White is not convinced of Alemseged’s early evidence of butchery. He believes crocodiles, not hominid tools, made the marks in the animal bones. Another skeptic is Sileshi Semaw, an Ethiopian archeologist at the National Center for the Investigation of Human Evolution in Spain, who codiscovered the oldest stone tools from 2.6 million years ago. White and his colleagues found signs of butchery from the same period. “Right after 2.6 million years, we have stone tools, cut marks on animal bones, the expansion of cranial capacity, and the emergence of our genus, Homo,” White said. “These things seem to be correlated.”
Alemseged responded to the criticism by suggesting that his colleagues may be fighting to keep their stories intact. “The resistance is not based on scientific grounds,” he said. In the museum facility, his team sorts through piles of rocks and bones collected in Dikika, in search of more evidence. His colleague William Kimbel, director of the Institute of Human Origins at Arizona State University, who works in the region where Lucy was found, is doing the same. With a cadre of young Ethiopian and international students now trained in the new facility, more paleontologists will be scouring Ethiopia than ever before. “Mark my words, we will find stone tools from 3.4 million years ago,” Alemseged said. “I can’t tell you where exactly they will be, but they will be discovered.”
As I discovered during my trip to Ethiopia, the field researchers love to argue. Questioning assumptions as new evidence comes to light is, after all, the sport of science. One afternoon Alemseged, Asfaw, Suwa, and Kimbel were going at each other over a splinter of hominid skull. Suwa mangled an English idiom in an attempt to describe his objection to Kimbel’s opinion; Asfaw stared at his friend of 30 years apologetically, unable to recall the phrase.
Even in their most acrimonious moments, field researchers form a tight-knit community based on respect for one another’s full-body approach to science. Their colleagues in offices, who run molecular and digital analyses of fossils, may not appreciate the effort that goes into unearthing the fossils in the first place. “They don’t know that the Jeep broke down in the desert and the driver fixed it on his back with an armed guard protecting him and scorpions beneath him, and he got malaria,” White said. Without field research, we’d still be telling a story about how crouching apes progressed to standing man against an imaginary savanna backdrop. We’d lack the fossils to tell us that elements of humanity began millions of years ago in a mosaic of environments.
As I traveled through Ethiopia with scientists and local guides, dodging thick sheets of rain in Addis Ababa, driving past Chinese manufacturing plants outside the city and into the Afar, where I was parched, hot, and hungry, I realized just how fragile the scattered remains of our past are. They are constantly under threat by development (as African countries mine and modernize), conflict (as political situations shift), and global warming (as floods and droughts increase in severity). Ironically, our exceptional tool-making skills now threaten to lead us toward eventual demise.
When considering how long the oldest members of our family survived before they went extinct, it’s impossible not to reflect on our species’ fate. “When you realize that you, as an individual, are part of a very long line, you begin to take it personally, you really are afraid to cut off that line,” Alemseged said to me one evening. “But I am not pessimistic, because humans are arguably the smartest species. We have the ability to reverse the damage we’ve done and push things forward.”
SETH MNOOKIN
One of a Kind
FROM The New Yorker
MATT MIGHT AND Cristina Casanova met in the spring of 2002, as 20-year-old undergraduates at the Georgia Institute of Technology. Cristina was an industrial-design major with an interest in philosophy; Matt was a shy computer geek obsessed with Star Trek. At first Cristina took no notice of him, but the two soon became friends, and that fall they began dating. Within a year they were married.
The couple had their first child, a son, on December 9, 2007, not long after Matt completed his PhD in computer science and Cristina earned her MBA. They named him Bertrand, in honor of the British philosopher and mathematician Bertrand Russell. After a few blissful weeks, the new parents began to worry. Matt and Cristina described Bertrand to friends as being “jiggly”; his body appeared always to be in motion, as if he were lying on a bed of Jell-O. He also seemed to be in near-constant distress, and Matt’s efforts to comfort him “just enraged him,” Matt says. “I felt like a failure as a father.” When the Mights raised their concerns with Bertrand’s doctor, they were assured that his development was within normal variations. Not until Bertrand’s six-month checkup did his pediatrician agree that there was cause for concern.
By then Matt had a new job, as an assistant professor at the University of Utah’s School of Computing. It took two months to get Bertrand on the schedule of a developmental specialist in Salt Lake City, and the first available appointment fell on the same day as a mandatory faculty retreat. That afternoon, when Matt was able to check his phone, he saw that Cristina had left several messages. “I didn’t listen to them,” he told me in an e-mail. “I didn’t have to. The number of them told me this was really bad.”
Bertrand had brain damage—or at least that was the diagnosis until an MRI revealed that his brain was perfectly normal. After a new round of lab work was done, Bertrand’s doctors concluded that he likely had a rare, inherited movement disorder called ataxia-telangiectasia. A subsequent genetic screen ruled out that diagnosis. When Bertrand was 15 months old, the Mights were told that urine screening suggested that he suffered from one of a suite of rare, often fatal diseases known as inborn errors of metabolism. During the next three months additional tests ruled out most of those ailments as well.
As Matt tried to get a foothold in his new job, Cristina struggled to care for a wheelchair-bound child whose condition seemed to worsen by the day. When Bertrand was hospitalized, she would stay by his bedside, often neglecting to eat; the constant stress contributed to osteoarthritis so severe that her doctor told her she’d need to have her right knee replaced. In April of 2009 the Mights flew to Duke University, in Durham, North Carolina, to meet with a range of specialists, including a geneticist named Vandana Shashi, whose clinical practice focuses on children with birth defects, intellectual disabilities, and developmental delays. After five days of tests and consultations, the Duke team told the Mights that there was widespread damage to Bertrand’s nervous system and that some of his odd behavior—wringing his hands, grinding his teeth, staring into space—was likely due to the fact that his brain appeared to be suffering from spikes of seizurelike activity.
When Bertrand was a newborn, Matt joked to friends that he would be so relaxed as a parent that he wouldn’t care which technical field his son chose to pursue for his PhD. In May of 2009 the Mights closed Bertrand’s college savings accounts so that they could use the money for medical care. That fall Bertrand was rushed to the emergency room after suffering a series of life-threatening seizures. When the technicians tried to start an IV, they found Bertrand’s veins so scarred from months of blood draws that they were unable to insert a needle. Later that evening, when Cristina was alone with Matt, she broke down in tears. “What have we done to our child?” she said. “How many things can we put him through?” As one obscure genetic condition after another was ruled out, the Mights began to wonder whether they would ever learn the cause of their son’s agony. What if Bertrand was suffering from a disorder that was not just extremely rare but entirely unknown to science?
In September of 2012 I visited the Mights in Salt Lake City, where they lived in a two-story brick Craftsman bungalow. Matt wore a striped Brooks Brothers polo shirt and jeans; with a neatly trimmed beard and shoulder-length brownish blond hair, he brought to mind Björn Borg of the late 1970s. Cristina, who is five feet ten, with porcelain skin and long black hair, greeted me with a hug and a wry smile.
In early 2010 the couple had decided to try to have a second child. This was a gamble: i
f Bertrand’s condition was indeed new to science, there was a chance that it was caused by a spontaneous, or de novo, mutation in the egg or sperm cell and was not in Matt’s or Cristina’s DNA. On the other hand, if the condition had a genetic history, the Mights could pass it on to other children. That summer Cristina learned that she was pregnant, and on April 14, 2011, she gave birth to a girl, Victoria. Within minutes of the delivery Matt and Cristina knew that their daughter was healthy; she moved with a fluidity that Bertrand never had. When I arrived at the Mights’ house, Victoria was bouncing around and grabbing at her mother’s sleeve. “Victoria, you need to wait for Mommy to say hello,” Cristina said. To me she added, “I had no idea how easy we had it with Bertrand.”
Bertrand, who was four at the time, was on the floor in the playroom, around the corner from the kitchen. He had round cheeks and a mop of brown hair. As with many children with genetic disorders, he also had some mild facial abnormalities: his eyelids drooped, and his nose was smaller than is typical, with an indentation on the bridge and slightly upturned nostrils. Two years earlier the Mights had noticed that Bertrand didn’t produce tears; every time he blinked it was as if sandpaper were scraping against his corneas. To keep the resulting scar tissue from causing permanent blindness, Matt and Cristina put medicated drops and lubricating ointment in Bertrand’s eyes every few hours, which made the skin around his eyes look as if it had been rubbed with Vaseline. Because Bertrand doesn’t reflexively align his head with his body, his face was often pointed away from where he was trying to look, and he ground his teeth with such force that it sounded as though he were chewing on rocks. Yet the Mights told me that for all of his medical issues and his many hospitalizations, he seemed oddly immune to more ordinary ailments, such as colds and allergies.
I had brought each of the kids a small plush doll; when I placed Curious George on Bertrand’s stomach, Victoria grabbed hold of Harry the Dirty Dog. When Cristina went to get something in the kitchen, she warned me not to let Victoria bite her brother. “She doesn’t understand that Bertrand just can’t interact with her the way everybody else can,” she said. “So she gets frustrated and does everything she can to get his attention.” Later, when I was lying on the floor with Bertrand and Victoria teetered into view, he seemed to flinch.
That evening, over pizza in their dining room, the Mights told me about a pattern they had noticed when Bertrand was a year old. At first, they said, he seemed to represent a challenging problem for each new specialist to solve. But as one conjecture after another was proved wrong, the specialists lost interest; many then insisted that the cause of Bertrand’s illness lay in someone else’s area of expertise. “There was a lot of finger-pointing,” Cristina said. “It was really frustrating for us—our child hot-potatoed back and forth, nothing getting done, nothing being found out, nobody even telling us what the next step should be.”
Then, in the summer of 2010, Vandana Shashi, the Duke geneticist, contacted the Mights about a new research project that was exploring whether genetic sequencing could be used to diagnose unknown conditions. There was a chance, Shashi said, that by looking for places where Bertrand’s genome differed from Matt’s and Cristina’s, Shashi and her colleagues would be able to pinpoint the cause of Bertrand’s problems. The Mights enrolled Bertrand in the study.
Genetic testing has been a part of regular medical practice since the 1970s; it enables doctors to search for mutations that cause known disorders, such as Tay-Sachs disease and sickle-cell anemia. Genetic sequencing, which entered the popular lexicon with the launch of the Human Genome Project in 1990, allows for the opposite type of search: comparing the entire genomes of people who suffer from an unknown disorder to see if they have genetic mutations in common. Sequencing also allows researchers to compare people who share genetic mutations, to see if they also share any previously unidentified disorders.
For years sequencing was too expensive for common use—in 2001 the cost of sequencing a single human genome was around $100 million. But by 2010, with the advent of new technologies, that figure had dropped by more than 99 percent, to roughly $50,000. To reduce costs further, the Duke researchers, including Shashi and a geneticist named David Goldstein, planned to sequence only the exome—the less than 2 percent of the genome that codes for proteins and gives rise to the vast majority of known genetic disorders. In a handful of isolated cases, exome sequencing had been successfully used by doctors desperate to identify the causes of mysterious, life-threatening conditions. If the technique could be shown to be more broadly effective, the Duke team might help usher in a new approach to disease discovery.
For their study, Shashi, Goldstein, and their colleagues assembled a dozen test subjects, all suffering from various undiagnosed disorders. There were nine children, two teenagers, and one adult; their symptoms included everything from spine abnormalities to severe intellectual disabilities. The researchers began by sequencing each patient and both biological parents—what’s known as a parent-child trio. There are between 30 and 50 million base pairs in the human exome; the average child’s exome differs from each of his parents’ in roughly 15,000 spots. The researchers could dismiss most of those variations—either they corresponded to already known conditions, or they occurred frequently enough in the general population to rule out their being the cause of a rare disease, or they were involved in biological processes that were unrelated to the patient’s symptoms. That left a short list of about a dozen genes for each patient.
The next step was to search through databases to see if any of those candidate genes were already associated with a rare disorder; if so, the patient was probably suffering from an unusual form of a known disease. In three of the twelve subjects, that’s exactly what the researchers found. Two others had de-novo mutations on the same gene, which meant that the Duke team had likely discovered the genetic basis of a new disorder. As a diagnostic tool, sequencing seemed to work. In several of the remaining cases, the technique helped identify genetic mutations that accounted for some, but not all, of a patient’s symptoms; in others it simply determined that none of the identified candidate genes were involved in the patient’s illness.
Then there was Bertrand. The Duke team thought it was likely that mutations on one of his candidate genes, known as NGLY1, were responsible for his problems. Normally NGLY1 produces an enzyme that plays a crucial role in recycling cellular waste, by removing sugar molecules from damaged proteins, effectively decommissioning them. Diseases that affect the way proteins and sugar molecules interact, known as congenital disorders of glycosylation, or CDGs, are extremely rare—there are fewer than 500 cases in the United States. Since the NGLY1 gene operates in cells throughout the body, its malfunction could conceivably cause problems in a wide range of biological systems.
In September of 2011 Goldstein sent an e-mail to Hudson Freeze, a glycobiologist at Sanford-Burnham Medical Research Institute, in La Jolla, California, and the foremost authority on CDGs. Goldstein told Freeze that he believed he’d found a child suffering from a glycosylation disorder that had never before been seen. That November, Goldstein shipped Freeze a supply of Bertrand’s cells. Freeze was unable to find evidence of a functioning NGLY1 gene. He soon reported back: Goldstein’s hypothesis—that Bertrand suffered from a new glycosylation disorder caused by NGLY1 mutations—was almost certainly correct.
On May 3, 2012, nearly two years after the sequencing study began, the Mights met with the Duke team in an examination room of a children’s hospital in Durham. Shashi explained that Bertrand’s condition was probably not caused by a de-novo mutation, as the Mights had thought; rather, Matt and Cristina each had a different NGLY1 mutation, and Bertrand had inherited both. Matt and Cristina had only to look at their daughter playing on the floor to realize how lucky they’d been: Victoria had had a 25 percent chance of being born with the same disorder as Bertrand. (Later testing showed that she had not inherited either parent’s NGLY1 mutation.)
Goldstein, who was meeting the M
ights for the first time, spoke next. He explained that until other patients with the same condition were found, there was a chance, however remote, that Bertrand’s disorder was caused by something else. Moreover, without additional cases, there was virtually no possibility of getting a pharmaceutical company to investigate the disorder, no chance of drug trials, no way even to persuade the FDA to allow Bertrand to try off-label drugs that might be beneficial. The Duke researchers estimated that there might be between 10 and 50 other patients in the country with Bertrand’s condition, which would make it one of the rarest diseases in the world. “That’s basically what they left us with—‘You need more patients,’” Matt told me. “And I said, ‘All right, we’ll get more.’”
As recently as a decade ago, researchers could spend years trying to find a second case of a newly discovered disease. When a paper describing two or more cases finally appeared in one of hundreds of medical journals, it still had to be read and remembered by clinicians in order for awareness of the disorder to spread. Genetic sequencing has dramatically sped up the process, theoretically enabling a child like Bertrand to receive a tentative diagnosis in just weeks or months.
But a number of factors prevent sequencing from reaching its full diagnostic potential. As a matter of protocol, researchers typically avoid sharing test results with subjects until the research is published; the Mights didn’t learn that NGLY1 was the likely cause of Bertrand’s condition until months after the Duke team reached that conclusion.
Researchers also hesitate to share data with potential competitors, both to protect their funding and to insure that they get credit for their work. In their attempt to confirm Bertrand’s condition, the Duke team searched for NGLY1 mutations in everyone who had been sequenced at Duke, and also combed through an exome database maintained by the National Heart, Lung, and Blood Institute. This gave them access to the genetic data of more than 6,000 people—a small fraction of those around the country who have been sequenced. Isaac Kohane, a pediatric endocrinologist at Boston Children’s Hospital, told me that many researchers believe, incorrectly, that patient-privacy laws prohibit sharing useful information.
The Best American Science and Nature Writing 2015 Page 25
