Genes shape our response to Covid virus
From infections with no symptoms to why men are more likely to be hospitalized in the ICU and die of COVID-19, new research shows that your genes play a significant role
Early in the pandemic, genetic research focused on the virus because it was readily available. Plus, the virus contains only 30,000 bases in a dozen functional genes, so it's relatively easy and affordable to sequence. Additionally, the rapid mutation of the virus and its ability to escape antibody control fueled waves of different variants and provided a reason to follow viral genetics.
In comparison, there are many more genes of the human immune system and cellular functions that affect viral replication, with about 3.2 billion base pairs. Human studies require samples from large numbers of people, the analysis of each sample is vastly more complex, and sophisticated computer analysis often is required to make sense of the raw data. All of this takes time and large amounts of money, but important findings are beginning to emerge.
Asymptomatics
About half the people exposed to SARS-CoV-2, the virus that causes the COVID-19 disease, never develop symptoms of this disease, or their symptoms are so mild they often go unnoticed. One piece of understanding the phenomena came when researchers showed that exposure to OC43, a common coronavirus that results in symptoms of a cold, generates immune system T cells that also help protect against SARS-CoV-2.
Jill Hollenbach, an immunologist at the University of California at San Francisco, sought to identify the gene behind that immune protection. Most COVID-19 genetic studies are done with the most seriously ill patients because they are hospitalized and thus available. “But 99 percent of people who get it will never see the inside of a hospital for COVID-19,” she says. “They are home, they are not interacting with the health care system.”
Early in the pandemic, when most labs were shut down, she tapped into the National Bone Marrow Donor Program database. It contains detailed information on donor human leukocyte antigens (HLAs), key genes in the immune system that must match up between donor and recipient for successful transplants of marrow or organs. Each HLA can contain alleles, slight molecular differences in the DNA of the HLA, which can affect its function. Potential HLA combinations can number in the tens of thousands across the world, says Hollenbach, but each person has a smaller number of those possible variants.
She teamed up with the COVID-19 Citizen Science Study a smartphone-based study to track COVID-19 symptoms and outcomes, to ask persons in the bone marrow donor registry about COVID-19. The study enlisted more than 30,000 volunteers. Those volunteers already had their HLAs annotated by the registry, and 1,428 tested positive for the virus.
Analyzing five key HLAs, she found an allele in the gene HLA-B*15:01 that was significantly overrepresented in people who didn’t have any symptoms. The effect was even stronger if a person had inherited the allele from both parents; these persons were “more than eight times more likely to remain asymptomatic than persons who did not carry the genetic variant,” she says. Altogether this HLA was present in about 10 percent of the general European population but double that percentage in the asymptomatic group. Hollenbach and her colleagues were able confirm this in other different groups of patients.
What made the allele so potent against SARS-CoV-2? Part of the answer came from x-ray crystallography. A key element was the molecular shape of parts of the cold virus OC43 and SARS-CoV-2. They were virtually identical, and the allele could bind very tightly to them, present their molecular antigens to T cells, and generate an extremely potent T cell response to the viruses. And “for whatever reasons that generated a lot of memory T cells that are going to stick around for a long time,” says Hollenbach. “This T cell response is very early in infection and ramps up very quickly, even before the antibody response.”
Understanding the genetics of the immune response to SARS-CoV-2 is important because it provides clues into the conditions of T cells and antigens that support a response without any symptoms, she says. “It gives us an opportunity to think about whether this might be a vaccine design strategy.”
Dead men
A researcher at the Leibniz Institute of Virology in Hamburg Germany, Guelsah Gabriel, was drawn to a question at the other end of the COVID-19 spectrum: why men more likely to be hospitalized and die from the infection. It wasn't that men were any more likely to be exposed to the virus but more likely, how their immune system reacted to it
Several studies had noted that testosterone levels were significantly lower in men hospitalized with COVID-19. And, in general, the lower the testosterone, the worse the prognosis. A year after recovery, about 30 percent of men still had lower than normal levels of testosterone, a condition known as hypogonadism. Most of the men also had elevated levels of estradiol, a female hormone (https://pubmed.ncbi.nlm.nih.gov/34402750/).
Every cell has a sex, expressing receptors for male and female hormones on their surface. Hormones docking with these receptors affect the cells' internal function and the signals they send to other cells. The number and role of these receptors varies from tissue to tissue.
Gabriel began her search by examining whole exome sequences, the protein-coding part of the genome, for key enzymes involved in the metabolism of sex hormones. The research team quickly zeroed in on CYP19A1, an enzyme that converts testosterone to estradiol. The gene that produces this enzyme has a number of different alleles, the molecular variants that affect the enzyme's rate of metabolizing the sex hormones. One genetic variant, CYP19A1 (Thr201Met), is typically found in 6.2 percent of all people, both men and women, but remarkably, they found it in 68.7 percent of men who were hospitalized with COVID-19.
Lung surprise
Lungs are the tissue most affected in COVID-19 disease. Gabriel wondered if the virus might be affecting expression of their target gene in the lung so that it produces more of the enzyme that converts testosterone to estradiol. Studying cells in a petri dish, they saw no change in gene expression when they infected cells of lung tissue with influenza and the original SARS-CoV viruses that caused the SARS outbreak in 2002. But exposure to SARS-CoV-2, the virus responsible for COVID-19, increased gene expression up to 40-fold, Gabriel says.
Did the same thing happen in humans? Autopsy examination of patients in three different cites found that “CYP19A1 was abundantly expressed in the lungs of COVID-19 males but not those who died of other respiratory infections,” says Gabriel. This increased enzyme production led likely to higher levels of estradiol in the lungs of men, which “is highly inflammatory, damages the tissue, and can result in fibrosis or scarring that inhibits lung function and repair long after the virus itself has disappeared.” Somehow the virus had acquired the capacity to upregulate expression of CYP19A1.
Only two COVID-19 positive females showed increased expression of this gene. The menopause status of these women, or whether they were on hormone replacement therapy was not known. That could be important because female hormones have a protective effect for cardiovascular disease, which women often lose after going through menopause, especially if they don’t start hormone replacement therapy. That sex-specific protection might also extend to COVID-19 and merits further study.
The team was able to confirm their findings in golden hamsters, the animal model of choice for studying COVID-19. Testosterone levels in male animals dropped 5-fold three days after infection and began to recover as viral levels declined. CYP19A1 transcription increased up to 15-fold in the lungs of the male but not the females. The study authors wrote, “Virus replication in the male lungs was negatively associated with testosterone levels.”
The medical community studying COVID-19 has slowly come to recognize the importance of adipose tissue, or fat cells. They are known to express abundant levels of CYP19A1 and play a significant role as metabolic tissue in COVID-19. Gabriel adds, “One of the key findings of our study is that upon SARS-CoV-2 infection, the lung suddenly turns into a metabolic organ by highly expressing” CYP19A1.
She also found evidence that SARS-CoV-2 can infect the gonads of hamsters, thereby likely depressing circulating levels of sex hormones. The researchers did not have autopsy samples to confirm this in humans, but others have shown that the virus can replicate in those tissues.
A possible treatment
Back in the lab, substituting low and high doses of testosterone in SARS-COV-2 infected male hamsters had opposite effects depending on testosterone dosage used. Gabriel says that hormone levels can vary so much, depending on health status and age and even may change throughout the day, that “it probably is much better to inhibit the enzyme” produced by CYP19A1 than try to balance the hormones.
Results were better with letrozole, a drug approved to treat hypogonadism in males, which reduces estradiol levels. The drug also showed benefit in male hamsters in terms of less severe disease and faster recovery. She says more details need to be worked out in using letrozole to treat COVID-19, but they are talking with hospitals about clinical trials of the drug.
Gabriel has proposed a four hit explanation of how COVID-19 can be so deadly for men: the metabolic quartet. First is the genetic risk factor of CYP19A1 (Thr201Met), then comes SARS-CoV-2 infection that induces even greater expression of this gene and the deleterious increase of estradiol in the lung. Age-related hypogonadism and the heightened inflammation of obesity, known to affect CYP19A1 activity, are contributing factors in this deadly perfect storm of events.
Studying host genetics, says Gabriel, can reveal new mechanisms that yield promising avenues for further study. It’s also uniting different fields of science into a new, collaborative approach they’re calling “infection endocrinology,” she says.
Your surgery could harm yourself and the planet. Here's what some doctors are doing about it.
This is part 1 of a three part series on a new generation of doctors leading the charge to make the health care industry more sustainable - for the benefit of their patients and the planet. Read part 2 here and part 3 here.
Susanne Koch, an anesthesiologist and neurologist, reached a pivot point when she was up to her neck in water, almost literally. The basement of her house in Berlin had flooded in the summer of 2018, when Berlin was pummeled by unusually strong rains. After she drained the house, “I wanted to dig into facts, to understand how exactly these extreme weather events are related to climate change,” she says.
Studying the scientific literature, she realized how urgent the climate crisis is, but the biggest shock was to learn that her profession contributed substantially to the problem: Inhalation gases used during medical procedures are among the most damaging greenhouse gases. Some inhalation gases are 3,000 times more damaging for the climate than CO2, Koch discovered. “Spending seven hours in the surgery room is the equivalent of driving a car for four days nonstop,” she says. Her job of helping people at Europe’s largest university hospital, the Charité in Berlin, was inadvertently damaging both the people and the planet.
“Nobody had ever even mentioned a word about that during my training,” Koch says.
On the whole, the medical sector is responsible for a disproportionally large percentage of greenhouse gas emissions, with the U.S. as the biggest culprit. According to a key paper published in 2020 in Health Affairs, the health industry “is among the most carbon-intensive service sectors in the industrialized world,” accounting for between 4.4 percent and 4.6 percent of greenhouse gas emissions. “It’s not just anesthesia but health care that has a problem,” says Jodi Sherman, anesthesiology professor and Medical Director of the Program on Healthcare Environmental Sustainability at Yale University as well as co-director of the Lancet Planetary Health Commission on Sustainable Healthcare. In the U.S., health care greenhouse gas emissions make up about 8.5 percent of domestic greenhouse gas emissions. They rose 6 percent from 2010 to 2018, to nearly 1,700 kilograms per person, more than in any other nation.
Of course, patients worry primarily about safety, not sustainability. Yet, Koch emphasizes that “as doctors, we have the responsibility to do no harm, and this includes making sure that we use resources as sustainably as possible.” Studies show that 2018 greenhouse gas and toxic air pollutant emissions resulted in the loss of 388,000 disability-adjusted life years in the U.S. alone. “Disease burden from health care pollution is of the same order of magnitude as deaths from preventable medical errors, and should be taken just as seriously,” Sherman cautions.
When Koch, the anesthesiologist, started discussing sustainable options with colleagues, the topic was immediately met with plenty of interest. Her experience is consistent with the latest representative poll of the nonprofit Foundation Health in Germany. Nine out of ten doctors were interested in urgently finding sustainable solutions for medical services but lacked knowhow and resources. For teaching purposes, Sherman and her team have developed the Yale Gassing Greener app that allows anesthesiologists to compare how much pollution they can avoid through choosing different anesthesia methods. Sherman also published professional guidelines intended to help her colleagues better understand how various methods affect carbon emissions.
Significant traces of inhalation gases have been found in Antarctica and the Himalayas, far from the vast majority of surgery rooms.
A solution espoused by both Sherman and Koch is comparatively simple: They stopped using desflurane, which is by far the most damaging of all inhalation gases to the climate. Its greenhouse effect is 2,590 times stronger than carbon dioxide. The Yale New Haven Hospital already stopped using desflurane in 2013, becoming the first known healthcare organization to eliminate a drug based on environmental grounds. Sherman points out that this resulted in saving more than $1.2 million in costs and 1,600 tons of CO2 equivalents, about the same as the exhaust from 360 passenger vehicles per year.
At the Charité, Koch claims that switching to other anesthesiology choices, such as propofol, has eliminated 90 percent of the climate gas emissions in the anesthesiology department since 2016. Young anesthesiologists are still taught to use desflurane as the standard because desflurane is absorbed less into the patients’ bodies, and they wake up faster. However, Koch who has worked as an anesthesiologist since 2006, says that with a little bit of experience, you can learn when to stop giving the propofol so it's timed just as well with a person’s wake-up process. In addition, “patients are less likely to feel nauseous after being given propofol,” Koch says. Intravenous drugs might require more skill, she adds, "but there is nothing unique to the drug desflurane that cannot be accomplished with other medications.”
Desflurane isn’t the only gas to be concerned about. Nitrous oxide is the second most damaging because it’s extremely long-lived in the environment, and it depletes the ozone layer. Climate-conscious anesthesiologists are phasing out this gas, too, or have implemented measures to decrease leaks.
Internationally, 192 governments agreed in the Kyoto protocol of 2005 to reduce halogenated hydrocarbons – resulting from inhalation gases, including desflurane and nitrous oxide – because of their immense climate-warming potential, and in 2016, they pledged to eliminate them by 2035. However, the use of inhalation anesthetics continues to increase worldwide, not least because more people access healthcare in developing countries, and because people in industrialized countries live longer and therefore need more surgeries. Significant traces of inhalation gases have been found in Antarctica and the Himalayas, far from the vast majority of surgery rooms.
Certain companies are now pushing new technology to capture inhalation gases before they are released into the atmosphere, but both Sherman and Koch believe marketing claims of 99 percent efficiency amount to greenwashing. After investigating the technology first-hand and visiting the company that is producing such filters in Germany, Koch concluded that such technology only reduces emissions by 25 percent. And Sherman believes such initiatives are akin to the fallacy of recycling plastic. In addition to questioning their efficiency, Sherman fears such technology “gives the illusion there is a magical solution that means I don’t need to change my behavior, reduce my waste and choose less harmful options.”
Financial interests are at play, too. “Desflurane is the most expensive inhalation gas, and some think, the most expensive must be the best,” Koch says. Both Koch and Sherman lament that efforts to increase sustainability in the medical sector are entirely voluntary in their countries and led by a few dedicated individual professionals while industry-wide standards and transparency are needed, a notion expressed in the American Hospital Association’s Sustainability Roadmap.
Susanne Koch, an anesthesiologist in Berlin, wants her colleagues to stop using a gas called desflurane, which is by far the most damaging of all inhalation gases to the climate.
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Other countries have done more. The European Union recommends reducing inhalation gases and even contemplated a ban of desflurane, except in medical emergencies. In 2008, the National Health Service (NHS) created a Sustainable Development Unit, which measures CO2 emissions in the U.K. health sector. NHS is the first national health service that pledged to reach net zero carbon by 2040. The carbon footprint of the NHS fell by 26 percent from 1990 to 2019, mostly due to reduced use of certain inhalers and the switch to renewable energy for heat and power. “The evidence that the climate emergency is a health emergency is overwhelming,” said Nick Watts, the NHS Chief Sustainability Officer, in a press release, “with health professionals already needing to manage its symptoms.”
Sherman is a leading voice in demanding action in the U.S. To her, comprehensive solutions start with the mandatory, transparent measurement of emissions in the health sector to tackle the biggest sources of pollution. While the Biden administration highlighted its efforts to reduce these kinds of emissions during the United Nations Climate Conference (COP27) in November 2022 and U.S. delegates announced that more than 100 health care organizations signed the voluntary Health Sector Climate Pledge, with the aim to reduce emissions by 50 percent in the next eight years, Sherman is convinced that voluntary pledges are not enough. “Voluntary measures are insufficient,” she testified in congress. “The vast majority of U.S. health care organizations remain uncommitted to timely action. Those that are committed lack policies and knowledge to support necessary changes; even worse, existing policies drive inappropriate consumption of resources and pollution.”
Both Sherman and Koch look at the larger picture. “Health care organizations have an obligation to their communities to protect public health,” Sherman says. “We must lead by example. That includes setting ambitious, science-based carbon reduction targets to achieve net zero emissions before 2050. We must quantify current emissions and their sources, particularly throughout the health care supply chains.”
Have You Heard of the Best Sport for Brain Health?
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend.
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Here are the promising studies covered in this week's Friday Five:
- Reprogram cells to a younger state
- Pick up this sport for brain health
- Do all mental illnesses have the same underlying cause?
- New test could diagnose autism in newborns
- Scientists 3D print an ear and attach it to woman