 |
 |
The release earlier this year of a final version of the entire human genome (well, at least 99 percent of it) was heralded as probably the most important scientific accomplishment in history, equaled only by splitting the atom or landing on the moon. We now know the sequence of three billion chemical bases arranged in pairs within the DNA of each human cell. This information is critical to ongoing research at leading medical centers, like Massachusetts Eye and Ear Infirmary – and creates seemingly limitless possibilities for research to understand, diagnose and more effectively treat human disease.
As a quick primer for readers, among these three billion bases are specific sequences of base pairs we know as genes, which encode instructions on how to make proteins. Proteins perform most life functions and make up the cellular structure that determines the function of each cell. Human cells each contain two copies of 30,000 genes, one from our mother and the other from our father. An individual's specific genetic sequence is determined by a combination of the mother's and father's genetic make-up, although 99 percent of the genome is exactly the same from person to person.
Using advanced computing technology, scientists comb through billions of bits of information to identify one or multiple gene sequences that are at least in part responsible for disease development. These genes may then be cloned and tested further in laboratory models. In some cases, when there seems to be only one gene involved, this information may be used immediately to screen people who have a known family history of a disease, or to develop a specific treatment to counteract the gene's affect.
In any event, the fundamental understanding gained through genetic research is laying the groundwork for helping to determine:
According to Thaddeus Dryja, M.D., director of the Ocular Molecular Genetics Institute at MEEI, research has led to a small number of genetics-based treatments, but widespread creation of therapeutics is still to come. “The legacy of our generation will include a critical understanding of the genetic causes of disease. With this foundation of knowledge of the causes of genetic diseases, the next generation will be able to concentrate on trying to develop cures,” he says. “Today’s scientists realize that if we work hard to speed up our discoveries of the causes of diseases, the sooner the work on cures will begin. In fact, for many diseases, the development and testing of novel therapies based on the genetic discoveries has already commenced.”
The Massachusetts Eye and Ear Infirmary provides an ideal setting for conducting such research. Large patient populations provide a treasure of information about diseases in patients and their unaffected family members. The research f aculty and clinical staff share ideas and knowledge about what works and what is needed most for patients. Researchers within a clinical setting feel a sense of urgency and motivation, according to James Rocco, M.D., Ph.D., a head and neck cancer specialist. Because treatment for advanced head and neck cancer can be disfiguring, or interfere with a patient's ability to eat and breathe, Dr. Rocco says he is especially motivated to find treatments that identify cancer before symptoms develop. "Patients are always a source of inspiration to me," he says. "I see their suffering and how hard they work to fight their cancer. I am reminded how much we need new ways to detect and treat cancer before it disrupts their lives."
Some examples of genetics-related research occurring at MEEI include:
Janey Wiggs, M.D., Ph.D., clinician/scientist in the Howe Laboratory, has embarked on several avenues of g enetics-related research in glaucoma. This group of diseases is characterized by elevated pressure in the eye that can damage the optic nerve and result in irreversible loss of sight. Dr. Wiggs says her research program focuses on finding genes related to glaucoma for three primary reasons: 1) to gain insight into the biological cause of glaucoma by identifying abnormal gene products (abnormal proteins); 2) to use this information to design therapies that treat the cause of the disease – something physicians are now unable to do; and 3) to develop diagnostic tests for glaucoma that will identify individuals at risk for the disease so treatment can begin before irreversible loss of sight occurs.
So far, painstaking sequencing studies, using DNA samples from patients and non-affected family members analyzed through cutting edge computing technology at MEEI, have led to the identification of a handful of genes responsible for rare forms of the disease in young patients. Dr. Wiggs has identified one gene that plays a role in the most common kind of glaucoma that develops in adults, primary open angle glaucoma (POAG). But with more than 20 genes likely to be linked to POAG and the environmental factors that no doubt play a role in adult forms of the disease, much work remains to be done, she says. Perhaps the most immediate benefit could come in the form of diagnostics, particularly in determining which patients with elevated eye pressure will actually experience progression to optic nerve damage. “As we are able to identify the genetic factors behind these differences,” says Dr. Wiggs, “we can make the best use of this information and determine who needs which treatment and when.”
In what could be called an almost 24-hour mining operation, the two gene sequencing machines in the Ocular Molecular Genetics Institute at MEEI are constantly helping researchers identify genes responsible for diseases such as retinoblastoma, retinitis pigmentosa, macular degeneration, Usher syndrome and Bardet-Biedl syndrome. Over a thousand DNA samples are sequenced each week by these machines, with a typical sequencing run obtaining the sequence of one piece of one gene in one patient. In addition, says Dr. Dryja, Infirmary researchers are studying the effects of the mutant proteins that result from the DNA mutations. The lab’s first success came in 1986 with the identification of the gene responsible for retinoblastoma, a potentially fatal eye tumor that affects young children. This was the first discovery of a human gene causing a hereditary cancer, and it has served as a model for the study of all human cancers, not just ocular cancer. That discovery has created a better diagnostic tool for the disease leading to more efficient monitoring and much earlier – and more successful – treatment. In addition, genetic testing can now identify potential parents who are carriers of this genetic abnormality.
An important milestone was a collaborative effort with Eliot Berson, M.D., director of the Berman-Gund Laboratory for the Study of Retinal Degenerations to identify the first gene responsible for retinitis pigmentosa in 1990. This was followed over the years by the identification of over a dozen other retinitis pigmentosa genes. Some of these discoveries have now been followed up by creating mouse models with the same defects, work that is currently being spearheaded at the Infirmary by Tiansen Li, Ph.D., of the Berman-Gund Laboratory. Therapies are being tested in these mice. It is likely that there are more than 100 genes that are responsible for different types of RP, but Drs. Dryja and Berson have already determined that just three of those genes are responsible for about 25 percent of RP cases. Work continues, both on identifying additional genes and on studying effects of the gene defects in laboratory models.
Dr. Dryja says that such work would not be possible without the cooperation of more than 12,000 patients, and family members of patients, diagnosed and genetically classified through the efforts of Dr. Berson and his colleagues over the last 35 years. A few hundred unaffected individuals have also volunteered to serve as a control group. Studies of patients with the common forms of RP have revealed that the treatment of vitamin A can add seven to 10 years of useful vision, although the mechanism by which vitamin A works in gene defects is unknown. Dr. Berson points out that the process of examining the course of RP is a complex undertaking that must take into account non-genetic factors such as nutrition and sunlight exposure as well as genetic factors. He sees great promise in the laboratory models being developed at the Infirmary that focus on the mechanisms of disease. In addition to Dr. Li, Meredithe Applebury, Ph.D., Vadim Arshavsky, Ph.D., Clint Makino, Ph.D., and Francesca Pignoni, Ph.D., all of the Howe Laboratory, are working on laboratory models of hereditary disease.
Age-related macular degeneration and juvenile macular degeneration Genetic study of age-related macular degeneration (AMD) is challenging for researchers for several reasons. Much remains unknown about the environmental factors that lead to the disease, such as diet; and because the disease strikes in older patients, it is often difficult to study genetic patterns in patients' families. Patients may also have different degrees of sight loss - the severity varies widely.
An estimated six million Americans have vision loss from AMD, with up to 15 million more expected to develop it. AMD is characterized by progressive deterioration of the macula, a small region in the center of the retina needed for central vision. Understanding the genetic causes could result in preventive measures or treatments that could slow or control this prevalent condition that is the leading cause of legal blindness in people over 50.
Johanna M. Seddon, M.D., Sc.M., director of the Epidemiology Unit at MEEI, began a groundbreaking study of the genetics of AMD at MEEI and HMS in 1989. Her initial study demonstrated that families of patients with AMD were more likely to have AMD compared with families of controls, or people who did not have AMD. As part of the search for genes responsible for AMD, Dr. Seddon has studied genes that have been positively identified for inherited, juvenile forms of the disease -- Stargardt macular degeneration and Best disease. The Stargardt gene seems to be related to a small proportion of AMD, while the Best disease gene does not. Further study of the Stargardt gene may lead to more specific information on AMD.
In another important effort, Joan W. Miller, M.D., director of the Angiogenesis Laboratory, is working with Meg DeAngelis, Ph.D., of the Ocular Molecular Genetics Institute, to study genetics and other risk factors for AMD through a large-scale study of “wet” AMD, the most severe form. By looking at patients and unaffected older siblings, they hope to better understand both genetic and other risk factors for this group of patients.
M. Charles Liberman, Ph.D., director of the Eaton-Peabody Laboratory (EPL), reports that several studies involving hearing loss are progressing in the lab. Otologist Michael McKenna, M.D., is studying otosclerosis, a disease of the temporal bone that prevents it from vibrating properly and transmitting sound. Using DNA samples from families with members who have the disease, research has come up with promising candidate genes for study of their role in bone development.
Variations in the vulnerability of mouse ears are of interest to Audiologist Sharon Kujawa, Ph.D. By studying human patients who seem to have “tender” ears that are susceptible to hearing loss over a short period of time and others who have “tough” ears that are less likely to develop hearing loss, the lab has identified genes that may be responsible for these traits. By studying these genes in mouse models, researchers hope to be able to understand what combinations make ears impervious to noise trauma.
In classic gene hunter fashion, EPL researcher Stefan Heller, Ph.D., is searching for genes in mice that are found only in the inner ear. He has identified potential genes by using animal models and by collaborating with clinical researchers who study families with members who have experienced profound deafness. The hope is that new understanding will lead to treatments for severe hearing deficits.
Two genes located on chromosome 9 are the research focus of Dr. Rocco. In squamous cell carcinomas of the head and neck, as well as other types of cancer, these two genes have been shown to regulate tumor suppression. If either gene is lost or abnormal, cancerous cells grow out of control. Through a series of studies, Dr. Rocco discovered that one of the genes prevented an adenovirus from growing in laboratory sample cells. His laboratory is now focusing on developing a therapeutic adenovirus that replicates only in abnormal cells, leaving healthy cells intact. Even better, since viral replication is dependent upon the disruption of the chromosome 9 genetic locus, researchers may be able to develop a treatment for head and neck cancer at its earliest and most curable stage.
Roland Eavey, M.D., director of pediatric otolaryngology at MEEI, likens his participation in the search for genes related to sensorineural hearing loss to reading a map. Once scientists identify an area of a chromosome that seems to be suspect for this type of defect, Dr. Eavey says, it is like knowing they need to look in New England. When they narrow their search to an exact gene sequence, it’s like knowing what neighborhood is the source of the problem.
Gaining insight into the way genes work in humans depends on being able to study gene function in the laboratory. One of the most useful models for studying sight and hearing development is the zebrafish. Jarema Malicki, Ph.D., in the Howe Laboratory, is analyzing the molecular circuitry involved in the development of sight and hearing in the zebrafish. The embryonic development of zebrafish occurs over a period of 24 hours. Researchers study how sight cells differentiate based on genetic encoding, then create genetic defects to examine the resulting changes on a cellular and molecular level. As for zebrafish hearing, researchers are screening up to 500 zebrafish a day looking for fish that fail to respond to sound stimuli. The goal is to isolate genes responsible for the development of hearing.
All of this research illustrates the pioneering efforts ongoing in the Infirmary to understand genetic diseases affecting the eye, ear, nose, throat, head and neck, with the ultimate goal of benefiting patients with these diseases.
During cataract surgery, the crystalline lens of the eye is removed and replaced with an artificial lens implant. The first such replacement was performed about 50 years ago. Since then, the variety of potential intraocular lens implant materials has grown. Today's standard lenses offer a good solution for most patients, yet they do not provide perfect sight.
While progress in intraoccular lenses has been swift over the past decade, many researchers are committed to improving lenses further.
Recently, Roberto Pineda, M.D., an ophthalmologist in the Massachusetts Eye and Ear Infirmary’s Cornea and Refractive Surgery Service, reviewed three promising lenses that recently have been approved by the Food and Drug Administration or are nearing approval. “It is very exciting to watch the development of new lens implant technology and be able to offer this next level of care to patients,” Dr. Pineda said.
One intraocular lens from Pharmacia, the Tecnis Z9000, is in the category termed "first wave-front designed" intraoccular lens. This lens addresses the concern of some patients that their ability to perceive contrast is not as strong as before surgery.
An example of a low-contrast problem is reading the newspaper. Printing methods use dark gray ink against light gray paper. This creates a low-contrast problem — there is not enough difference between the dark and light tones in view. A typical eye exam chart of bold black letters against a crisp white background doesn't effectively measure vision problems related to low contrast. So, in the past, this difficulty has been hard to identify, let alone measure.
To improve contrast sensitivity, this silicone "first wave-front designed" lens has a wavy front surface, enhancing contrast sensitivity and mimicking the human lens at age 20.
The lens has been approved, and it may be a good option for some patients. Once results are in from a larger group of patients, and after practice confirms clinical studies, Dr. Pineda expects MEEI to begin using the lenses.
Another lens implant, the Crystalens by eyeonics Inc., is the "vision-accommodative" intraoccular lens. This proprietary silicone lens aims to compensate for the natural loss in "accommodative" ability that most people experience in their early 40s. In theory, it can render obsolete the almost-universal need for reading glasses among middle-aged people. This accommodative lens can focus over multiple distances, both near and far.
Another new entry to the field is a "light-adjustable" lens by Calhoun Vision that is likely to be approved in the next several years. It offers two significant differences from today's standard lenses. First, it can be folded in three, which means surgeons can make smaller incisions. Second, it is made of a light-sensitive substance that can be changed by special ultraviolet light. So, if a patient finds that a new lens is creating near-sightedness, for instance, a doctor can shine an ultraviolet light onto the artificial lens while it is in the patient's eye. The UV light can thin or thicken the light-sensitive material to reset its power, or prescription. Currently, when a patient needs a new prescription, glasses are given or in rare cases the lens implant is surgically removed and a new one is implanted.
As the variety of artificial lens implants grows, is it possible patients could struggle to select a single lens? Not to worry, says Dr. Pineda. A knowledgeable eye surgeon can review the newest intraocular lenses and their inevitable strengths and weaknesses and can work with a patient to identify the right lens for each individual situation.
It was observing the nervous system of crustaceans that piqued Dr. Joseph B. Nadol's interest in Otology as a medical student at Johns Hopkins while spending summers exploring biology at the Marine Biological Laboratory at Woods Hole.
Almost 32 years later, Dr. Nadol, now Chief of Otolaryngology and Director of the Otology Service, is still involved in what sparked the early interest that has shaped his career and, in many ways, his life.
"The complexity of sensory structures in the field of Otolaryngology fascinated me," he says.
Now, the Department is creating a lab that will examine deafness at the molecular and cellular level. Information gained in the lab will help translate basic scientific knowledge into ways to restore hearing.
"Otology can be primarily an 'observational' discipline,’" says Dr. Nadol. "We can tell you what is happening now and what is likely to happen as someone loses hearing. But we cannot stop it from happening in most cases." His hope is that the new lab will open up possibilities for just such an intervention.
The development of this new area is just one in a series of such efforts. Dr. Nadol has been the force behind much of the growth and progress in Otolaryngology at the Infirmary over the last 20 years.
In the middle of his career, Dr. Nadol says, he reached an epiphany: the realization that he could accomplish more as part of a group than he ever could on his own. His motivations changed and matured, he says, as he took the reins as Acting Chief of Otolaryngology.
"Success for me is measured in the success of others," he says. "Fun is in collaborating with colleagues to conceive and develop a new idea or area."
During his tenure, he has witnessed the expansion of the Otolaryngology Division, which focuses on ear, nose, throat, head and neck problems, from a hospital-based physician staff of three to 35. He expanded what had been an exclusive focus on auditory physiology into a broader exploration of anatomy, physiology and disease processes in many areas of the discipline of otolaryngology.
He has fostered research areas that parallel those of clinical care, reflecting the importance he places on basic science and understanding why something is happening.
He has overseen the opening of a vestibular (balance) lab that adds diagnostic and basic science components to clinical care.
He has helped to create a new Division of Laryngology, which focuses on the larynx (voice box) and voice-related communication disorders and treatments.
He was the first to evaluate the hearing of newborns at MEEI using the auditory brainstem test, which has become a regular practice in hospitals throughout the nation.
His personal research and leadership in using cochlear implants to mitigate hearing loss has strengthened understanding and treatment. His desire to investigate the process of hearing and deafness fueled his interest in the National Temporal Bone Registry, housed at the Infirmary.
"In most cases I wasn't responsible for all of the daily work," he says, diverting credit to others. "I just worked with people to help make those accomplishments happen."
An earlier epiphany -- deducing that to be his best he would have to surround himself with people who were more knowledgeable than himself -- brought him to the Infirmary.
During medical training at Johns Hopkins, Dr. Nadol spent a brief time at the Infirmary under the guidance of Harold F. Schuknecht, M.D. He was so impressed with Dr. Schuknecht and the caliber of the people and minds he encountered that he was determined to practice at MEEI upon graduation.
In the years before he assumed his current position, Dr. Nadol honed his scientific and clinical acumen. His successes are documented in virtually every relevant journal in the field. Leading societies have bestowed on him their highest honors. He has published nearly 200 articles and books.
Dr. Nadol says that the more important lessons were the less medical, more universal ones.
“I learned to be able to acknowledge that I did not know the answers to many questions from Dr. Schuknecht," Dr. Nadol says. "It was a turning point in my life, a crucial step in advancing from a competitive individual to a collaborator."
Dr. Nadol points to another turning point, a major shift in the way he thought. He moved from being focused on present accomplishments to having the patience to develop a long-term view, for carefully planning future growth for the department he leads.
"I learned about patience, about the long term, from Nelson Kiang," Dr. Nadol says of Nelson Yuan-Sheng Kiang, Ph.D., an internationally respected hearing scientist.
The young, aggressive medical student was transformed into a team player with the wisdom and patience to build the future of a department that is among the largest and finest in the world. Now, as an active figure in the Infirmary’s residency program, he is mentoring young physicians the way he was mentored.
When Dr. Nadol describes the people at the Infirmary, it doesn't seem that he is talking about co-workers. For Dr. Nadol, life and work --personal and professional -- merge. The lines of differentiation blur.
"Some people work and have outside entertainment," he says. "For me, work and fun overlap. My friends are my colleagues. My wife, Ruth, volunteers here with the Friends of the MEEI. Our trips are built around medical and scientific conferences. My work is my recreation.
"I've been fortunate that the parts of my life blend," says Dr. Nadol. "I really enjoy my daily life."
The 18th Annual Reynolds Society Dinner and Achievement Awards will be held on Friday, Nov. 5, at the Fairmont Copley Plaza in Boston. Named for Edward Reynolds, M.D., co-founder of the Infirmary, the Reynolds Society honors friends who contribute $2,000 or more to the Infirmary in a given year (Oct. 1 to Sept. 30).
The evening will include inspirational speakers and awardees, including Heather Whitestone McCullum, former Miss America who has become an advocate for the deaf. Dr. Mallika Marshall, HealthWatch reporter for CBS4 news on CBS4 and UPN38, will serve as emcee for the event. Dr. Marshall is also a regular contributor to the CBS Early Show, CBS Newspath and the CBS Evening News with Dan Rather. The Quirk Auto Dealership is a platinum sponsor for the evening. For more information about joining the Reynolds Society or becoming a dinner sponsor, contact Melissa Paul at 617-573-4168.
 | We comply with the HONcode standard for
health trustworthy information: Verify here. |
|
|
|
