Researchers Aim to Use Light—Not Electric Jolts—to Restore Healthy Heartbeats

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When a beating heart slips into an irregular, life-threatening rhythm, the treatment is well known: deliver a burst of electric current from a pacemaker or defibrillator.

But because the electricity itself can cause pain, tissue damage and other serious side-effects, a Johns Hopkins-led research team wants to replace these jolts with a kinder, gentler remedy: light.

In a paper published Aug. 28 in the online journal Nature Communications, five biomedical engineers from Johns Hopkins and Stony Brook universities described their plan to use biological lab data and an intricate computer model to devise a better way to heal ailing hearts. Other scientists are already using light-sensitive cells to control certain activities in the brain. The Johns Hopkins-Stony Brook researchers say they plan to give this technique a cardiac twist so that doctors in the near future will be able to use low-energy light to solve serious heart problems such as arrhythmia.

“Applying electricity to the heart has its drawbacks,” said the project’s supervisor, Natalia Trayanova, the Murray B. Sachs Professor of Biomedical Engineering at Johns Hopkins. “When we use a defibrillator, it’s like blasting open a door because we don’t have the key. It applies too much force and too little finesse. We want to control this treatment in a more intelligent way. We think it’s possible to use light to reshape the behavior of the heart without blasting it.”

To achieve this, Trayanova’s team is diving into the field of optogenetics, which is only about a decade old. Pioneered by scientists at Stanford, optogenetics refers to the insertion of light-responsive proteins called opsins into cells. When exposed to light, these proteins become tiny portals within the target cells, allowing a stream of ions—an electric charge—to pass through. Early researchers have begun using this tactic to control the bioelectric behavior of certain brain cells, forming a first step toward treating psychiatric disorders with light.

In the Nature Communications paper, the researchers reported that they had successfully tested this same technique on a heart—one that “beats” inside a computer. Trayanova has spent many years developing highly detailed computer models of the heart that can simulate cardiac behavior from the molecular and cellular levels all the way up to that of the heart as a whole. At Johns Hopkins, she directs the Computational Cardiology Lab within the Institute for Computational Medicine.

As detailed in the journal article, the Johns Hopkins computer model for treating the heart with light incorporates biological data from the Stony Brook lab of Emilia Entcheva, an associate professor of biomedical engineering. The Stony Brook collaborators are working on techniques to make heart tissue light-sensitive by inserting opsins into some cells. They also will test how these cells respond when illuminated. “Experiments from this lab generated the data we used to build our computer model for this project,” Trayanova said. “As the Stony Brook lab generates new data, we will use it to refine our model.”

In Trayanova’s own lab, her team members will use this model to conduct virtual experiments. They will try to determine how to position and control the light-sensitive cells to help the heart maintain a healthy rhythm and pumping activity. They will also try to gauge how much light is needed to activate the healing process. The overall goal is to use the computer model to push the research closer to the day when doctors can begin treating their heart patients with gentle light beams. The researchers say it could happen within a decade.

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Johns Hopkins Team Deploys Hundreds of Tiny Untethered Surgical Tools in First Animal Biopsies

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A step toward the ultimate goal of making surgical procedures noninvasive

By using swarms of untethered grippers, each as small as a speck of dust, Johns Hopkins engineers and physicians say they have devised a new way to perform biopsies that could provide a more effective way to access narrow conduits in the body as well as find early signs of cancer or other diseases.

In two recent peer-reviewed journal articles, the team reported successful animal testing of the tiny tools, which require no batteries, wires or tethers as they seize internal tissue samples. The devices are called “mu-grippers,” incorporating the Greek letter that represents the term for “micro.” Instead of relying on electric or pneumatic power, these star-shaped tools are autonomously activated by the body’s heat, which causes their tiny “fingers” to close on clusters of cells. Because the tools also contain a magnetic material, they can be retrieved through an existing body opening via a magnetic catheter.

In the April print edition ofGastroenterology, the researchers described their use of the mu-grippers to collect cells from the colon and esophagus of a pig, which was selected because its intestinal tract is similar to that of humans. Earlier this year, the team members reported in the journal Advanced Materialsthat they had successfully inserted the mu-grippers through the mouth and stomach of a live animal and released them in a hard-to-access place, the bile duct, from which they obtained tissue samples.

“This is the first time that anyone has used a sub-millimeter-sized device—the size of  a dust particle—to conduct a biopsy in a live animal,” said David Gracias, an associate professor of chemical and biomolecular engineering whose lab team developed the microgrippers. “That’s a significant accomplishment. And because we can send the grippers in through natural orifices, it is an important advance in minimally invasive treatment and a step toward the ultimate goal of making surgical procedures noninvasive.”

Another member of the research team, physician Florin M. Selaru of the Johns Hopkins School of Medicine, said the mu-grippers could lead to an entirely new approach to conducting biopsies, which are considered the “gold standard” test for diagnosing cancer and other diseases.

The advantage of the mu-grippers, he said, is that they could collect far more samples from many more locations. He pointed out that the much larger forceps used during a typical colonoscopy may remove 30 to 40 pieces of tissue to be studied for signs of cancer. But despite a doctor’s best intentions, the small number of specimens makes it easy to miss diseased lesions.

“What’s the likelihood of finding the needle in the haystack?” said Selaru, an assistant professor in the Division of Gastroenterology and Hepatology. “Based on a small sample, you can’t always draw accurate inferences. We need to be able to do a larger statistical sampling of the tissue. That’s what would give us enough statistical power to draw a conclusion, which, in essence, is what we’re trying to do with the microgrippers. We could deploy hundreds or even thousands of these grippers to get more samples and a better idea of what kind of or whether a disease is present.

Although each mu-gripper can grab a much smaller tissue sample than larger biopsy tools, the researchers said each gripper can retrieve enough cells for effective microscopic inspection and genetic analysis. Armed with this information, they said, the patient’s physician could be better prepared to diagnose and treat the patient.

This approach would be possible through the latest application of the Gracias lab’s self-assembling tiny surgical tools, which can be activated by heat or chemicals, without relying on electrical wires, tubes, batteries or tethers. The low-cost devices are fabricated through photolithography, the same process used to make computer chips. Their fingerlike projections are made of materials that would normally curl inward, but the team adds a polymer resin to give the joints rigidity and to keep the digits from closing.

Prior to a biopsy, the grippers are kept on ice, so that the fingers remain in this extended position. An endoscopy tool then is used to insert hundreds of grippers into the area targeted for a biopsy. Within about five minutes, the warmth of the body causes the polymer coating to soften, and the fingers curl inward to grasp some tissue. A magnetic tool is then inserted to retrieve them.

Although the animal testing results are promising, the researchers said the process will require further refinement before human testing can begin. “The next step is improving how we deploy the grippers,” Selaru said. “The concept is sound, but we still need to address some of the details. The other thing we need to do is thorough safety studies.”

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Computational Medicine Begins to Enhance the Way Doctors Detect and Treat Disease

Many challenges must still be overcome before computational medicine becomes a routine part of patient care

Computational medicine, a fast-growing method of using computer models and sophisticated software to figure out how disease develops–and how to thwart it–has begun to leap off the drawing board and land in the hands of doctors who treat patients for heart ailments, cancer and other illnesses. Using digital tools, researchers have begun to use experimental and clinical data to build models that can unravel complex medical mysteries.

These are some of the conclusions of a new review of the field published in the Oct. 31 issue of the journal Science Translational Medicine. The article, “Computational Medicine: Translating Models to Clinical Care,” was written by four Johns Hopkins professors affiliated with the university’s Institute for Computational Medicine.

The institute was launched in 2005 as collaboration between the university’s Whiting School of Engineering and its School of Medicine. The goal was to use powerful computers to analyze and mathematically model disease mechanisms. The results were to be used to help predict who is at risk of developing a disease and to determine how to treat it more effectively.

In recent years, “The field has exploded. There is a whole new community of people being trained in mathematics, computer science and engineering, and they are being cross-trained in biology,” said institute director Raimond Winslow. “This allows them to bring a whole new perspective to medical diagnosis and treatment. Engineers traditionally construct models of the systems they are designing. In our case, we’re building computational models of what we trying to study, which is disease.”

Looking at disease through the lens of traditional biology is like trying to assemble a very complex jigsaw puzzle with a huge number of pieces, he said. The result can be a very incomplete picture. “Computational medicine can help you see how the pieces of the puzzle fit together to give a more holistic picture,” Winslow said. “We may never have all of the missing pieces, but we’ll wind up with a much clearer view of what causes disease and how to treat it.”

Biology in both health and disease is very complex, Winslow added. It involves the feed-forward flow of information from the level of the gene to protein, networks, cells, organs and organ systems. This is already complex, he said, and to make matters even more difficult, it also involves feed-back pathways by which, for example, proteins, mechanical forces at the level of tissues and organs, and environmental factors regulate function at lower levels such as the gene.

Computational models, Winslow said, help us to understand these complex interactions, the nature of which is often highly complex and non-intuitive. Models like these allow researchers to understand disease mechanisms, aid in diagnosis, and test the effectiveness of different therapies. By using computer models, he said, potential therapies can be tested “In Silico” at high speed.  The results can then be used to guide further experiments to gather new data to refine the models until they are highly predictive.

“Our intent in writing this journal article was to open the eyes of physicians and medical researchers who are unfamiliar with the field of computational medicine,” said Winslow, who is first author of the Science Translational Medicine overview. He also wanted to describe examples of computational medicine that are making their way out of research labs and into clinics where patients are being treated. “This transition,” he said, “is already under way.”

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