Dieting Device Tricks Brain into Feeling Full

In mid-January a novel obesity treatment surfaced in the public market. There are no constricting bands or rerouted intestines; the device hinges on the “feeling” of hunger—or lack thereof. Recently green-lighted by the FDA, the device, called the Maestro Rechargeable System, uses a pacemaker-like approach to curb appetite. It targets part of the body called the vagus nerve, which controls a handful of vital human functions, like heartbeat and breathing. But Entero Medics, producer of the device, focuses on its role as the hunger nerve, capitalizing on its ability to regulate brain-body satiety.

Doctors and researchers working with the Maestro System promote it as a new, safe and effective option in treating obesity. And though it’s an intriguing prospect, some clinicians grapple with the device’s feasibility as a practical option for most obese patients. For some, the sheer novelty is enough to be wary, but most concerns center on a hefty price tag and a modest weight loss.

But regardless of the system’s future, it’s the first FDA-approved obesity device since 2007 and a positive step in advancing obesity treatment and technology. Since the American Medical Association officially declared obesity a disease in 2013, researchers and patients are increasingly treating it as such, rather than a lack of self-restraint.

“It’s like having high blood pressure. You don’t blame somebody for having high blood pressure, you treat it,” says Susan Fried, Professor of Endocrinology, Diabetes and Nutrition at Boston University’s School of Medicine. “But we do blame people for being obese. I think people mistakenly assume it’s all environment since we can’t find one gene that’s responsible for obesity, and that’s not true.”

The Maestro Rechargeable System treats obesity with a surgically implanted chip paired with a battery pack and coiled portable charger. After a full charge, the device’s power lasts 2-3 days—which is more than most can say for their cell phones. But it’s the patient’s responsibility to keep a full charge as long as they have the device, which potentially, is the rest of their life.

Upon implantation, surgeons suture the device’s electrodes in a specific region of the lower abdomen, isolating the portion of the vagus nerve that innervates the stomach. These electrodes periodically send impulses into the nerve and block the signal from the stomach to the brain that causes the “hungry” sensation, hoodwinking the body into thinking that it’s full.

This electrical strategy is known as VBLOC therapy (vagal blocking therapy), and though stimulating the vagus nerve to improve health isn’t a new concept, doctors don’t fully understand how these electrical pulses stop vagal communication. They do, however, know that complete blockage of the vagus nerve is ineffective. Other mechanisms in the body recognize the loss of appetite signal and attempt to compensate for the deadpan nerve. That’s why the device works in pulses instead of one giant electrical blockade.

But the pulses aren’t the same for everyone—every patient has a different pulse-to-weight-loss ratio, and the trick is striking the right balance. During the clinical trials, doctors monitored patients’ weight loss closely, tailoring millivolts to best elicit feelings of fullness.

“The pulses aren’t random. They’re dependent on the patient,” says Dr. Caroline Apovian, Director of Nutrition and Weight Management Center at Boston Medical Center. “Patients follow up with their doctors to hit the sweet spot of pulse generation,” she adds. After doctors insert the device, they tune each patient’s electrical impulses based on how hungry they feel. Descriptors vary, but doctors monitor patients for feelings of fullness, pressure and heartburn to gauge satiety.

Under the umbrella of bariatric surgery, the Maestro Rechargeable System is the safest, but is most modest in weight loss. Over a one year period in a clinical trial called ReCharge, patients with the device lost an average of 9.6% of their total body weight. For contrast, the gastric bypass, currently the “gold standard” of bariatric procedures, stands out for its dramatic weight loss effects—around 33% of total body weight. But in terms of safety and post-surgery complications, the Maestro System is the better option.

“This surgery is quite possibly the safest thing we have right now,” says Dr. Sanjani Shah, Assistant Professor of Surgery at Tufts University School of Medicine. “It’s completely reversible—we’re not cutting or pasting anything. There’s nothing being rerouted.”

During the ReCharge trial, less than 4% of the 233 patients enrolled experienced severe problems ending in re-hospitalization or removal of the device. For the most part, patients who did report side effects complained of moderate ailments like bloating, nausea or upset stomach. But for some, like local Boston patient, Mike Magnant, the device seems virtually flawless.

“I’ve not been nauseous, no headaches, never felt dizzy. I don’t have any restrictions on what I can eat,” Mike says.

After hearing an ad for the Maestro System on the radio, Mike enrolled in Entero Medics’ first clinical trial. He fit the criteria: between 18 and 65 years old, unsuccessful long-term weight loss in other structured programs, and a Body Mass Index between 35 and 45 kg/m2 (between 260 and 330 lbs for a 6-foot male adult). After having the device for three years, Mike says he wouldn’t give it back even if the FDA hadn’t approved it.

“To lose 70 pounds and not gain it back? There are so many benefits to losing that weight, and to me, the best part is keeping the weight off,” he says. “This is forever for me.”

The patients from the Maestro System’s clinical trials have, on average, maintained the weight lost. But the trials are still in relatively early stages, and only time can tell if the system will prove effective over a lifetime.

While Mike’s experience is successful, it’s not necessarily representative of all patients with the device. Some doctors speculate that VBLOC therapy may be more of a fad than an emerging go-to in obesity treatment. Dr. Lee Kaplan, Associate Professor of Medicine at Harvard and Director of the Massachusetts General Hospital Weight Center, puts it in perspective when he points out the patient-to-patient variation that inevitably comes with any disease treatment. In this case, patients that receive the device have no way to tell if their weight loss will be above, below, or on par with the average.

“What we really need is a parameter predicting how well the person may do with the device, but as of now we have no evidence for that,” says Dr. Kaplan. “So the question is, ‘Is it the best idea to use this device, which requires surgery?’ I think it’s going to be a hard sell, given the cost.”

Though Entero Medics hasn’t landed on a price or whether insurance will cover part or all of the cost, speculative prices hover around $15,000-$30,000. In considering the device’s relatively slight results, some patients may find it too expensive. But Entero Medics highlights the safety and sustainability of weight loss as key players in their future push to market.

Currently, doctors and researchers are continuing to follow patients with the device in a five-year, post FDA-approved study to monitor sustained and continued weight loss and any complications that may surface.

Looking forward, Dr. Shah hopes the Maestro Rechargeable System continues to gain attention from the public as an option for obesity treatment. “I’d be really happy if it got out in the public eye and patients understand the option—to say hey, this is a great other option if you’re considering surgery in morbid obesity.”

Fluorescent Tumors - Cutting on the Glowing Line

For decades cancer surgeons have had two tools with which to guide their scalpel: their hands and their eyes. Surgical tumor removal is the cornerstone of many cancer therapies, but in 20-50% of patients, microscopic scraps of cancerous tissue are accidentally left behind, and eventually, the tumors return. During surgery, it’s been virtually impossible to know if the entire tumor has been removed — until now.

Recent clinical research at the University of Pennsylvania is zeroing in on a technique that allows surgeons to more precisely define the boundary between cancerous and noncancerous tissue by making tumors fluoresce.

Before surgery, doctors inject a dye into the bloodstream, known as indocyanine green, or ICG, and wait about 24 hours for the dye to accumulate within the tumor. Because tumors grow so quickly, they stretch and develop “leaky walls,” allowing ICG to infiltrate and collect in the tumor. After the dye seeps into the tumors, doctors use a near infrared, or NIR, imaging system to image the cancerous tissue, which glows green on the surgeon’s computer screen. This fluorescence allows surgeons to remove tumors more accurately and helps limit the traces of post-surgery cancer.

The study, led by Dr. Sunil Singhal and David Holt, and surgical professor at UPENN, was published in PLOS ONE.

After researching the fluorescence methods in mice and dogs, five patients in a clinical trial were treated using ICG and the NIR imaging system. In all five cases, the tumors fluoresced onscreen, showing the efficacy of this technique in humans. In one of the four patients, the tumor seemed to be located clearly in one part of the lung; the rest of the lung looked and felt normal according to doctors and pre-surgical tumor scans. But under NIR light, parts of the lung still fluoresced.

“We initially thought there was a problem with our machine,” said Holt. “But it turns out, that patient had diffuse microscopic cancer.” Confirmed by biopsy, the patient received proper treatment and survived.

But there are still a few issues to work out. The ICG-NIR imaging technique was unable to distinguish between noncancerous inflamed tissue and cancerous tumors. If normal tissues are inflamed, chances are they also have leaky vessels, allowing dye to collect, just as it collects in tumors. In future research, Holt hopes that tumor-specific dyes can be used to differentiate and avoid confusion between noncancerous inflamed tissue and cancer.

Map My Brain

With every smell, memory, or flicker of emotion, tangled pathways of electrical activity light up in our brains and process the information, creating a concise impression of a world photoshopped by our neurons.

But these neuronal pathways don’t line up in a simple, linear transfer of information — there are trillions of synapses, and only recently have researchers really begun to dive into the extensive connections.

Each circuit is an intricate wiring of neurons that transmits signals through an electrical patchwork. Ultimately, every human function comes down to these “wiring diagrams” — maps of specific neuron connections that promote proper brain function.

Neuroscience is starting to move away from more traditional studies, like that of neuron structure or general functions in areas of the brain, and is shifting toward tracking connectivity. Scientists are trying to fill in the middle ground, to untangle the brain’s highly complex neural circuitry, and ultimately lay it out in a decipherable map.

Researchers are tweaking their techniques, incorporating elements of bioengineering and computational optics to expand the realm in which they can study the neuron and its connections in the brain. Some researchers have adapted Nobel-prize winning super resolution microscopy to scrutinize tiny details of neurons that were previously undistinguishable. Scientists hope that eventually these techniques can compile a new foundation for understanding cognition and mental health.

“Figuring out how the neurons come together to make these circuits is a big, rapidly advancing area of neuroscience today,” says Joshua Sanes, Harvard professor and researcher at Harvard’s Center for Brain Science. “Our motivations come from the fact that [neurons] underlay all brain activities, and that there are some psychiatric diseases that are suspected to occur through mis-wirings in the brain.”

In 2007, Sanes helped neuroscience reach a colorful breakthrough. Jeff W. Lichtman, Harvard professor of neuroscience and researcher at Harvard’s Center for Brain Science, and Sane’s research teams developed a technique known as Brainbow, a part of the Center’s Connectome Project.

Meant to tease apart the long tracks of neurons in the brain, the Brainbow method individually labels neurons with fluorescent proteins. These proteins express up to 100 different colors at a time, bringing colorful order to what was once an indiscriminate glob of neurons.

Sanes compares it to the wirings of a computer. All of the wires need to be accounted for and correctly connected, especially the ones involved in complicated circuits. Neurons are a lot like that, there are long “wires” that come from the bodies of neurons called axons and dendrites, and they hook up with other neurons to make precise patterns of connectivity. But if the wires aren’t correctly connected, the neural message gets distorted and can lead to mental deterioration.

“Having the wires in different colors lets you trace them and see where they go,” says Sanes. Currently, he and other scientists are building off of this colorful map to develop other research techniques that help chart connections in the brain.

Outside of the Connectome Project, other researchers at Harvard like Adam Cohen, professor of chemical biology and physics, and Venkatesh Murthy, professor of molecular and cellular biology, are using stimulation techniques to activate neurons and study their response in real time. Cohen has engineered a technique in which the neuron itself is able to make a protein that lights up to indicate electrical activity, and this light can then propagate through circuits of up to 100 neurons.

“The particular trick that Adam Cohen’s lab did is a phenomenally rational and beautiful design,” says Murthy. “It’s one of the best forms of this type of indicator.”

The light-up protein is called “Optopatch” and when engineered to a neuron, can be stimulated by a particular kind of light. This light activates the electrical impulse, and researchers can watch as Optopatch’s red glow fluoresces outwards, highlighting the signal’s path.

Murthy hopes to use this light-up pathway to help track neurons and even map the neural counterparts of particular smells.

While Murthy and Sanes aim to decipher larger neural circuits in the brain, researchers like Jan Tonnesson, at the University of Bordeaux, are taking a more detailed approach, zooming in on intricacies of the neuron that, until recently, have never been seen before. Tonnesson and his colleagues have applied the Nobel-prize winning microscopy technique called STED, more commonly known as super resolution microscopy, to study tiny details of the neuron — specifically, miniscule spines that extend from one neuron to the next, making the synapses that create the connections Sanes and Murthy are interested in studying.

“It opens up a completely new world for us,” says Tonnesson.

Super resolution microscopy allows researchers to clearly see images up to four times smaller than other microscopy techniques, and Tonnesson is taking advantage of that, exploring the microcosms of single neurons.

He and his colleagues at the University of Bordeaux stimulate each spine as if by another neuron and use the super resolution to gather data on how each spine responds individually to the contact. A single neuron may have thousands of spines, and while each spine is independently contacted, the total stimulation is what elicits a signal down the neuron, potentially propagating a circuit.

Tonnesson recognizes that, while super resolution is new to neuroscience, it offers a new angle in analyzing neurons and how neuronal structures may affect proper signal sending.

“We should treat a lot of this as on-going, moment-to-moment innovation,” says Murthy. “None of this is the final product, and I think part of the excitement is simply that we’re seeing what is possible. Sure, there are specific things that we are discovering now, but they’re opening doors to many more things in the upcoming decades.”

Accelerator Physicist Invents New Way to Clean Up Oil Spills

Four years ago, Fermilab accelerator physicist Arden Warner watched national news of the BP oil spill and found himself frustrated with the cleanup response.

"My wife asked 'Can you separate oil from water?' and I said 'Maybe I could magnetize it!'" Warner recalled. "But that was just something I said. Later that night while I was falling asleep, I thought, you know what, that's not a bad idea."

Sleep forgone, Warner began experimenting in his garage. With shavings from his shovel, a splash of engine oil and a refrigerator magnet, Warner witnessed the preliminary success of a concept that could revolutionize the process of oil spill damage control.

Warner has received patent approval on the cleanup method.

The concept is simple: Take iron particles or magnetite dust and add them to oil. It turns out that these particles mix well with oil and form a loose colloidal suspension that floats in water. Mixed with the filings, the suspension is susceptible to magnetic forces. At a barely discernible 2 to 6 microns in size, the particles tend to clump together, and it only takes a sparse dusting for them to bond with the oil. When a magnetic field is applied to the oil and filings, they congeal into a viscous liquid known as a magnetorheological fluid. The fluid's viscosity allows a magnetic field to pool both filings and oil to a single location, making them easy to remove. (View a 30-second video of the reaction.)

"It doesn't take long — you add the filings, you pull them out. The entire process is even more efficient with hydrophobic filings. As soon as they hit the oil, they sink in," said Warner, who works in the Accelerator Division. Hydrophobic filings are those that don't like to interact with water — think of hydrophobic as water-fearing. "You could essentially have a device that disperses filings and a magnetic conveyor system behind it that picks it up. You don't need a lot of material."

Warner tested more than 100 oils, including sweet crude and heavy crude. As it turns out, the crude oils' natural viscosity makes it fairly easy to magnetize and clear away. Currently, booms, floating devices that corral oil spills, are at best capable of containing the spill; oil removal is an entirely different process. But the iron filings can work in conjunction with an electromagnetic boom to allow tighter constriction and removal of the oil. Using solenoids, metal coils that carry an electrical current, the electromagnetic booms can steer the oil-filing mixture into collector tanks.

Unlike other oil cleanup methods, the magnetized oil technique is far more environmentally sound. There are no harmful chemicals introduced into the ocean — magnetite is a naturally occurring mineral. The filings are added and, briefly after, extracted. While there are some straggling iron particles, the vast majority is removed in one fell, magnetized swoop — the filings can even be dried and reused.

"This technique is more environmentally benign because it's natural; we're not adding soaps and chemicals to the ocean," said Cherri Schmidt, head of Fermilab's Office of Partnerships and Technology Transfer. "Other 'cleanup' techniques disperse the oil and make the droplets smaller or make the oil sink to the bottom. This doesn't do that."

Warner's ideas for potential applications also include wildlife cleanup and the use of chemical sensors. Small devices that "smell" high and low concentrations of oil could be fastened to a motorized electromagnetic boom to direct it to the most oil-contaminated areas.

"I get crazy ideas all the time, but every so often one sticks," Warner said. "This is one that I think could stick for the benefit of the environment and Fermilab."

[This article was written for Fermilab Today: http://www.fnal.gov/pub/today/] 

Epigenetics in the Fight against Cancer

All of biology lives and dies by four letters: A, T, C, and G — the components of DNA. Our functions and physicalities, our organs, blood and bones, all reduce to this one cardinal script.

But in this intricate system, even the smallest changes can trigger genetic disaster. Until recently, doctors and researchers focused on small, permanent changes, called mutations, in the DNA sequence as the main instigator of some diseases, like cancer. But researchers are finding that many illnesses arise from more than just genetic mishaps. They’re finding that changes on the surface of the DNA, rather than in the DNA sequence itself, increasingly affect the onset and subsequent treatment of the disease.

The idea of DNA surface changes has sparked a discussion about the very way scientists study cancer, leading one researcher to ask a novel, yet critical question: Is there an off button?

The emerging field is known as epigenetics. Epi (meaning over, outside of, or around) indicates that the modifications to the DNA do not take place in the sequence itself, but rather, as additions to chromosomes (compacted molecular sticks that contain DNA) or the proteins that help make them.

Epigenetics research is based in the idea that what we breathe, eat, or are simply exposed to can reprogram gene expression and change how physical traits manifest in our bodies. It’s not exactly “you are what you eat,” but researchers have made strong, and in some cases undeniable, connections between environment and disease. The link between smoking and lung cancer is a prime example: smoking not only changes the sequence of DNA itself, but also makes changes outside the DNA that influence how it’s expressed in the lung, which contributes to uncontrolled cell growth and tumors.

“Traditionally, most researchers look at the genetic effects and only treat the symptoms of the mutation,” says Liang Gangning, associate professor of research at the University of Southern California’s Keck School of Medicine. But treating the symptoms doesn’t necessarily treat the cause, he says.

Sibaji Sarkar, an instructor at Boston University’s School of Medicine, centers his research on exactly that idea, focusing on two main epigenetic changes that he thinks are linked to cancer onset and relapse. Both involve chemical additions that alter large scale DNA expression. Once bonded to the chromosome or protein, the chemical acts as a switch that shifts how the DNA gets expressed as physical characteristics.

Part of Sarkar’s research explores the concept that cancer mimics a natural process in our bodies called epigenetic differentiation. Though it sounds daunting, this process is a normal, and vital, part of how humans develop various tissue types. The lungs and liver, for example, comprise cells that all contain the exact same DNA, yet carry out two different functions. Different snippets of DNA called genes regulate different parts of the body, based on their activation patterns. For example, the genes that control lung function are active in the lungs, but not the liver, and the genes that control liver function are active in the liver, but not the lungs. It’s the changes outside the DNA sequence that control activation of these genes. Sarkar thinks this process mirrors how normal cells get changed, or activated, into cancerous ones.

Of course, epigenetic changes alone don’t cause cancer. Cancer progression is an enormously complex mechanism involving both DNA mutation and epigenetic changes. On the genetic side, if the DNA sequence becomes mutated, it sends out a message that’s inconsistent with the original molecular blueprint. RNA, DNA’s sister molecule, translates the DNA’s message into proteins, but if the DNA is mutated the proteins come out defective.

Sarkar compares the mutation process to the rankings of the military. He compares the DNA to a general who devises a strategy, the RNA to the lieutenant who relays the message, and proteins to the troops that fight and do the actual work. But mutated DNA compromises the genetic strategy, skewing the message, which leaves the protein troops unable to properly do their job. Depending on the protein, that means uncontrolled cell growth.

Flawed DNA, however, is only part of what causes cancer. On the epigenetic side, a process that adds chemicals to the DNA, known as methylation, attracts the most attention. During methylation, a string of carbons binds onto a section of DNA and prevents the cell from reading the gene’s instructions. Our cells contain genes called “tumor suppressors” which control cell growth. But methylation of the tumor suppressor gene interferes with its purpose. As a result, cells grow more than they should, which can lead to tumors.

Depending on what region of the DNA it affects, methylation can elicit a huge range of responses. But these changes aren’t necessarily permanent: the carbons can detach from the DNA naturally. This reversibility gives researchers like Sarkar and Gangning a new angle in developing drugs for cancer. These drugs aim to reverse or stop the methylation from impeding the proper function of the cancer-fighting genes by binding to and blocking the site on which methyl groups dock. In May 2014, Sarkar suggested the possibility of a cancer “on-off switch,” the idea that, if demethylated, silenced tumor suppressor genes could turn on again and stop tumor growth, and even future relapse.

Four months later, Gangning and his colleagues found that an epigenetic drug, called 5-Aza-CdR, did indeed reactivate some tumor suppressor genes by removing the methylation. Without the suppressive methylation, the genes can recover its original purpose—suppressing tumors.

Epigenetics and cancer researchers like Sarkar and Gangning don’t aim to replace radiation and chemotherapy with epigenetic drugs. They see it as a supplement. The epigenetic drugs work synergistically to increase potency of the traditional treatments and decrease the rate of relapse.

“These epigenetic drugs are fine adjustments to the treatments we have currently — fine but extremely important,” says Sarkar.

The FDA approved a handful of epigenetic drugs for some end-stage cancer therapies. But the drugs are not yet widespread in clinical recommendations, mostly because they are non-specific and affect the genome as a whole. That is, instead of just demethylating the tumor suppressor genes, the drug has the potential to demethylate any gene, at random. This concerns many doctors because it can lead to other serious genomic complications.

Currently, the National Health Institute is pushing to develop more specific ways to target just the cancerous cells for demethylation. Other epigenetic studies use animal models to explore treatment time frames, as well as decide the best technique to administer therapies.

“Cancer is very complex, and to totally eradicate it is equally as complex. You have to cover all the bases,” says Sarkar. “It’s not just DNA changes; it’s changes on the DNA too, and that’s why these [epigenetic] drugs are necessary.”