An old two-storey brick building in a shabby part of Cambridge, Massachusetts, formerly a distribution centre for Budweiser beer, is now the world’s most powerful factory for analysing genes from people and viruses.
And it is a factory. At any given time, 10,000 tiny test tubes each holding a few drops of gene-containing fluid are being processed by six technicians, working 24 hours a day, 365 days a year — two on the night shift — using 50 dishwasher-sized machines in two large rooms.
The machines spit out sequence data onto a computer screen in the form of a long list, in order of the letters that make up genetic material.
That is three billion letters if the genes are from a person. Another 64 technicians do the more labour-intensive work of preparing the samples for analysis.
It is all in service of researchers who work for the Broad Institute, a gleaming, lavishly endowed genetics centre a few blocks away. The sequencing centre has worked on human DNA from an international effort, the 1,000 Genomes Project, that looks at the genes of thousands of people from around the world. It has gotten sequences of microbes, like dengue fever, malaria and West Nile virus. It has gotten genetic sequences from animals like chimpanzees.
And it is here that Broad scientists studying Ebola and a similar deadly disease, Lassa, send their samples, taking advantage of what the centre’s manager, Andrew J Hollinger, referred to as superfast track sequencing in their urgent work on these diseases ravaging West Africa. Those scientists receive their sequence data in about 40 hours, compared with days for the usual work.
The Ebola and Lassa group, led by Pardis Sabeti, wants to know what the viruses look like. Do they mutate while they are infecting people, possibly evading the immune system? Are some strains more deadly than others? And what about the genetics of the people who are infected? Are some people more resistant, perhaps even immune, to these viruses because of tweaks in their own genes?
The research is emblematic of a new direction in public health, which uses powerful genetic methods and applies them to entire populations.
The aim is to get a detailed picture of disease epidemiology, as the disease is happening. Armed with such data, doctors should be better able to stop epidemics and researchers can get clues to treating and preventing infections.
In one of their first investigations, the group traced the start of the Ebola epidemic in Sierra Leone from a single funeral in May that ended up infecting 14 women. One person who had been at that funeral showed up at Kenema Government Hospital a few hours drive away from the village where the funeral was held.
As the group examined the genetics of the Ebola viruses in different patients — 78 in the first few weeks of the outbreak in Sierra Leone — they noticed the virus was continually mutating, which raises questions about whether it could become airborne or more deadly. Sabeti said the mutations were not a surprise because that’s what viruses do. But, she added, “it is also always something we should be concerned about.”
While Sabeti and others work on Ebola, they also are working on Lassa and asking the same questions.
Lassa virus is much more common than the Ebola virus, but Lassa and Ebola infections have many of the same symptoms: fever, vomiting, bleeding in some cases.
Lassa also can have dreadful consequences — only 16 per cent of those admitted to hospitals in Sierra Leone with Lassa survive. Lassa, unlike Ebola, infects the brain, so survivors often end up with permanent neurological damage like deafness or dizziness or psychiatric symptoms.
Sabeti’s interest in Lassa was piqued seven years ago, before sequencing reached today’s low price and fast speed. She had decided to look at already-determined DNA sequences from people around the world with a simple question: Are there new gene mutations, ones that only recently emerged in a population, that might protect against disease? The idea was that if a disease entered a population and was deadly, those who carried a protective mutation would survive and reproduce and soon that good mutation would become common.
She saw one such mutation in Nigeria — it was a slight tweak in a gene and so common that 34 per cent of the population there has it. The gene, called LARGE, named because it is so huge, is 10 to 50 times bigger than other genes. The gene still functioned, but why did so many people have this variation?
Elsewhere in the world, the mutation was unheard-of. This told her that it was likely that the mutation was protective. To confirm her suspicion, she had to get data —cells from people who were exposed to Lassa and fell ill and those with similar exposure who resisted the virus. That way, she could test whether the LARGE mutation was linked to a better outcome. It is a difficult project and still underway, but so far, based on a small set of data, the mutation in LARGE does appear to be protective.
“There are hundreds of mutations evolving in individuals,” she added. She said the work could also help with the development of methods of diagnosing the diseases as well as work on vaccines and treatments.
There should be practical payoffs, too. People who come to clinics ill with fevers or diarrhoea or vomiting could receive an accurate diagnosis. Many clinics send blood samples to labs to test for Ebola, but those with Lassa have just been sent away, told that what they had was “not Ebola,” which does not help much.
“I proposed years ago to do a genetic study with Ebola,” Sabeti said. But it was infeasible: There were too few patients. The situation, unfortunately, has changed.