HOWARD F. FINE, MD, MHSc Medical Director of the Louis V. Gerstner Clinical Research Center The Helen & Martin Kimmel Assistant Professor of Clinical Ophthalmology

Preserving Vision with Robots One of the first things Howard Fine does to prepare for a test run of a new robot for eye surgery is to crack open an egg.    It’s not breakfast he is interested in; rather, Dr. Fine uses the membrane inside the shell of fertilized chicken eggs as an animal model for retina surgery. The tiny blood vessels in the membranes are nearly identical mechanically to those in the human retina and perfect for fine-tuning the robotic surgical techniques that Dr. Fine hopes will soon be able to reverse what is a leading cause of blindness in the United States.    Just as atherosclerosis clogs vessels in the heart, leading to heart attacks, atherosclerosis also obstructs the tiny vessels in the retina, which can lead to blindness. More than 2 million people are stricken each year in the United States with obstructed retina vessels, and more than a half million go blind from the disease. No treatment exists to restore blood flow and prevent vision loss.    “We want to apply the techniques of interventional cardiology to reopen retinal blood vessels with miniature stents,” says Dr. Fine. Until now, however, the size difference between coronary arteries and retinal vessels has prevented eye surgeons from even attempting the procedure. “The retina’s vessels are 10 to 20 times smaller than coronary arteries – about the width of a human hair – and inserting a stent into one requires more precision than human hands are capable of.”    That’s where the Intra-Ocular Dexterity Robot comes in – designed by Nabil Simaan, PhD, assistant professor of mechanical engineering and head of the Advanced Robotics & Mechanism Applications (ARMA) Lab at Columbia; Dr. Fine; two ARMA engineering graduate students, Wei Wei and Roger Goldman; and Stanley Chang, MD, chairman of ophthalmology. With two robots perched on a ring (which will eventually hover over a patient’s eye but now hangs over the chick membrane), Dr. Fine uses joysticks to manipulate the robot’s dual snake-like arms to insert nearly invisible metal stents into blood vessels.    “While robots have revolutionized a number of surgical fields, their use has been lacking to date in ophthalmology, in part because of the small size and high precision required,” Dr. Fine says. This robot is one of the most precise medical robots ever built, capable of manipulating tools with 5-micron precision, an order of magnitude improvement over unassisted human hands.    With the fundamentals of the robot and the surgical procedure now in place, Dr. Fine says it will probably take six months to a year of tinkering before the team can attempt the insertion of stents into the retinal blood vessels of lab animals. Once the stents appear safe over the long term, Dr. Fine plans to apply to the FDA to start a clinical trial in humans.    “I think we have the potential to help countless patients who have lost vision from retinovascular disease,” Dr. Fine says. “And if this technology is successful for ophthalmology, it might be useful in other areas of the body as well.”

ADAM RATNER, MD, MPH Assistant Professor of Pediatrics and Microbiology

Our Bodies, Our Bacteria Judging strictly by cell number, about 90 percent of you isn’t really you. For every one of the 10 trillion human cells in your body, 10 bacteria cells also make your body their home.    “People usually think of the gut when they think of the microbiome, but humans are colonized by bacteria in all sorts of places: the nose, the skin, the genital tract,” says Dr. Ratner. “Usually we live happily side by side, but on occasion, something changes to tip the balance toward disease. So we have to wonder, how much of our health, or illness, stems from us and how much stems from the bacteria we harbor. It’s clear the bacteria contribute, but it’s not well understood in what way.”    Take the example of premature birth, which Dr. Ratner studies with the help of the Gerstner scholarship. An overgrowth of Gardnerella vaginalis and other bacteria in the genital tract is strongly suspected to cause about a quarter of all premature births in the United States. “It’s a big number and a huge public health issue,” Dr. Ratner says. “If we can find a way to eliminate the risk associated with the infection, we could prevent about 100,000 preterm births, about 6,000 infant deaths, and severe neurological disability in 6,000 more.” But there are few clues as to how these infections contribute to preterm birth. The major roadblock in unraveling the role of Gardnerella has been the lack of an animal model to study, Dr. Ratner says. Mice, rabbits and nonhuman primates have all been inoculated with the bacterium in the past    Dr. Ratner’s recent findings may finally provide the long-awaited breakthrough. Hamster cells, he found, can be made vulnerable to a toxin from Gardnerella if they express a human molecule called CD59, which Gardnerella uses to recognize human cells. He is now trying to create transgenic mice that express the molecule, which may lead to treatments, although he admits a breakthrough probably lies a good deal in the future.    “Anytime you’re working on something that’s not well-characterized, there is an element of risk,” he says. “It’s possible we’re wrong about the role of Gardnerella, but we won’t know if we don’t do the experiments.”

KARA GROSS, MD Assistant Professor of Clinical Pediatrics – Gastroenterology and Nutrition

Studying the Role of Neurotransmitters In Inflammatory Bowel Disease An ostomy is a drastic option for children with inflammatory bowel disease, (IBD), and Kara Gross, a pediatric gastroenterologist, tries to avoid doing them. But for some patients, this step may be the only thing that will relieve the painful intestinal cramps and frequent bouts of diarrhea from which they suffer.    “The problem with today’s pharmaceutical treatments for IBD is that, for some patients, these either don’t work or they don’t work for long,” Dr. Gross says. “Even with the strongest medications we have, many patients will suffer a relapse of disease within a year. When a patient is only 15 and already facing experimental therapies, all we can do sometimes is to hope that something better becomes available in the future.”    Finding something better for her patients often keeps Dr. Gross up at night feeding the mice she uses in her IBD research, which is putting the disease in a new perspective.    For a long time, IBD – when it wasn’t thought to be all in a patient’s head – was considered solely a problem of the way the immune system functioned in the gastrointestinal tract. The immune system keeps the gut in a constant state of low-grade inflammation to protect the body from foreign invaders; IBD is believed to start when the immune system malfunctions for unknown reasons, allowing inflammation to flare out of control. All of today’s treatments suppress the immune system.    Research by Dr. Gross and others now focuses on the role of neurotransmitters in the gastrointestinal tract. The gut’s neurons and the immune system communicate with each other, and recent studies suggest that the neurons may be stoking inflammation by recruiting inflammatory cells. Neurons do this by secreting chemical messengers, known as neurotransmitters or neuromodulators.    Altering neuro-immune communication may succeed in reducing inflammation in the bowel, and Dr. Gross’ own studies, in collaboration with Martha Welch, MD, assistant clinical professor in psychiatry and in neuroscience with Michael Gershon, MD, professor of pathology and cell biology, already suggest one way to achieve that. Using oxytocin – an anti-inflammatory neuromodulator that neurons use to “talk” to the immune system – Dr. Gross is trying to decrease the intestinal inflammation in mice with IBD.    “I’m optimistic that we’ll eventually get to drug testing,” Dr. Gross says, “but the biggest issue now is that we need more preliminary data to secure NIH support. The Gerstner grant allows me to spend large amounts of time in the lab, doing what I need to do to really get this project going.”

IGOR MATUSHANSKY, MD, PHD Assistant Professor of Medicine

Sarcoma Pioneer or Alchemist? When Igor Matushansky tells his oncology colleagues that he wants to cure sarcoma by turning malignant cells back into normal cells, instead of killing the tumor, the most frequent response is, “With what? Alchemy?”According to Dr. Matushansky, however, the idea is fully grounded in laboratory research, not magic.    He would not even be the first to try what he calls “differentiation therapy.” For the past two decades patients with acute promyelocytic leukemia have been successfully treated with retinoic acid, which converts malignant cells into normal white blood cells.    The idea of reprogramming malignant cells has been accepted among lymphoma, leukemia and other “liquid” cancer researchers for decades, but Dr. Matushansky – who did his PhD research on leukemia – was surprised to learn that solid tumor researchers generally do not subscribe to this approach.    If a clinical trial he is planning proves successful in sarcoma patients, Dr. Matushansky hopes to start changing a few minds. Survival in sarcoma patients has not improved much in the last 25 years; half of all tumors return within three years, and with recurrence, patients usually have about a year to live.    The trial will test whether low doses of drugs that can reprogram cancer cells in the laboratory also work in recently diagnosed sarcoma patients. “If the tumor comes back, its cells should be more differentiated and mature, and we already know that such tumors have a much better prognosis.”    One “reprogramming” drug, Zolinza, has already been approved for use in some cancers. But in a twist that Dr. Matushansky finds perplexing, the drug is currently used at maximally tolerated/cytotoxic doses to kill cells, not to differentiate them.    “People sometimes ask me if it’s really important for me to treat patients while I do my research,” Dr. Matushansky says. “The answer is yes, and this is one reason why. If I weren’t treating patients, I never would have known that drugs explored for their reprogramming properties are now being used as cytotoxic agents in practice.    “If drugs like Zolinza are used instead in low doses to reprogram cells, I believe we can dramatically change the prognosis for patients with a relapse of sarcoma from a six-month survival rate to about 10 years,” he says. And that would surely have some oncologists believing in magic.

Chang, Gerstner Honored as Eye Institute Turns 75

Stanley Chang, MD, second from left, shown here with his wife, Jean, second from right, was honored with Louis V. Gerstner Jr. at a gala celebration at the Metropolitan Club in New York on Sept. 18. Dr. Chang is the Edward S. Harkness Professor of Ophthalmology and K.K. Tse and Ku Teh Ying Professor of Ophthalmology. Mr. Gerstner, the retired CEO of IBM, and his wife, Robin, left, are long-time supporters of the Edward S. Harkness Eye Institute. About $1.2 million was raised at the event for eye research.

—All stories by Susan Conova
Photos: Eileen Barroso and Michael Dames