Is Finding Out Your Baby’s Genetics A New Responsibility of Parenting?
Hours after a baby is born, its heel is pricked with a lancet. Drops of the infant's blood are collected on a porous card, which is then mailed to a state laboratory. The dried blood spots are screened for around thirty conditions, including phenylketonuria (PKU), the metabolic disorder that kick-started this kind of newborn screening over 60 years ago. In the U.S., parents are not asked for permission to screen their child. Newborn screening programs are public health programs, and the assumption is that no good parent would refuse a screening test that could identify a serious yet treatable condition in their baby.
Learning as much as you can about your child's health might seem like a natural obligation of parenting. But it's an assumption that I think needs to be much more closely examined.
Today, with the introduction of genome sequencing into clinical medicine, some are asking whether newborn screening goes far enough. As the cost of sequencing falls, should parents take a more expansive look at their children's health, learning not just whether they have a rare but treatable childhood condition, but also whether they are at risk for untreatable conditions or for diseases that, if they occur at all, will strike only in adulthood? Should genome sequencing be a part of every newborn's care?
It's an idea that appeals to Anne Wojcicki, the founder and CEO of the direct-to-consumer genetic testing company 23andMe, who in a 2016 interview with The Guardian newspaper predicted that having newborns tested would soon be considered standard practice—"as critical as testing your cholesterol"—and a new responsibility of parenting. Wojcicki isn't the only one excited to see everyone's genes examined at birth. Francis Collins, director of the National Institutes of Health and perhaps the most prominent advocate of genomics in the United States, has written that he is "almost certain … that whole-genome sequencing will become part of new-born screening in the next few years." Whether that would happen through state-mandated screening programs, or as part of routine pediatric care—or perhaps as a direct-to-consumer service that parents purchase at birth or receive as a baby-shower gift—is not clear.
Learning as much as you can about your child's health might seem like a natural obligation of parenting. But it's an assumption that I think needs to be much more closely examined, both because the results that genome sequencing can return are more complex and more uncertain than one might expect, and because parents are not actually responsible for their child's lifelong health and well-being.
What is a parent supposed to do about such a risk except worry?
Existing newborn screening tests look for the presence of rare conditions that, if identified early in life, before the child shows any symptoms, can be effectively treated. Sequencing could identify many of these same kinds of conditions (and it might be a good tool if it could be targeted to those conditions alone), but it would also identify gene variants that confer an increased risk rather than a certainty of disease. Occasionally that increased risk will be significant. About 12 percent of women in the general population will develop breast cancer during their lives, while those who have a harmful BRCA1 or BRCA2 gene variant have around a 70 percent chance of developing the disease. But for many—perhaps most—conditions, the increased risk associated with a particular gene variant will be very small. Researchers have identified over 600 genes that appear to be associated with schizophrenia, for example, but any one of those confers only a tiny increase in risk for the disorder. What is a parent supposed to do about such a risk except worry?
Sequencing results are uncertain in other important ways as well. While we now have the ability to map the genome—to create a read-out of the pairs of genetic letters that make up a person's DNA—we are still learning what most of it means for a person's health and well-being. Researchers even have a name for gene variants they think might be associated with a disease or disorder, but for which they don't have enough evidence to be sure. They are called "variants of unknown (or uncertain) significance (VUS), and they pop up in most people's sequencing results. In cancer genetics, where much research has been done, about 1 in 5 gene variants are reclassified over time. Most are downgraded, which means that a good number of VUS are eventually designated benign.
While one parent might reasonably decide to learn about their child's risk for a condition about which nothing can be done medically, a different, yet still thoroughly reasonable, parent might prefer to remain ignorant so that they can enjoy the time before their child is afflicted.
Then there's the puzzle of what to do about results that show increased risk or even certainty for a condition that we have no idea how to prevent. Some genomics advocates argue that even if a result is not "medically actionable," it might have "personal utility" because it allows parents to plan for their child's future needs, to enroll them in research, or to connect with other families whose children carry the same genetic marker.
Finding a certain gene variant in one child might inform parents' decisions about whether to have another—and if they do, about whether to use reproductive technologies or prenatal testing to select against that variant in a future child. I have no doubt that for some parents these personal utility arguments are persuasive, but notice how far we've now strayed from the serious yet treatable conditions that motivated governments to set up newborn screening programs, and to mandate such testing for all.
Which brings me to the other problem with the call for sequencing newborn babies: the idea that even if it's not what the law requires, it's what good parents should do. That idea is very compelling when we're talking about sequencing results that show a serious threat to the child's health, especially when interventions are available to prevent or treat that condition. But as I have shown, many sequencing results are not of this type.
While one parent might reasonably decide to learn about their child's risk for a condition about which nothing can be done medically, a different, yet still thoroughly reasonable, parent might prefer to remain ignorant so that they can enjoy the time before their child is afflicted. This parent might decide that the worry—and the hypervigilence it could inspire in them—is not in their child's best interest, or indeed in their own. This parent might also think that it should be up to the child, when he or she is older, to decide whether to learn about his or her risk for adult-onset conditions, especially given that many adults at high familial risk for conditions like Alzheimer's or Huntington's disease choose never to be tested. This parent will value the child's future autonomy and right not to know more than they value the chance to prepare for a health risk that won't strike the child until 40 or 50 years in the future.
Parents are not obligated to learn about their children's risk for a condition that cannot be prevented, has a small risk of occurring, or that would appear only in adulthood.
Contemporary understandings of parenting are famously demanding. We are asked to do everything within our power to advance our children's health and well-being—to act always in our children's best interests. Against that backdrop, the need to sequence every newborn baby's genome might seem obvious. But we should be skeptical. Many sequencing results are complex and uncertain. Parents are not obligated to learn about their children's risk for a condition that cannot be prevented, has a small risk of occurring, or that would appear only in adulthood. To suggest otherwise is to stretch parental responsibilities beyond the realm of childhood and beyond factors that parents can control.
Obesity is a risk factor for worse outcomes for a variety of medical conditions ranging from cancer to Covid-19. Most experts attribute it simply to underlying low-grade inflammation and added weight that make breathing more difficult.
Now researchers have found a more direct reason: SARS-CoV-2, the virus that causes Covid-19, can infect adipocytes, more commonly known as fat cells, and macrophages, immune cells that are part of the broader matrix of cells that support fat tissue. Stanford University researchers Catherine Blish and Tracey McLaughlin are senior authors of the study.
Most of us think of fat as the spare tire that can accumulate around the middle as we age, but fat also is present closer to most internal organs. McLaughlin's research has focused on epicardial fat, “which sits right on top of the heart with no physical barrier at all,” she says. So if that fat got infected and inflamed, it might directly affect the heart.” That could help explain cardiovascular problems associated with Covid-19 infections.
Looking at tissue taken from autopsy, there was evidence of SARS-CoV-2 virus inside the fat cells as well as surrounding inflammation. In fat cells and immune cells harvested from health humans, infection in the laboratory drove "an inflammatory response, particularly in the macrophages…They secreted proteins that are typically seen in a cytokine storm” where the immune response runs amok with potential life-threatening consequences. This suggests to McLaughlin “that there could be a regional and even a systemic inflammatory response following infection in fat.”
It is easy to see how the airborne SARS-CoV-2 virus infects the nose and lungs, but how does it get into fat tissue? That is a mystery and the source of ample speculation.
The macrophages studied by McLaughlin and Blish were spewing out inflammatory proteins, While the the virus within them was replicating, the new viral particles were not able to replicate within those cells. It was a different story in the fat cells. “When [the virus] gets into the fat cells, it not only replicates, it's a productive infection, which means the resulting viral particles can infect another cell,” including microphages, McLaughlin explains. It seems to be a symbiotic tango of the virus between the two cell types that keeps the cycle going.
It is easy to see how the airborne SARS-CoV-2 virus infects the nose and lungs, but how does it get into fat tissue? That is a mystery and the source of ample speculation.
Macrophages are mobile; they engulf and carry invading pathogens to lymphoid tissue in the lymph nodes, tonsils and elsewhere in the body to alert T cells of the immune system to the pathogen. Perhaps some of them also carry the virus through the bloodstream to more distant tissue.
ACE2 receptors are the means by which SARS-CoV-2 latches on to and enters most cells. They are not thought to be common on fat cells, so initially most researchers thought it unlikely they would become infected.
However, while some cell receptors always sit on the surface of the cell, other receptors are expressed on the surface only under certain conditions. Philipp Scherer, a professor of internal medicine and director of the Touchstone Diabetes Center at the University of Texas Southwestern Medical Center, suggests that, in people who have obesity, “There might be higher levels of dysfunctional [fat cells] that facilitate entry of the virus,” either through transiently expressed ACE2 or other receptors. Inflammatory proteins generated by macrophages might contribute to this process.
Another hypothesis is that viral RNA might be smuggled into fat cells as cargo in small bits of material called extracellular vesicles, or EVs, that can travel between cells. Other researchers have shown that when EVs express ACE2 receptors, they can act as decoys for SARS-CoV-2, where the virus binds to them rather than a cell. These scientists are working to create drugs that mimic this decoy effect as an approach to therapy.
Do fat cells play a role in Long Covid? “Fat cells are a great place to hide. You have all the energy you need and fat cells turn over very slowly; they have a half-life of ten years,” says Scherer. Observational studies suggest that acute Covid-19 can trigger the onset of diabetes especially in people who are overweight, and that patients taking medicines to regulate their diabetes “were actually quite protective” against acute Covid-19. Scherer has funding to study the risks and benefits of those drugs in animal models of Long Covid.
McLaughlin says there are two areas of potential concern with fat tissue and Long Covid. One is that this tissue might serve as a “big reservoir where the virus continues to replicate and is sent out” to other parts of the body. The second is that inflammation due to infected fat cells and macrophages can result in fibrosis or scar tissue forming around organs, inhibiting their function. Once scar tissue forms, the tissue damage becomes more difficult to repair.
Current Covid-19 treatments work by stopping the virus from entering cells through the ACE2 receptor, so they likely would have no effect on virus that uses a different mechanism. That means another approach will have to be developed to complement the treatments we already have. So the best advice McLaughlin can offer today is to keep current on vaccinations and boosters and lose weight to reduce the risk associated with obesity.
Air pollution can lead to lung cancer. The connection suggests new ways to stop cancer in its tracks.
Forget taking a deep breath. Around the world, 99 percent of people breathe air polluted to unsafe levels, according to data from the World Health Organization. Activities such as burning fossil fuels release greenhouse gases that contribute to air pollution, which could lead to heart disease, stroke, asthma, emphysema, and some types of cancer.
“The burden of disease attributable to air pollution is now estimated to be on a par with other major global health risks such as unhealthy diet and tobacco smoking, and air pollution is now recognized as the single biggest environmental threat to human health,” wrote the authors of a 2021 WHO report.
The majority of lung cancer is attributed to smoking. But as pollution levels have increased, and anti-smoking campaigns have discouraged smoking, the proportion of lung cancers diagnosed in non-smokers has grown. The CDC estimates that 10 to 20 percent of lung cancers in the U.S. currently occur in non-smokers.
The mechanism between air pollution and the development of lung cancer has been unclear, but researchers at London’s Francis Crick Institute recently made an important breakthrough in understanding the connection. Lead investigator Charles Swanton presented this research last month at a conference in Paris.
Pollution awakens mutations
The Crick Institute scientists were able to identify a new link between common air pollutants and non-small cell lung cancer (NSCLC). They focused on pollutants called particulate matter, or PM, that are 2.5 microns wide, narrower than human cells.
Most cancer diagnosed in non-smoking people is NSCLC, but this type of cancer hasn’t received the same research attention as more common lung cancers found in smokers, according to Clare Weeden, a cancer researcher at the Crick Institute and a co-author of the study.
“This is a really underserved and under-researched population that we really need to tackle, as well as lung cancers that occur in smokers,” she says. “Lung cancer is the number one cancer killer worldwide.”
In the past, some researchers believed air pollution caused mutations that led to cancer. Others believed these mutations could remain dormant without any detriment to health until pollutants or other stressors triggered them to become cancerous. Reviving the latter hypothesis that carcinogens may activate pre-existing mutations, instead of directly causing them, the Crick researchers analyzed samples from 463,679 people in the UK and parts of Asia, noting mutations and comparing changes in gene expression in mice and human cells.
“The mutation can exist in a nascent clone without causing cancer,” says Emilia Lim, a bioinformatics expert and a co-first author of the Crick study. “It is the carcinogen that promotes a conducive environment for this one little clone to grow and expand into cancer. Through our work, we were able to revive excitement for this hypothesis and bring it to light.”
The study explains a confusing pattern of lung cancer developing, particularly in women, despite a lack of environmental risk factors like smoking, secondhand smoke, or radon exposure. The culprit in these cases may have been too much PM 2.5 exposure.
Other researchers had previously identified a link between mutations in certain genes that control epidermal growth factor receptors, or EGFR mutations, and the development of NSCLC. In a 2019 study of 250 people with this type of cancer, about 32 percent had the mutation. Women are more likely to have EGFR mutations than men.
Not everyone who has the EGFR mutation will develop lung cancer. Respirologist Stephen Lam studies lung cancer at the BC Cancer Research Centre in Vancouver, Canada, but was not involved in the Crick Institute research. He says the study explains a confusing pattern of lung cancer developing, particularly in women, despite a lack of environmental risk factors like smoking, secondhand smoke, or radon exposure. The culprit in these cases may have been too much PM 2.5 exposure.
More exposure leads to inflammation and lesions
The Crick researchers found that an excess of PM 2.5 in the air sparked an inflammatory process in cells within the lung. This inflammation set the stage for NSCLC to develop in people and mice with existing EGFR mutations.
The researchers also exposed mice without EGFR mutations to PM 2.5 pollution—an experiment that couldn’t be ethically conducted in humans—to link pollution exposure to NSCLC. The mice experiments also showed that NSCLC is dose-dependent; higher levels of exposure were associated with higher number of cancerous lesions forming.
Ultimately, the study “fundamentally changed how we view lung cancer in people who have never smoked,” said Swanton in a Crick Institute press release. “Cells with cancer-causing mutations accumulate naturally as we age, but they are normally inactive. We’ve demonstrated that air pollution wakes these cells up in the lungs, encouraging them to grow and potentially form tumors.”
Preventing cancer before it begins
Targeted therapies already exist for people with EGFR mutations who’ve developed NSCLC, but they have many side effects, according to Weeden. Researchers hope that making more definitive links between pollutants and cancer could help prevent people with EGFR or other mutations from developing lung cancer in the first place.
Along those lines, as an additional component of their study presented last month, the Crick researchers were able to prevent cancer in mice that had the EGFR mutations by blocking inflammation. They used an antibody to inhibit a protein called interleukin 1 beta, which plays a key role in inflammation. Scientists could eventually use such antibodies or other therapies to make a drug treatment that people can take to stop cancer in its tracks, even if they live in highly polluted areas.
Such potential could reach beyond lung cancer; in the past, Crick and other researchers have also found associations between exposure to air pollution and mesothelioma, as well as cancers of the small intestine, lip, mouth, and throat. These links could be meaningful to a growing number of people as climate change intensifies, and with increases in air pollution from fossil fuel combustion and natural disasters like forest fires.
Plus, air pollution is just one external condition that can flip the switch of these inflammatory pathways. Identifying a link between pollution and cancer “has wide ramifications for many other environmental factors that may [play] similar roles,” Weedon says. She hopes that the Crick study and future research in this area will offer some hope for non-smokers frustrated by cancer diagnoses.