Leslie Gordon and her husband, Scott Berns, could not figure out what was ailing their infant son, even though they were both pediatricians. The baby was failing to gain weight as he should, had cut no teeth and was losing his hair.
The diagnosis, when it came in the summer of 1998, was devastating: Sam had progeria, a rare genetic condition that resembles the aging process sped up. Gordon had never heard of it. She and Berns dropped everything and set about trying to learn more.
The news over the next week was bleak. Although progeria is a mysterious illness, some facts about it are undisputed. There was no cure and no treatment. Their son would get sicker and sicker, and there was nothing they could do. The average age at which children with progeria died was 13.
There weren’t even any drugs in the pipeline. There was almost no research going on, says Gordon. “There was no funding. There was no central resource for families. It seemed like a huge void of nothing.”
In one way that’s unsurprising: Only 80 children in the world are known to have progeria. But the science void was something that Gordon could tackle. She quit her pediatrics residency to set up the Progeria Research Foundation, with the goals of finding a cure and providing support for affected families.
Gordon’s team and other researchers in this field have one mantra: Understanding progeria won’t only help a few children and their families. It will also help unlock the secrets of the aging process we all experience.
New evidence suggests they are at least partly right. Progeria does have parallels with normal aging, at least in one key aspect: how blood vessels deteriorate. And aging blood vessels lead to two of the major causes of death, heart disease and stroke. “We have not had a brand-new avenue for studying aging and cardiovascular disease in some time,” Gordon says. “Progeria gives that.”
Progeria was first described in 1886 by the British doctor Jonathan Hutchinson and then in 1897 by his countryman Hastings Gilford. (The full name of the best-known form is Hutchinson-Gilford progeria syndrome. That’s what Sam Gordon has.)
Children with progeria develop normally for the first year, but then their growth begins to slow. Soon they develop problems that are usually limited to elderly people. Their bones weaken, their joints stiffen and they may get dislocated hips. Their skin becomes less elastic and creases into wrinkles. They often lose their hair.
Like many old people, children with progeria tend to die from a heart attack or stroke. The walls of their blood vessels thicken and stiffen, and can accumulate cholesterol-laden plaques and calcium, a direct cause of high blood pressure and heart disease.
Children with progeria do not get dementia or memory loss, nor are they more prone to cancer, the other main disease of aging. That apart, progeria resembles aging gone into hyperdrive. So the question has always been: Is progeria relevant to what happens to us as we get older, or is it just masquerading as aging?
Not everyone is convinced the two are linked. “The chances that [progeria syndromes] represent an authentic recapitulation of how aging leads to symptoms, I think, is a stab in the dark,” says Richard A. Miller, who researches aging at the University of Michigan in Ann Arbor. William Ershler, head of the Institute for Advanced Studies in Aging and Geriatric Medicine in Gaithersburg, agrees, saying, “I think it can be important in certain aspects of aging, but I don’t think it explains ‘the clock.’ ”
One problem is that we know so little about normal aging. While science has documented a vast list of changes that occur as we grow older at the level of our organs, hormones, cells and now genes, cause and effect are far from clear.
The first progeria breakthrough came in 2003, when two groups published their discovery of the gene for Hutchinson-Gilford progeria syndrome in the same week. One, funded by Gordon’s foundation, was led by Francis Collins, who is now head of the National Institutes of Health. The other was a European group.
Both found that the problem was a point mutation — in other words, the swapping of just one “letter” of DNA — in a gene called LMNA. The gene encodes lamin A, a protein found in a cell’s nucleus. This is a major part of the lamina, a kind of scaffolding on the inner side of the nuclear envelope. It is also associated with DNA itself.
There is still a lot to discover about lamin A’s function, but one thing is for sure: The effects of the mutation are profound. Cells in people with progeria have strange, knobbly nuclei, quite unlike the smooth, spherical nuclei seen in normal human cells.
Also, in people without progeria, most DNA is tightly coiled, with the only uncoiled genes those that are “switched on” — in other words, their protein is being produced. Not so in progeria, where all DNA is uncoiled, although not all genes are switched on.
One effect of the progeria mutation is fairly well understood. A sticky molecule called farnesyl is normally added to lamin A while it is being made, which helps the protein reach the lamina. Then the farnesyl group should be lopped off, allowing lamin A to properly join the scaffold structure. But the mutation keeps the farnesyl group in place, and the sticky mutated form of lamin A, dubbed progerin, piles up at the nuclear envelope.
Finding the LMNA gene has opened the door to drug treatments for progeria. The enzyme that adds farnesyl to lamin A is overactive in some types of tumors, and drugs that block its action are being investigated as cancer therapies. After these farnesyl transferase inhibitors (FTIs) showed promise in a mouse version of progeria, the first human drug trial, involving 28 children, began in 2007.
The results from this trial are still being analyzed, but in 2008 work on cells grown in the lab suggested there may be a hitch: Blocking the addition of farnesyl led to a different fatty group being added to lamin A later on, resulting in the same pileup at the lamina.
But a Spanish group studying the problem showed that both additions could be blocked by statins, usually used to lower cholesterol, and bisphosphonates, bone-strengthening agents for treating osteoporosis. So two more trials have begun, with first results expected soon.
In April, Nicolas Levy, the leader of the European research group, reported that the results from his first six patients were “encouraging.” But he acknowledged it is hard to know if the drugs are acting on progeria itself or just lessening its impact on heart and bone health.
The discoveries of the progeria gene and progerin have galvanized basic research in this area. A 2006 study showed that progerin turns up at low levels in the skin cells of people without progeria — and the older the individuals were, the more progeria-like changes appeared in the nucleus.
In progeria, the mutation in the LMNA gene causes a so-called splicing error in the multi-step process of copying DNA into a string of RNA. This error seems to occur spontaneously in people without progeria, perhaps more often as we get older.
Then last year, two papers firming up the connection between progeria and normal aging were published. These look even more medically relevant, because they related to cardiovascular disease and connections to calcification of arteries.
And last month more findings from Collins’s group at NIH made researchers take notice. They concern telomeres, which some think are key to cellular aging.
A cell’s DNA is organized into discrete strings or chromosomes, 46 per cell in the case of humans. On the chromosome ends are protective sequences of DNA bound with protein, the telomeres; they are often likened to the plastic caps on shoelaces. When a cell divides, its telomeres shorten, and this seems to help set a cell’s life span, which could explain many aspects of how our tissues age.
The new research was on skin cells from people without progeria. As the cells divided and grew older in the lab, the normal shortening of telomeres caused splicing errors with several genes, including lamin A.
Collins’s group also showed that the immunosuppressive drug rapamycin reduced the buildup of progerin in cells grown in the lab; these researchers plan to start trials of the drug in children with progeria.
Tom Misteli of the National Cancer Institute is trying to develop a drug to block the mutated splice site in the LMNA gene. Pharmaceutical companies are involved, and Misteli is screening a library of small molecules to find one that does the job.
A medicine with a potential market of 80 people would probably rank low on most companies’ priority list. But nothing could be a higher priority for those, such as Gordon, with an affected child. Gordon will not say if Sam, now 14, is in any of the drug trials, commenting only that he is doing well, is active in Boy Scouts and the school band. “These are incredible, courageous kids,” she says. “It’s essential to do everything we can for them.”
Bhattacharya is a consultant for New Scientist magazine, from which this article is excerpted. It can be found at www.newscientist.com.