María Branyas, 113 years old and believed to be the oldest woman in Spain, had only mild symptoms of Covid-19. In New Jersey, Governor Phil Murphy praised Sylvia Goldsholl for beating the novel coronavirus at the age of 108. Connie Titchen, 106, received a round of applause from doctors and nurses as she was wheeled out of Birmingham’s City Hospital. She said she felt very lucky to have fought off the virus.
One of the established facts about Covid-19 is that it hits older people hardest — which is why stories of centenarians beating Covid-19 piqued the curiosity of geneticist Mayana Zatz. According to the Centers for Disease Control and Prevention, the risk of dying due to Covid-19 is 630 times higher in people over the age of 85 as compared to young adults ages 18 to 29. So how come some of the oldest of the old are surviving Covid-19 unharmed?
Zatz, who directs the Human Genome and Stem-Cell Research Center at the University of São Paulo, in Brazil, has a hunch that sheer luck is not enough to explain it. She has always been intrigued by how certain seniors seem to effortlessly overcome all kinds of health issues. In the past few years, her team sequenced the whole genome of 1,170 people over 60. One goal of the project, which is the largest genome study of older adults in Latin America, was to identify genetic traits that may contribute to healthy aging. Zatz was in the process of writing the results when the pandemic hit.
“When people ask me why these people are surviving, I usually answer that it’s probably precisely because they are centenarians.”
Now focused on those older than 95 who defeated Covid-19, Zatz is already recruiting and collecting blood samples from people in that age group who were either diagnosed with Covid-19 or were in very close contact with symptomatic Covid-19 patients. “When people ask me why these people are surviving, I usually answer that it’s probably precisely because they are centenarians,” Zatz says. “Apparently, these people have a huge resistance to any challenge coming from the environment, including Covid-19.”
Through whole genome sequencing, she hopes to identify possible genetic mutations associated with Covid-19 super-resistance. “We suspect it’s not a single gene, but a combination of genes,” Zatz says. And if such mutations exist, she wants to know what they do. Are the mutations responsible for altering the function of a certain protein that might contribute to the body’s defense against the virus, for example? If scientists can find a way to trigger that same effect in people without such mutations, that could be a potential new treatment strategy to be explored.
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Another step of the research is to use the centenarians’ blood cells to generate other types of cells in the lab, such as cardiac, respiratory, or nervous cells, and watch how they respond to Covid-19 compared to the cells of people with the disease who developed severe symptoms. In the lab, it is possible to reprogram blood cells into the so-called induced pluripotent stem cells (IPS). These cells behave just like certain cells in a human embryo that are able to grow into different types of tissues. Observing how the virus behaves in the centenarians’ tissues may also open new avenues for treatments, Zatz says.
So far, her research center has enrolled six volunteers, all women, ages 98 to 106, who had only mild symptoms of Covid-19 or no symptoms at all, despite being in close contact with someone diagnosed with the virus.
One of the volunteers is 98-year-old Carmen Ferri. Her 72-year-old son, Antonio, had flulike symptoms in March. Through an online doctor’s appointment, he was misdiagnosed with a sinus infection and treated with antibiotics at home, where he lives with his wife and Carmen. For about 10 days, Antonio continued to have close contact with his mother. As one of Carmen’s main caregivers, he helps her get around the house and use the toilet. These were the early days of the pandemic in Brazil, and no one in the house wore masks.
When Antonio’s symptoms worsened, his son-in-law took him to the hospital, where he was diagnosed with Covid-19 and spent 15 days at the semi-intensive care unit. “We thought it was very curious that my grandmother didn’t get sick after having such close contact with my infected father,” says Adriana Ferri, a former genetics researcher and Carmen’s granddaughter. “I believe there is something different about her. Maybe a protective gene or a strong immune system. I am very curious to see what this research will find.”
To broaden her quest for a resistance gene, Zatz included another group of people in her research: couples where only one of the two got infected with Covid-19. People who managed to escape the virus despite sharing the bed with a symptomatic partner are also potentially resistant, and the scientist hopes their genomes will help answer some of her questions.
Studying these people might also lead to an assessment of how much of the population is naturally resistant to the virus. “Most studies estimate the number of people infected at a given population by looking at the percentage of those with antibodies. But we have no idea how many people, despite not having antibodies, are resistant to the virus,” Zatz says.
Looking at the other outliers
Just as there are centenarians surviving Covid-19, there are, unfortunately, young people without any underlying conditions being defeated by the disease. Zatz’s lab partnered with another team of researchers at the University of São Paulo’s Medical School who are conducting minimally invasive autopsies on people who died with suspected Covid-19. Her team will select young people who died with the disease and no comorbidities and will sequence their genome from skin samples.
In this case, the goal is to look for vulnerability genes. Zatz’s research center is collaborating, alongside several institutions around the world, with an international consortium called the Covid Human Genetic Effort to find the genetic basis of severe coronavirus infection in young people. In a recent article, the team described the hypothesis that severe cases in the young and healthy are due to what’s referred to as “monogenic inborn errors of immunity,” single genes that disrupt a person’s immunity to certain pathogens. The group has recently submitted their first results, still unpublished, to the journal Science.
The idea that there is an interplay between a person’s genetics and how vulnerable they are to a certain pathogen has been around for a while. Long before genome sequencing was made possible, this relationship was explored through twin studies, which are good for revealing if genes are playing a role in a certain disease. A 1943 twin study revealed, for example, that genetic factors may account for a vulnerability to tuberculosis.
Thanks to modern gene sequencing techniques, the search for resistance and vulnerability genes is now possible, and genetics may be the key to solve the mystery of why Covid-19 is so devastating for some people but not for others.