Younger siblings often outgrow their older brothers and sisters, but for Brooke Greenberg of Baltimore, the difference in development between her and her siblings was startling.
Greenberg passed away last Thursday at the young age of 20, still looking like a toddler. Developmentally, she stalled at the age of 5, never weighing more than 17 lb. (7.7 kg). Her condition, which she shares with a handful of other people around the world and which kept her both physically and mentally stunted, was labeled Syndrome X by her doctors, but the X was merely a stand-in for unknown. Although it was clear that Greenberg — eventually called “a child frozen in time” — was developmentally abnormal, scientists, researchers, and physicians could not diagnose why.
Greenberg’s doctors started with the usual suspects. The slow growth of her eyes and ears suggested a congenital condition, but she came back negative for every birth defect known. When she turned 3, she started developing all sorts of physical breakdowns and diseases, from seizures to long-lasting pneumonia and even suffering a stroke.
That was when Greenberg started seeing geneticists. Originally it was to determine if there was a possible explanation and treatment for her condition, but eventually, researchers transitioned to a larger undertaking: Could the girl who wouldn’t grow up hold the answer to a longer life? Her family was — and is — willing to let researchers find out. ”Brooke is the nucleus of our family. What if Brooke holds the secret to aging? … We’d like to help people. Everybody’s here for a reason. Maybe this is why Brooke is here,” her father, Howard Greenberg, told ABC News when she originally underwent testing.
“It was a pretty amazing genotype that she had, suspended development and lack of aging on the outside. It sounded pretty amazing, and the more I checked it out, the more interesting it became,” says Eric Schadt, the director of the Icahn Institute for Genomics and Multiscale Biology at the Mount Sinai Medical Center in New York City.
Even though the specifics of Brooke Greenberg’s biological situation remain a mystery, researchers believe her genome is a trove of information with the potential to reveal secrets to longevity. Oddly, when scientists first sequenced her genome everything looked normal. She also had no abnormalities in her endocrine system, and no chromosomal abnormalities either, so they started to dig deeper.
After sequencing, Schadt and his team identified three mutated genes that hadn’t been seen before in the general population. Two of the three have the potential to be related to aging processes, but their exact roles are unclear. “The only way to compare her genes is to make stem cells from her in order to study what the gene mutation might be doing functionally,” says Schadt.
By making a variety of stem cells from neuron cells to liver cells to cells from Greenberg’s skin, the scientists can look at how the molecular state of the cells changes with the mutations. And by exposing then to a variety of conditions, they can study how they interact in different environments. “If one of those genes is a true candidate, it would shed real light on aging and development, which would be a big contribution to the scientific community,” says Schadt.
Another investigator, Richard F. Walker, a medical researcher at All Children’s Hospital in St. Petersburg, Fla., has also sequenced Greenberg’s genome as well as those of three other girls with similar phenotypes, including Gabby Williams, a young girl from Billings, Mo., with a similar developmental problem.
Walker’s theory is that development is a combination of integration and change within the body. All our parts need to align with the changes that are happening to them and around them and after we reach our physical peak — like an old car — there’s internal friction and we start to deteriorate. When Walker started studying Greenberg, he presumed that the genetic mechanism that causes change is damaged in her. “This was very exciting because it meant that if it was damaged, that the mutation would be a marker for the genes that cause us to change, and that, therefore, might be an aging gene,” he says.
By comparing the genomes of all four girls, Walker is hopeful his research team is getting closer to identifying a gene, which if interfered with, could stall aging. Which is what everyone is racing to find.
“We are all hoping for the fantasy scenario where we lock onto some key modulator of aging processes that would not only enable an understanding of how to manipulate lifespan and make us live longer, but could it also make us more well,” says Schadt. For instance, easing the disease burden of disorders like Alzheimer’s, by having the ability to slow its progression.
Even though Greenberg has now passed away, researchers say the work can continue since they still have her DNA. The scientists now have the capabilities of resequencing her genes and trying again. When Greenberg started to get very ill this summer, Schadt and his team went to the hospital to get both tissue and blood samples for future sequencing.
“We still know very little about aging. Progress in understanding aging hasn’t been amazing. Many of the paths taken haven’t delivered as we thought they would,” says Schadt. “The contribution of someone like Brooke could help tremendously. Because a case like hers is so unique, the advances it could drive could be amazing and well worth the effort to explore.”