Publications : General Interest Articles
|1. Researchers Discover Gene Related to Fibroids|
|2. Ultrasound Surgery Shrinks Symptomatic Uterine Fibroids|
|3. Gene Dreams|
|Taped to a refrigerator in the laboratory of Cynthia Morton, PhD, is a tattered poster that hints of scientists' burgeoning knowledge about human genes. Represented here are all 23 pairs of chromosomes, each a storehouse of genes that orchestrate every aspect of cell development and repair. Each chromosome is cross-hatched with labels pinpointing the locations of genetic traits and of mutations-errors that can lead to diseases and conditions both common and rare...|
|Cynthia Morton, PhD, and colleagues study gene flaws that predispose millions of women to uterine fibroid tumors, a leading cause of infertility. Fibroid samples are frozen and stored in canisters (at left). Morton, appointed jointly to the hospital's departments of Pathology and Obstetrics and Gynecology, is helping physicians investigate nonsurgical treatments for fibroids.|
|Many of these genes were first mapped by Morton and colleagues. On chromosome 11, for example, lies a gene for the oxygen-carrying hemoglobin molecule which, when damaged, results in various blood diseases. Chromosome 14 harbors an immune-system gene that, when moved or "translocated" to chromosome 8, gives rise to a rare cancer known as Burkitt lymphoma. And scattered hither and yon are hundreds of genes that are in some way involved in hearing, inner ear disorders and hereditary deafness.|
|Morton has used a gene-mapping technique called FISH-fluorescence in situ hybridization-to determine quickly and accurately the location of genes on chromosomes. This experimental method involves tagging chunks of DNA with fluorescent dye, which renders them visible on a computer screen.|
the poster's 1994 publication date, postdoctoral fellow Anne Skvorak,
PhD, shakes her head. "Gosh, that's so old," she says.
"Today we know so much more."
At a time when sheep cloning is making headlines around the world, gene mapping is routine and proceeding apace. Since 1983, while a postdoctoral fellow in the laboratory of Harvard Medical School Chairman of Genetics Philip Leder, MD, Morton has mapped hundreds of human genes. Today she is a participant in the Human Genome Project, an international effort to identify and locate all 100,000-plus genes by the year 2000. Much of Morton's energy is focused on genes that underlie a major health problem in American women: benign tumors of the uterus known as fibroids.
Present in as many as 77 percent of American women, fibroids are the leading cause of hysterectomy, or surgical removal of the womb, the most common surgical procedure after cesarean section. "These non-cancerous tumors account for more than 200,000 hysterectomies every year," Morton notes. An expert on tumor-causing genes, Morton happened upon the fibroid problem while setting up a clinical laboratory to examine solid tumors. "In talking with gynecologists," she says, "I found out that fibroids are the most common, least studied tumors in the world."
Many women never even know they have fibroids. But the tumors can cause excessive bleeding, severe pelvic pain, constipation and incontinence. Invaders of the womb, fibroids can also cause premature labor, spontaneous abortion and infertility. "Women don't like to complain about fibroids," observes Morton, explaining their status as an unspoken problem. "They don't make for good cocktail party conversation."Morton remembers the moment her team found the first fibroid gene, dubbed HMGIC, after months of sleuthing. "It felt like winning the lottery," she says. "The next step is to figure out what role the gene plays in fibroids' development. And the next step, down the road, is to see whether we can use that knowledge to come up with effective new medical treatments."
AS AN EIGHTH GRADER, Cynthia Morton got hooked on human genetics through a term paper on twinning. The project set her on the path to graduate school and advanced training at Children's Hospital and Harvard Medical School. In 1987, she came to Brigham and Women's Hospital to direct a clinical laboratory dedicated to analyzing human chromosomes. Serving not one but three medical centers-BWH, its Partners HealthCare System affiliate, the Massachusetts General Hospital, and Children's Hospital-the Cytogenetics Laboratory bridges the gap between the laboratory bench and the bedside. Here, technicians apply geneticists' rapidly accumulating knowledge to the diagnosis of chromosomal abnormalities.
Morton and colleagues use a wide variety of methods to screen patients for genetic abnormalities. Many patients are would-be parents; others are still in the womb. From the chromosomes of cells grown from blood or amniotic fluid, the staff can determine whether they are at risk for certain hereditary disorders.
Using computer imaging equipment introduced a few years ago, technicians can examine a patient's full complement of chromosomes on the screen. They look for numerical and gross structural changes-for example, three copies of chromosome 21, which indicates Down syndrome; or rearrangements of pieces of chromosomes, as in certain forms of leukemia. Such scramblings can yield clues about a patient's prognosis and guide physicians in selecting a course of therapy.
Through the identification and molecular analysis of chromosomal aberrations found in fibroids, Morton hopes to shed light on these tumors' varied behavior and troubles they cause (see sidebar on page 19). A long-run goal is to find a drug that counteracts the gene defects and shrinks or eradicates the tumors, providing an effective alternative to surgery.In early studies, Morton and colleagues discovered that in some fibroids, a piece of chromosome 12 had traded places with part of chromosome 14. "We began looking for our fibroid gene right around the breakpoint," explains Morton, beginning with chromosome 12, since that chromosome is known to be damaged in many kinds of tumors.
Morton believes that HMGIC regulates the activities of other genes. When damaged, HMGIC causes a string of genes to go awry, perhaps sparking excess production of substances known as growth factors. The resulting cell growth and division may be unruly indeed; the largest fibroid ever recorded weighed 140 pounds.
Interestingly, Morton notes, these tumors stop short of spreading in the way that cancerous tumors do. Uncovering the steps by which fibroids form and grow could shed light on the crucial difference between benign tumors, which aren't necessarily life-threatening, and cancerous tumors, which spread throughout the body.
In the short term, Morton predicts, researchers will focus on finding a way to counteract the effects of the HMGIC gene in fibroids, to limit growth-factor production and stop tumors from growing. In the long run, gene therapy holds out hope for introducing repaired genes into the body. To date, scientists have logged few successes with this approach, but the field is in its infancy-just as human genetics was in the 1980s.
At BWH, using knowledge gained in the laboratory to improve patient care is known as "translational" research. In an effort to enhance the diagnosis, prevention and treatment of disease and birth defects, Morton is working to bring BWH geneticists and clinicians closer together.
The potential rewards of such a collaboration are clear. "I didn't set out specifically to tackle a major women's health issue," says Morton. "But as a woman, I'm glad to be doing just that."
Alternatives to hysterectomy?
Scientists and clinicians search for new medical treatments
Elizabeth A. Stewart, M.D. outlines nonsurgical fibroid treatment options, including the drug pirfenidone, to a patient.
For years, hysterectomy has been routinely recommended for gynecological maladies ranging from pain to hemorrhaging to an abnormal pap smear. Although the reasons for symptoms weren't always clear, the response was uniform: Take it out.
"Doctors used to think that once childbearing was over, it made no sense to keep the uterus, and they saw no harm in removing it," says Brian Walsh, MD, Chief of Surgical Gynecology at Brigham and Women's. But times have changed. "While hysterectomy offers immediate relief from painful fibroids and is the only effective option for many women," he says, "it is major surgery, requiring six weeks' recuperation and the loss of work and family time."
And that's not all, notes Madelon Ali, MS, RN, CS, a gynecologic nurse who counsels women considering hysterectomy. "The uterus is integral to a woman's body image," she says. Like the breasts, "it is so much a part of womanhood that many women are psychologically unprepared to part with it."
New research suggests that the uterus may in fact have roles beyond reproduction. Preliminary evidence suggests that it is an important part of the hormone system-a source of natural pain killers, for example, as well as substances that reduce blood clotting. Currently, alternatives to hysterectomy are limited. Myomectomy, or surgical removal of fibroids themselves, is an option for some women that can frequently be performed through the vagina. Some women benefit from medications that shrink fibroids by blocking hormone production.
A new generation of fibroid treatments will be based on understanding how fibroids grow and develop-the sort of knowledge Cynthia Morton, PhD, and colleagues are amassing in the laboratory. Obstetrician-gynecologist Elizabeth A. Stewart, MD, plans to conduct tests of a new drug, pirfenidone, which blocks a chemical that helps fibroids grow. Morton will analyze chromosomes from patients' tumors following their treatment to explore pirfenidone's effects. "The more you understand fibroids' biological behavior, the better you're equipped to find a treatment that works," Stewart says.
|4. Researchers Take Aim at Uterine Fibroids|
New Techniques Expand Treatment Options to Help Women Avoid Major Surgery