et Marie Curie in Paris; and by Jeff Clune, a former visiting scientist at Cornell and currently an assistant professor of computer science at the University of Wyoming.

Editing the genome with high precision

Researchers at MIT, the Broad Institute and Rockefeller University have developed a new technique for precisely altering the genomes of living cells by adding or deleting genes. The researchers say the technology could offer an easy-to-use, less-expensive way to engineer organisms that produce biofuels; to design animal models to study human disease; and  to develop new therapies, among other potential applications.

To create their new genome-editing technique, the researchers modified a set of bacterial proteins that normally defend against viral invaders. Using this system, scientists can alter several genome sites simultaneously and can achieve much greater control over where new genes are inserted, says Feng Zhang, an assistant professor of brain and cognitive sciences at MIT and leader of the research team.

“Anything that requires engineering of an organism to put in new genes or to modify what’s in the genome will be able to benefit from this,” says Zhang, who is a core member of the Broad Institute and MIT’s McGovern Institute for Brain Research.

Zhang and his colleagues describe the new technique in the Jan. 3 online edition of Science. Lead authors of the paper are graduate students Le Cong and Ann Ran.

Early efforts

The first genetically altered mice were created in the 1980s by adding small pieces of DNA to mouse embryonic cells. This method is now widely used to create transgenic mice for the study of human disease, but, because it inserts DNA randomly in the genome, researchers can’t target the newly delivered genes to replace existing ones.

In recent years, scientists have sought more precise ways to edit the genome. One such method, known as homologous recombination, involves delivering a piece of DNA that includes the gene of interest flanked by sequences that match the genome region where the gene is to be inserted. However, this technique’s success rate is very low because the natural recombination process is rare in normal cells.

More recently, biologists discovered that they could improve the efficiency of this process by adding enzymes called nucleases, which can cut DNA. Zinc fingers are commonly used to deliver the nuclease to a specific location, but zinc finger arrays can’t target every possible sequence of DNA, limiting their usefulness. Furthermore, assembling the proteins is a labor-intensive and expensive process.

Complexes known as transcription activator-like effector nucleases (TALENs) can also cut the genome in specific locations, but these complexes can also be expensive and difficult to assemble.

Precise targeting

The new system is much more user-friendly, Zhang says. Making use of naturally occurring bacterial protein-RNA systems that recognize and snip viral DNA, the researchers can create DNA-editing complexes that include a nuclease called Cas9 bound to short RNA sequences. These sequences are designed to target specific locations in the genome; when they encounter a match, Cas9 cuts the DNA.

This approach can be used either to disrupt the function of a gene or to replace it with a new one. To replace the gene, the researchers must also add a DNA template for the new gene, which would be copied into the genome after the DNA is cut.

Each of the RNA segments can target a different sequence. “That’s the beauty of this — you can easily program a nuclease to target one or more positions in the genome,” Zhang says.

The method is also very precise — if there is a single base-pair difference between the RNA targeting sequence and the genome sequence, Cas9 is not activated. This is not the case for zinc fingers or TALEN. The new system also appears to be more efficient than TALEN, and much less expensive.

The new system “is a significant advancement in the field of genome editing and, in its first iteration, already appears comparable in efficiency to what zinc finger nucleases and TALENs have to offer,” says Aron Geurts, an associate professor of physiology at the Medical College of Wisconsin. “Deciphering the ever-increasing data emerging on genetic variation as it relates to human health and disease will require this type of scalable and precise genome editing in model systems.”

The research team has deposited the necessary genetic components with a nonprofit called Addgene, making the components widely available to other researchers who want to use the system. The researchers have also created a website with tips and tools for using this new technique.

Engineering new therapies

Among other possible applications, this system could be used to design new therapies for diseases such as Huntington’s disease, which appears to be caused by a single abnormal gene. Clinical trials that use zinc finger nucleases to disable genes are now under way, and the new technology could offer a more efficient alternative.

The system might also be useful for treating HIV by removing patients’ lymphocytes and mutating the CCR5 receptor, through which the virus enters cells. After being put back in the patient, such cells would resist infection.

This approach could also make it easier to study human disease by inducing specific mutations in human stem cells. “Using this genome editing system, you can very systematically put in individual mutations and differentiate the stem cells into neurons or cardiomyocytes and see how the mutations alter the biology of the cells,” Zhang says.

In the Science study, the researchers tested the system in cells grown in the lab, but they plan to apply the new technology to study brain function and diseases.

Experimental prosthetic leg lets amputees ‘feel’ each step

Human prosthetics have come a long way in recent decades. We’ve gone from simple plastic molds that vaguely resemble the original limb, to high-tech articulating devices that return most of a person’s mobility. Through all this progress, one nagging issue has continued to plague doctors — there’s still no way for a patient to feel a prosthetic. A new project out of UCLA might be on the path to changing that.

Having something that acts like a leg turns out to be only part of the puzzle, says UCLA grad student Zachary McKinney. When you take a step with your flesh-and-blood leg, the limb is constantly sending sensory signals back to the brain that inform you when it touches the ground, how much weight is on it, and how that weight is distributed among other things. Lacking that kind of feedback in a prosthetic causes long-term problems like uneven gait or strain on the remaining limb.

The UCLA project is not seeking to exactly replicate the sensation of having a real leg, but to provide a system that can relay the same information. The system currently consists of four sensors in the shoe of the prosthetic leg. As the subject takes a step, the system register how much pressure is on each sensor and sends that data to a small computer strapped to the user’s midsection.

The computer will analyze the data, and control the inflation of a series of small balloons on the thigh cuff. These 12 dime-sized silicon balloons are split into four sets of three, each one corresponding to one of the shoe sensors. The more pressure detected, the larger the balloons inflate. Current lag time is roughly 0.1 seconds, which is only a little slower than nerve impulses. For the patient, it is functionally instantaneous.

Results have been encouraging in initial testing. Nine subjects who had lost a leg were asked to walk across a 30-foot wide space with a normal prosthetic. After being given time to acclimate to the pressure-sensitive system, the test was run again. According to the researchers, seven distinct measurements of gait improved with the test rig.

Crawling Bio-Robot Runs on Rat Heart Cells

A new biological robot has been made from rat heart cells and synthetic materials, a new study says—and the machine could someday lead to others that will attack diseases inside the human body.

The centimeter-long “biobot" was made by attaching heart muscle cells onto a flexible structure, or body, of hydrogel—the same material used to make contact lenses for human eyes.

To make the biobot’s body, the team used a 3-D printer, which creates solid objects by laying down successive layers of soft materials that fuse together and harden.

Gathering the heart cells was a bit trickier. The researchers removed whole hearts from anesthetized newborn rats, cut the organs into tiny pieces, and then processed the fragments to loosen and separate the heart cells. The cells were then added to the robot body—each bot contains between a few thousand and a few hundred thousand.

"In a few days they start beating, and the bots start to move," explained study co-author Rashid Bashir, an engineer at the University of Illinois at Urbana-Champaign who helped develop the robot.

As the biobot’s “engine,” the heart cells’ contractions bend the machine’s body, causing it to move forward fractions of an inch per second. The biobot has two legs, one that propels it forward and another that acts as a stabilizer.

Heart cells were chosen for the biobot because they spontaneously contract, or “beat,” in time with one another, Bashir said by email.

Stanford’s touch-sensitive plastic skin heals itself

Nobody knows the remarkable properties of human skin like the researchers struggling to emulate it. Not only is our skin sensitive – sending the brain precise information about pressure and temperature – but it also heals efficiently to preserve a protective barrier against the world. Combining these two features in a single synthetic material presented an exciting challenge for Stanford chemical engineering Professor Zhenan Bao and her team.

Now, they have succeeded in making the first material that can both sense subtle pressure and heal itself when torn or cut. Their findings will be published Nov. 11 in the journal Nature Nanotechnology.

In the last decade, there have been major advances in synthetic skin, said Bao, the study’s principal investigator, but even the most effective self-healing materials had major drawbacks. Some had to be exposed to high temperatures, making them impractical for day-to-day use. Others could heal at room temperature, but repairing a cut changed their mechanical or chemical structure, so they could heal themselves only once. Most important, no self-healing material was a good bulk conductor of electricity, a crucial property.

"To interface this kind of material with the digital world, ideally you want it to be conductive," said Benjamin Chee-Keong Tee, a researcher on the project.

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Scientists Build ‘Mechanically Active’ DNA Material That Responds With Movement When Stimulated

Artificial muscles and self-propelled goo may be the stuff of Hollywood fiction, but for UC Santa Barbara scientists Omar Saleh and Deborah Fygenson, the reality of it is not that far away. By blending their areas of expertise, the pair have created a dynamic gel made of DNA that mechanically responds to stimuli in much the same way that cells do.

The results of their research were published online in the Proceedings of the National Academy of Sciences.

"This is a whole new kind of responsive gel, or what some might call a ‘smart’ material," said Saleh, associate professor of materials, affiliated with UCSB’s Biomolecular Science and Engineering program. "The gel has active mechanical capabilities in that it generates forces independently, leading to changes in elasticity or shape, when fed ATP molecules for energy — much like a living cell."

Their DNA gel, at only 10 microns in width, is roughly the size of a eukaryotic cell, the type of cell of which humans are made. The miniscule gel contains within it stiff DNA nanotubes linked together by longer, flexible DNA strands that serve as the substrate for molecular motors.

"DNA gives you a lot more design control," said Fygenson, associate professor of physics and also affiliated with UCSB’s BMSE program. "This system is exciting because we can build nano-scale filaments to specifications." Using DNA design, she said, they can control the stiffness of the nanotubes and the manner and extent of their cross-linking, which will determine how the gel responds to stimuli.

Cell Mechanism Findings Could One Day be Used to Engineer Organs

Biologists have teamed up with mechanical engineers from the The University of Texas at Dallas to conduct cell research that provides information that may one day be used to engineer organs.

The research, published online in the Proceedings of the National Academy of Sciences, sheds light on the mechanics of cell, tissue and organ formation. The research revealed basic mechanisms about how a group of bacterial cells can form large three-dimensional structures.

“If you want to create an organism, the geometry of how a group of cells self-organizes is crucial,” said Dr. Hongbing Lu, professor of mechanical engineering and holder of the Louis Beecherl Jr. Chair at UT Dallas and an author of the study. “We found that cell death leads to wrinkles, and the stiffer the cell the fewer wrinkles.”

Organ formation is the result of individual cells teaming with others. The aggregate of the cells and their environment form a thin layer of what is known as a biofilm. These biofilms form 3-D wrinkled patterns.

With his knack for knowing what stem cells want, Yoshiki Sasai has grown an eye and parts of a brain in a dish.

All it took to grow a retina, it turned out, were a few tweaks, such as a reduction in the concentration of growth factors and the addition of a standard cell-culture ingredient called Matrigel. The result closely mimics eye development in the embryo. By the sixth day in culture, the brain balls start sprouting balloon-like growths of retinal cells, which then collapse in on themselves to make the double-walled optic cups. Sasai’s team snip them off — “like taking an apple from a tree”, says Sasai — transfer them to a different culture and let them be. Two weeks later, the cups have formed all six layers of the retina, an architecture that resembles the eye of an 8-day-old mouse (which, at that age, is still blind). That the cells could drive themselves through this dramatic biomechanical process without surrounding tissues to support them stunned Sasai as much as anyone else. “When I saw it, I thought, ‘Oh my god.’ Shape, topology and size are all recapitulated,” he says. Carefully explaining the pun to come, he adds: “In English, when you are surprised, you say ‘eye-popping’ — so we really thought this was eye-popping.”

(Source: nature.com)