Monday, 13 January 2014 14:15

Sam Berns, the Face and the Heart of Basic Research into Rare Accelerated Aging Disorder

Written by  ASCB Post Staff
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sam berns credit HBODespite his extremely rare accelerated-aging disorder,
Sam Berns was known for his upbeat personality.
Photo credit: HBO
The impetus behind new basic research into Hutchinson-Gilford progeria syndrome (HGPS) and the most prominent public face of this extremely rare accelerated-aging disorder caused by a defect in nuclear lamins, Sam Berns died Friday, January 10, from HGPS complications. He was 17.

Sam Berns's parents, Leslie Gordon and Scott Berns, established the Progeria Research Foundation (PRF) in 1999 to find the cause and develop a treatment and cure for the genetic disorder. HGPS, first described in 1886, is extremely rare. Worldwide, a few hundred children are known to be affected. From the beginning, doctors were struck by its parallels with normal aging. HGPS newborns begin life in apparent good health, but between 6 and 18 months stop growing and quickly develop signs of premature aging including hair loss, thin skin, loss of subcutaneous fat, stiff joints, osteoporosis, and rampant arteriosclerosis. The average life span of an HGPS patient is 13 with death usually caused by stroke or heart attack.

Sam Berns was diagnosed with HPGS at 22 months old, and his mother, Leslie Gordon, a physician-scientist at Brown University and a former ASCB member, switched the focus of her own research to progeria. As an MD/PhD, Gordon was uniquely positioned to appeal to Francis Collins, who was then the Director of the National Human Genome Research Institute at the NIH, to map the HGPS gene.

Through the database of the Human Genome Project, the progeria gene, LMNA, was mapped in 2003. LMNA encodes important structural proteins in the cell nucleus called lamins, which form tough but adaptable rope-like filaments that line the inner membrane of the nuclear envelope and extend throughout the nucleus. The most common HGPS-causing mutation is sporadic, meaning that the DNA change occurs spontaneously in the child and is not inherited from either parent. The mutated LMNA gene creates a defective lamin A protein, known as "progerin," which lacks a large section (typically, 50 amino acids) near its C-terminal end. This deletion wreaks havoc because the defective protein can still associate with normal lamins and it disturbs their organization in the nucleus.

But the identification of progerin and knowledge from basic research on nuclear lamins led to a clinical drug trial in 2009 of a "failed" cancer drug called Lonafarnib. The drug had been declared safe but ineffective in pediatric cancer trials but Lornafarnib was a farnesyl transferase inhibitor. Thanks to the decades of basic research on the nuclear proteins and their farnesyl anchors, a safe farnesyl transferase inhibitor seemed the ideal candidate for an HGPS treatment. In just under five years from the identification of the defective LMNA gene, the first dose of farnesyl transferase inhibitors was administered to children with progeria. A 2012 study by Gordon and colleagues at Boston's Dana Farber Cancer Institute reported that the treatment led to improved cardiovascular status for the children receiving it. Though the farnesyl transferase treatment is now available to HGPS children, there's still no cure.

Sam Berns was known for his upbeat personality. HBO aired a documentary based on Berns, "Life According to Sam," in October. Berns also appeared on Katie Couric's daytime talk show, gave a TEDx talk on his philosophy for a happy life, and inspired the New England Patriots with a locker-room speech before a recent game. Berns aspired to become a cell biologist.

The American Society for Cell Biology has been reporting on progeria since 2006. In 2008, the ASCB Newsletter published a report on the proposed clinical drug trial, which was highlighted at that year's Annual Meeting in a special translational research session. Speakers included Gordon, Collins, Elizabeth Nabel, Director of the NIH National Heart, Lung, and Blood Institute, and Robert Goldman, a leading nuclear lamins researcher at Northwestern University and the ASCB organizer of the panel. In September 2012, the ASCB highlighted the first clinical trial of treatment for progeria.

In a release posted this morning, Collins, now NIH Director, wrote of his personal relationship with Sam. "But beyond the ways in which Sam inspired all of us to seek answers in research, he also taught us to cherish every day as a gift." In 2011, Sam presented Collins with the "SAM" (Science and Medicine) award from the PRF, a handmade plate with an inscription by Sam Berns and his handprint. "In the rush of deadlines and challenges that make up today's world, I confess that I don't always succeed at that. But those exhortations will come back to me each time I look at Sam's handprint on that plate—and I will be thankful for the privilege of having known this remarkable young man."

Collins added, "This plate sits on the shelf in my home office where I see it several times a day, reminding me that medical research is not just an academic exercise—it is about real people whose hopes and dreams depend on us."