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Imagine transplanting adult mouse stem cells into a chicken embryo to see how the cells react. Imagine enabling a deaf mouse — and eventually, a deaf person — to hear. Imagine creating drugs to maintain hearing. Welcome to the research laboratory of cell biologist Stefan Heller, Ph.D., a principal investigator at the Eaton-Peabody Laboratory (EPL) at Massachusetts Eye and Ear Infirmary (MEEI).
“I am fascinated with the ear because it is a unique niche for a young researcher,” said Dr. Heller, who is also an assistant professor in the Department of Otology and Laryngology at Harvard Medical School (HMS). “The ear is very complicated and very little is known about inner-ear development. The most common problems in the ear are deafness and the failure of the organ to self-repair.”
Humans are born with approximately 15,000 hair cells in each ear, and deafness occurs when many of them die off. Dr. Heller described hair cells as “little microphones that are the primary sensory inputs for sound. They vibrate forcefully as energy goes through the ear. The higher the frequency, the faster the hair cells vibrate. It’s the high-frequency hair cells that die first.”
Dr. Heller’s research at the EPL comes at a critical time: hearing loss has grown to epidemic proportions. Half of all Americans over age 70 have significant hearing problems due to heredity, disease, medications long-term exposure to excessive noise, or the aging process. While previous generations accepted deafness as they aged, today’s seniors consider deafness to be a quality of life issue and expect to hear until they die.
Experiments are being conducted at MEEI in a large laboratory designed by Dr. Heller and equipped with a cell culture facility, fluorescent microscopes, chicken-breeding incubators, and a confocal microscope shared with the Department of Ophthalmology. Dr. Heller’s team includes Huawei Li, Ph.D., a postdoctoral associate who is joining the faculty this fall, and Albert Edge, Ph.D., a tissue transplantation expert.
Since being recruited by MEEI in 2000, Dr. Heller has been working with embryonic and adult inner ear stem cells from mice and, more recently, from humans. He is hopeful that his research will lead to the creation of drugs that could, within five or 10 years, be administered during cochlear implant surgery to slow down the degenerative processes in the inner ear. “We’re still a ways from a doctor giving a patient a drug for hearing loss,” Dr. Heller said.
One project involved transplanting adult stem cells from the inner ear of a mouse into chicken embryos. The mouse cells regenerated into hair cells in the correct position within the chicken ear. “The chicken cells communicated with the mouse cells, signaling that it was time to generate as hair cells,” said Dr. Heller. “Perhaps this signal can be identified and developed into a drug that can instruct a mouse cell to regenerate.”
In an experiment requiring painstaking physical skill, Dr. Heller and Dr. John Brigande, of Oregon Health & Science University in Portland, are experimenting on a mouse with a genetic deficit that leads to hair cell degeneration. The mouse develops hearing two weeks after birth, only to lose it within a couple of days. Dr. Heller ships mouse adult stem cells to Dr. Brigande, who surgically implants the cells into the inner ears of mouse embryos. The goal is to make the deaf mouse hear a little bit. It will realistically take a few years to learn whether deaf mice can hear after such a surgery because the success rate of the microsurgical implants is relatively low.
Dr. Heller acknowledges that the strides he is making would not be possible without funding from men and women who recognize and support the mission of the EPL. “Without generous gifts from donors, I would never have been able to explore novel ideas and novel approaches to understanding the complexities of the human ear,” he said. “In particular, it is very difficult to get funding for exploratory research, which is so important to discovering new approaches to finding a cure for deafness. I am very thankful to the people who so generously helped us get started at MEEI.”
This past summer, Dr. Heller co-organized a 10-week meeting at the Marine Biological Laboratory in Woods Hole, Massachusetts, with four researchers and two postdoctoral associates from around the country who share his interest in inner ear development and inner ear cell regeneration. The group strategized about what approaches would be most productive over the next five years to expedite stem cell regeneration. Dr. Heller hopes that new projects will arise from this meeting and that the National Institutes of Health or private foundations can be encouraged to sponsor future meetings, perhaps an annual summer course on the latest technology for post-doctoral fellows and students.
“We hope to publish our results from Woods Hole this fall. One goal is to make the isolation of adult inner ear stem cells more efficient,” he said. “With mice, it’s not a problem. You just take another mouse. In human studies, you only get two or three stem cells per person. We can’t turn them into the hundreds of thousands of cells that we need. We experimented on mice this summer and whatever we learned will be applied to humans.”
Dr. Heller envisions doing research to understand the function of hair cells as well as their regeneration. Very little is known about how hair cells transduce sound and mechanical stimulation into an electric signal. “There aren’t a lot of cells in the ear. If we grow a lot of hair cells in a culture, we can study their function as well,” he said.
Dr. Heller says, “I couldn’t find a better place to do my work. Because the Infirmary is a hospital, one has access to doctors who work with patients, and that’s a big a dvantage.”
Welcoming a new baby into the world is a celebratory occasion. But parental joy can quickly turn to devastation if the little one is diagnosed with retinoblastoma, the most common form of eye cancer in children. Fortunately, retinoblastoma is considered one of the most treatable of the pediatric cancers, partly because it is confined to the eye and partly because it is often detected early. The disease, which affects approximately 250 children in the United States annually, has a mortality rate of less than 5%.
The Massachusetts Eye and Ear Infirmary (MEEI) is known around the world for its efforts to combat retinoblastoma through innovative treatments and for important research in areas such as early detection. Leading these efforts is Shizuo Mukai, MD, a Surgeon in Ophthalmology at MEEI and an Assistant Professor of Ophthalmology at Harvard Medical School. Every week, Dr. Mukai sees approximately 25 children, many of whom have the disease. He likes working with children because they are more challenging and the surgeries are more difficult, and because of his research interest in pediatric eye cancers.
Retinoblastoma refers to a tumor that develops in the retina in early childhood. Retinoblastoma can be hereditary or non-hereditary. In hereditary retinoblastoma (cases are bilateral or have positive family history), a child can develop multiple tumors in both eyes. Youngsters with non-hereditary retinoblastoma generally develop a tumor in only one eye. Both forms of the disease arise from a mutation in the retinoblastoma gene.
The key to successfully treating retinoblastoma is early detection. A tumor can often be seen in a child’s eyes or it may appear in a photograph as a white dot in the eye. At the MEEI, youngsters with a family history of retinoblastoma are screened every three months until the age of 3 and annually until age 4 or 5.
Unilateral retinoblastoma is often diagnosed when a child is relatively older; the average age being 12 to 18 months. “We don’t know when this form of tumor develops,” explained Dr. Mukai. “By the time the tumor is discovered, the disease may be at an advanced stage, often necessitating the removal of the eye.”
Treatment for retinoblastoma depends on the size, location, and nature of the tumors and may include radiotherapy, chemotherapy, laser treatment, cryotherapy, or surgery to remove the eye.
Treating tumors with the proton beam is considered the optimal treatment if you need to irradiate an eye, said Dr. Mukai, who led the ophthalmology team at MEEI in the development and clinical use of this treatment.
“The difference between proton radiotherapy and conventional radiotherapy is like that between a laser beam and a flashlight. The profile of the proton beam is very sharp around the borders," he explained. “You don’t have the diffuse scattering that you see with a flashlight. In addition, protons can also be stopped very abruptly unlike a laser beam that can blow right through healthy tissue. The goal is minimizing the exposure of any normal tissue to radiation to reduce its complications, such as a secondary malignancy in patients with hereditary retinoblastoma.” For many children, the proton beam have been live-saving.
In addition to treating patients, Dr. Mukai is also working on several exciting research projects. Eager to make strides in early detection, Dr. Mukai and Dr. Paul Yates, a resident in ophthalmology at the Infirmary, are designing a system that uses commercially available digital cameras to take sharp retinal pictures. “Because the camera would be relatively inexpensive, it would be available to more doctors,” explained Dr. Mukai. “For example, a digital photo could be sent to a specialist over the Internet for consultation. It would make evaluation of suspicious cases easier even in remote areas of the world.”
With Meredithe Appleberry, Ph.D., a principal investigator at the Howe Laboratory at MEEI, and Dr. Thomas Lee of Cornell University, Dr. Mukai is also looking at cells that behave like retinae stem cells or progenitor cells that were isolated from retinoblastoma tumors. The team is investigating the function of these stem cells in the tumors. Are these cells the cells of origin for retinoblastoma? Do these stem cells in the retina behave like stem cells in cancerous tissue in other parts of the body? Do these cells help the tumor grow or do they inhibit it? “Our findings may help us determine potential new treatment approaches,” he said, “and we will certainly better understand the disease.”
With Bruce Ksander, Ph.D., at the Schepens Eye Research Institute, Dr. Mukai is using the immune system to treat eye tumors in a mouse model. Experiments on mice over the past two years have stopped the cancer in the eye, reduced the spread of cancer to the liver, and decreased the mortality rate by 50%. “If you take these same cancer cells and introduce them into the mouse that survived, the cancer doesn’t grow,” Dr. Mukai said. “This work might have an application for a cancer vaccine.”
Believing that advances in retinoblastoma can also be made by bringing together specialists from the clinic and the laboratory, Dr. Mukai and Dr. Eric Grabowski of Massachusetts General Hospital established the New England Retinoblastoma Group. Twenty clinicians and researchers meet regularly to discuss new treatment methods and difficult cases.
Said Dr. Mukai, “We now have a protocol that is region-wide, and we are investigating new ways to treat youngsters using tumor therapy.” Retinoblastoma affects between 12 and 20 children in the Boston area per year.
Dr. Mukai conducts his research with several goals in mind. “We want to investigate new ways to treat this tumor because even though mortality is low, there is still significant morbidity,” he explained. “Early detection is also important — the earlier the better — as is coming up with an approach that minimizes the morbidity and complications from treatment, such as secondary malignancies. Hereditary retinoblastoma is a systemic disease; these kids can get other cancers later on and depending on their age, different tissues are susceptible. We want to treat the eye problem, make sure the patients get screened for other cancers as they grow up, and be able to treat the tumors without causing other cancers.”
Daniel G. Deschler, M.D., F.A.C.S., has been appointed Director of the Head and Neck Surgical Oncology at the Massachusetts Eye and Ear Infirmary effective Nov. 1, 2004. The announcement was made by Joseph B. Nadol, Jr., M.D., Chief of Otolaryngology at MEEI and Chairman of Otolaryngology at Harvard Medical School (HMS).
A graduate of Creighton University and HMS, Dr. Deschler is an Assistant Professor of Otology-Laryngology at HMS. He joined the medical staff of MEEI in 2000 and serves as associate coordinator of medical student education for Otolarynology and on hospital numerous committees.
Dr. Deschler has an active clinical practice and treats patients with head and neck cancer, with a specialization in laryngeal disorders and microvascular free flap reconstruction. His primary research focus is in the evaluation of laryngeal speech following total laryngectomy and pharyngeal reconstruction. He is the author of numerous papers and serves as editor and co-author for Otolaryngology-Head and Neck Surgery Clinics of North America on the topic of “Voice Following Laryngeal Cancer Surgery.”
“Dr. Deschler is a very talented clinician, teacher and researcher and a valued member of our faculty, and I look forward to working with him in his new role,” said Dr. Nadol.
Dr. Deschler and his wife, Eileen Reynolds, M.D., live in Lexington, Mass., with their two children, Jack and Will.
According to the Journal of American Medical Association (JAMA), 1,500 people die each year due to accidental carbon monoxide (CO) poisoning and an additional 10,000 seek medical attention. Because CO poisoning occurs mostly in winter months, it is often mistaken for the flu and ignored, leading to serious illness and even death.
The following information can educate the public about CO, the of CO poisoning and what they can do to prevent a tragedy from occurring.
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