Leslie Gordon, a scientist and mother of a child with a premature aging syndrome, is doing everything she can to find a cure for the disorder.
On 10 October 2002, physicians Leslie Gordon and Scott Berns were heading out to celebrate their ninth wedding anniversary. Then the phone rang. Francis Collins, director of the National Human Genome Research Institute in Bethesda, Maryland, and Maria Eriksson, a postdoc in his lab, were calling with long-hoped-for news. "I think we might have an anniversary present," Collins recalls telling Gordon, who got Berns on the line as well. "So here's the scoop." Eriksson's efforts had identified the genetic flaw underlying a rare illness that causes symptoms in childhood that resemble aging. "It was pretty wild," says Gordon, an M.D.-Ph.D. cell biologist at Tufts University School of Medicine in Boston. She and Berns went to dinner, stunned but ecstatic.
Gordon had been working with Eriksson and Collins as part of a scientific consortium that had been searching for the gene that underlies Hutchinson-Gilford progeria syndrome, or HGPS, for less than a year (see "Of Hyperaging and Methuselah Genes" ). But her exhilaration over the speedy discovery, which would be published in Nature a few months later (see "Lamin-tation" ), was more than intellectual. Gordon and Berns's son, Sam, has HGPS. Children with the disorder survive an average of 13 years and usually die from heart disease. Since Sam was diagnosed in 1998, his parents have poured their energy into understanding the syndrome and finding a cure. They set up the Progeria Research Foundation (PRF) to lobby for and fund investigations into the condition and to create research resources for scientists, including a repository of cell and tissue samples from children with HGPS.
Although doctors first described HGPS 118 years ago, the scientific community made no significant headway toward helping children with the disease until last year's gene discovery. One major obstacle is the syndrome's rareness; it strikes only one in 4 million to 8 million newborns (worldwide, only 25 to 30 cases are known at any given time), making access to patients difficult. But with a mother's fierce love, a doctor's caring bedside manner, and a scientist's passion for rallying research into the syndrome's molecular underpinnings, Gordon has galvanized this corner of gerontology. She spearheaded the creation of the gene-hunting consortium and persuaded parents of children with HGPS to participate in the studies.
"Without the Progeria Research Foundation, without Leslie's personal effort to identify affected individuals and to get cell samples in a very high quality form that could be distributed to researchers like us, we wouldn't have been able to move as quickly," says Collins. "Leslie's a real heroine of our time." Huber Warner, an associate director of the National Institute on Aging (NIA) in Bethesda, Maryland, agrees. Before Gordon came along, research on HGPS was basically stalled, he says: "I consider her totally responsible for moving this field forward." Gordon's persuasiveness in drawing others into the cause catalyzed much of that success, admirers say. She is "a powerful force of nature," says Collins. "You could not be in the room with Leslie talking about progeria and not be caught up in the importance of doing something about this condition."
Drive and Determination
Gordon, a 39-year-old with a rosy complexion and long brown hair with bangs, brings an air of optimistic purpose to her work, whether she's lobbying for research dollars or feeding her HGPS cell lines. On a recent morning at her Tufts lab, she removes from an incubator a flat cell-culture flask filled with dark pink liquid broth, places it under a microscope, and peers through the eyepiece at the cells. "Oh, oh, ... they look awesome! Oh my gosh, they grew so much. They're healthy. They're very happy," she says with relish. She invites a visitor to take a gander. At the center of the microscope's field of view is a tiny clump of skin cells taken from a 3-year-old with HGPS. "See it? Isn't it great?" she says, grinning. The long, spindle-shaped cells have been growing for a couple of weeks, spreading across the bottom of the dish. "It'll take at least a month more before I feel calm, because then we'll be able to freeze some down," Gordon says. "They are multiplying, but I sort of treat them like my babies and hope that nothing goes wrong. ... They're precious." Because parents of HGPS children are often reluctant to subject the youngsters to biopsies, Gordon can't count on getting another skin sample from this donor.
The cells hold the key to deciphering HGPS and proceeding toward clinical trials (see "On Trial" ) for treatments that could help children like Sam. Although Gordon could never have imagined this mission that now dominates her days and nights, she had, in a sense, been training for it her entire life. She grew up in North Shore, Massachusetts, 25 kilometers north of Boston, studying hard and riding horses. By her early teens, the workings of the human body had captivated her, and she liked the idea of taking care of people's health. In high school, she volunteered and worked at several nursing homes and once spent a day shadowing an oral surgeon. She decided that she would be a doctor too. "I remember the drive, the feeling that Yes, this is really what I want to do," she says.
In college at the University of New Hampshire, Durham, she took premed courses, concentrating in zoology with a minor in biochemistry. But when she graduated in 1986, both medicine and science tantalized her. She took a break from school and worked for 3 years as a technician in biology labs at Tufts and Boston University. During that time, she says, she "got the bug for research." She recognized that big scientific findings arise from years of prior studies by hundreds of other researchers. That collective forging of knowledge appealed to her. Gordon likens science to a beach: "It has a zillion grains of sand, and if you can just contribute a grain--one novel thing--I think it's very important. Because without all of those grains of sand, you can't have a beach. You can't find the answers to things."
While working at Boston University, she met Berns, who was finishing his medical school training there. Gordon decided that she would become a physician--but one who also did science. In 1990, she began an 8-year M.D.-Ph.D. program at Brown University in Providence, Rhode Island. Her Ph.D. work, in the lab of immunologist Paul Knopf, focused on immune system responses to brain tumor development. Meanwhile, during her medical rotations, she found her calling in the pediatric ward. "When children walk into your office, you know that you can make their day," she says. "You know that you can make them smile and make [their visit] a good experience--and hopefully, make a difference in their health. It's just the most rewarding thing on Earth."
A Sudden Change of Direction
Gordon and Berns married in 1993 and, 3 years later, Sam was born. When she graduated from Brown in 1998, Gordon planned to specialize in pediatric ophthalmology because she enjoyed the fine work of microsurgery. She would do 1 year of a general pediatrics residency at Hasbro Children's Hospital in Providence--where Berns served as head of pediatric trauma--and then she would train further at the Massachusetts Eye and Ear Infirmary in Boston.
But Gordon's plans for the future fell into chaos when Sam was diagnosed at 21 months. The signs had initially been subtle: He hadn't been eating well, he had been vomiting a bit, and his growth had slowed. His teeth weren't coming in, and his hair was thinning. One day in summer 1998, Berns received a phone call from a family friend and physician, Monica Kleinman. Sam's appearance, she told him, reminded her of a child she had seen years ago, who had progeria. In HGPS, the bones fail to grow normally, hair falls out, skin takes on an aged look; cardiovascular disease sets in later. Within a week, Gordon and Berns took Sam to his pediatrician for x-rays to check his bone development. The tests showed typical signs of the syndrome.
Neither Gordon nor Berns had heard of progeria during their pediatrics training. They combed the research literature to learn about studies of HGPS, but they uncovered few publications. Gordon called the National Institutes of Health (NIH) and the Office of Rare Diseases to find out whether grants were available for studying the disease. "There was pretty much nothing out there," she says. Through her digging, Gordon learned of W. Ted Brown, a geneticist at the New York State Institute for Basic Research in Developmental Disabilities on Staten Island, who is a leading expert on HGPS. The couple took Sam to see Brown, who confirmed the diagnosis.
Soon afterward, Gordon left Hasbro--and her pediatric ophthalmology career--to concentrate on the progeria puzzle. She immersed herself in the HGPS literature, but "I had to bounce my ideas off somebody," she says. For help, she turned to her Ph.D. adviser, Knopf, and another grad school mentor, Brown physiologist Christine Harling-Berg. Gordon also consulted Brown geneticist emeritus Frank Rothman, who studied aging in roundworms. Although none of these scientists knew anything about progeria, they began meeting with Gordon regularly to discuss journal articles relating to HGPS. "We just looked at each paper and said, 'OK, what's with the growth, what's going on here, what's going on there? Can we go down any of these avenues, try to explore this?'" she says. Gordon calls the group "the brainstormers."
A Family Pulls Together--And Reaches Out
Gordon and Berns looked around for organizations focused on medical care for HGPS patients and research into HGPS. They found the nonprofit Sunshine Foundation, which brings together children with progeria for a vacation each summer, but no charity with a scientific mission existed. "There was nobody funding the scientists; there was no central place where medical information was collected," says Gordon. "These kids were really on their own. Their physicians were on their own--physicians who, maybe once in their career, will see a child with progeria. Maybe. They don't know what to do on a daily basis, a long-term basis, for clinical treatment."
To help plug these gaps, Gordon and Berns launched PRF. They drew heavily on Berns's experience in organizing pediatric safety programs such as the Rhode Island Buckle-Up Hotline, which promotes the use of car safety restraints for children. He also sat on the boards of directors of several nonprofit agencies, including the Rhode Island SAFEKIDS Coalition and state chapter of the March of Dimes. Gordon would serve as PRF's medical director. Her family also jumped in. Her sister, Audrey Gordon, a lawyer, helped file the paperwork to establish it as a nonprofit organization in March 1999; later, she became its full-time executive director. And the Gordon sisters' mother, Barbara, also a lawyer, became a corporate officer of PRF.
Gordon reached out beyond kin as well, tapping every connection she could think of. The Brown "brainstormers" joined PRF's medical research committee. Gordon called Rabbi Harold Kushner, who had written When Bad Things Happen to Good People in response to his own son's death from HGPS. Kushner and his wife, Suzette, joined the PRF board. The first fundraising drive in the second half of 1999 drew $75,000 from friends and family. Since then, the campaign has gone international largely through word of mouth, media coverage, and the Internet. "It's just been a whirlwind ever since; it's been special events, more people involved, more donations," says Audrey Gordon. The group has pulled in $1.4 million in 5 years. Audrey Gordon says that her sister's determination and infectious enthusiasm has been a key to PRF's success: "She has this ability to capture her audience, to find the right people, the right scientists ... and hook them into this wonderful organization."
Getting Researchers What They Need
In mapping out PRF's goals, Gordon kept her eye on two questions: What does the field need to study HGPS, and How could the organization help? A lack of money and researcher tools was the main barrier to attracting scientists to the area. So in an initial step, PRF gave out small grants. The first one went to Gordon in August 1999, to study a molecule called hyaluronic acid, which some studies had detected in larger-than-normal quantities in the urine of children with HGPS. Gordon contacted Bryan Toole, a cell biologist at Tufts who was studying hyaluronic acid's role in tumor cell growth, and she arranged a postdoc in his lab starting in fall 1999. Her studies showed that HGPS patients actually do not have elevated concentrations of the substance.
Next, Gordon and Berns decided to create the cell and tissue bank at Tufts; they also arranged a partnership with the Rutgers University Cell and DNA Repository in New Jersey, which stores and distributes the HGPS cell lines. And, working with Brown University's Center for Gerontology and Health Care Research, Gordon and PRF set up a clinical database that tracks the medical status and treatment history of HGPS patients from around the world.
Seeds of hope. Gordon's lab at Tufts University School of Medicine maintains a repository of cell and tissue samples from children with Hutchinson-Gilford progeria syndrome (HGPS). [Credit: Joe Keller]
PRF's efforts also took Gordon to Washington, D.C. With the pro bono help of a lobbying firm, Gordon, Berns, and Audrey Gordon visited members of Congress from Massachusetts and Rhode Island to enlist their support in funding progeria research. "We didn't get money--we got something better," Gordon says. When Congress passed the Children's Health Act of 2000, which called for more research into rare childhood diseases, the legislation singled out two afflictions by name: HGPS and Friedreich's ataxia, a degenerative nerve disorder that impairs muscle coordination. The law directed NIH to develop a 5-year plan to meet the legislation's goal.
That coup led to a meeting in late 2000 between Gordon and NIA's Warner and representatives from NIH's Office of Rare Diseases and National Institute of Child Health and Human Development. NIH agreed to work with PRF and help fund a scientific workshop on HGPS in November 2001. Gordon decided which researchers to invite. Her list included a valuable recent contact: geneticist Collins.
Collins had run into Berns--who was spending a year in Washington, D.C., in the White House Fellows program--at a reception in the office of Donna Shalala, then the secretary of Health and Human Services. Around 20 years earlier, Collins had taken care of a progeria patient and had been frustrated about the lack of treatment and research options. Meeting Berns and, later, Gordon, Collins remembers being taken by the unusualness of the situation: a rare disease striking "like a bolt from the blue" in the child of two physicians, one of whom is an M.D.-Ph.D. "If there were ever an opportunity for something to get done about this disease, this must be it," he recalls thinking to himself. "So we'd better get on board and make sure it happens."
Collins agreed to attend the progeria meeting. At a dinner during the workshop, he suggested to Gordon that they form a consortium to find the HGPS gene. With one sentence, he had opened up a new avenue for PRF. Within weeks, Gordon was pulling together the research collaboration, which involved 20 scientists including New York geneticist Brown. "So as you can see, way leads on to way," she says, summing up how unforeseen opportunities have led her from one road to another in her research journey.
Collins says he thought the odds of success were "pretty low, because we were really looking for a needle in a haystack." No one even knew whether the rare disease was inherited. By a stroke of luck, Brown had years before reported a defect in chromosome 1 in most--but not all--cells from one HGPS patient. The consortium decided to take a closer look at the chromosome and ultimately followed the trail to the culprit gene, which makes a protein called lamin A.
Crucial to making that discovery was the ability to gather DNA samples from patients and their parents. Over the years, Brown had contributed a dozen HGPS cell lines to an NIH-sponsored aging cell bank, but additional lines came from PRF's cell and tissue bank. Gordon was in charge of collecting those newer samples, many of them from children she had met through PRF. She launched a worldwide search for other patients, tracking them down by phone and e-mail, sometimes through their personal physicians. Today, the PRF bank houses cells from 27 children with HGPS and their families from approximately 20 countries, ranging from the United States and the Netherlands to South Africa and Vietnam.
Getting samples of DNA, cells, and tissue for any research was a delicate task. In the past, some parents of children with HGPS had decided they didn't want scientists studying or pricking their children with needles because there was little prospect of a cure, says Brown. But Gordon and Berns were in an ideal position to persuade families to participate in research, he says, because as Sam's mother and father "they could relate to the other parents as parents." They went with their son to one of the Sunshine Foundation's summer reunions with hopes of collecting blood from children there. Some families declined to donate samples because they felt that the reunion's purpose was for the children to have fun, not to be examined and prodded, says Brown. Nonetheless, Gordon built a bridge to many parents. Some of them agreed to have their children's blood drawn at the get-together, whereas others took collection kits home and got their doctors to mail in samples later.
Since the announcement of the gene discovery in April 2003, PRF has established a diagnostic testing program. By screening for the flawed gene, doctors can verify previous diagnoses of HGPS and make new ones earlier. Gordon and her colleagues are now exploring potential strategies for developing a treatment, including gene therapy.
Mother and Scientist
Even as the research has gained momentum, Sam remains Gordon's most important priority. Now age 7, he receives physical and occupational therapies at school and takes growth hormone, which has helped him eat more and grow. His cardiovascular health is currently fine, but he pops a baby aspirin every other day to help prevent heart attacks. Sam attends a public elementary school, and aside from sometimes wearing a hat to cover his baldness, he behaves like any other child, Gordon says: "He's smart, he's funny, he has friends in the community." A big sports fan, he enjoys golfing and bowling. Lately he's been quizzing her on Red Sox trivia. ("Who are the two players who just got traded from the Red Sox? ... How can you not know?!" he said to her a few months ago.)
Gordon's days are tightly scheduled. She wakes early and works in pajamas at her home office until it's time to put Sam on the school bus. Then she drives to Tufts--where she took over Toole's lab last year after he moved to South Carolina--or to Brown University, where she oversees the PRF clinical and research database, and tends to her professional responsibilities for several hours. In the late afternoon, she heads home to meet Sam when he returns from school. After he goes to bed around 7:30 p.m., she switches back into scientist mode and works late, sometimes until 2 a.m.
She is running a race against the clock. But the question of whether scientists can find a solution in time to help Sam is one she doesn't dwell upon, she says. "That's not productive. As long as I know personally that I'm doing everything I can do, I have got to be satisfied with that. Otherwise I just would not be able to function." And although her mission began as a personal quest, it has blossomed into an endeavor involving the fate of not just one boy, but every child with HGPS. Through PRF's efforts, Gordon says with a proud smile, hundreds of people are now working on behalf of children who have the syndrome: "I don't think you ever do anything important alone." Grain by grain, the scientific beach of knowledge about progeria is growing.
Hutchinson-Gilford Progeria Syndrome Workshop , 28-29 November 2001, Bethesda, Maryland, agenda and summary
Hutchinson-Gilford Progeria Syndrome Workshop , 28-29 July 2003, Bethesda, Maryland, agenda and abstracts
1. W. T. Brown, Progeria: A human-disease model of accelerated aging. Am. J. Clin. Nutr. 55, 1222S-1224S (1992). [Abstract] 
Citation: I. Chen, Racing Against Time. Sci. Aging Knowl. Environ. 2004 (25), nf59 (2004).