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.
How Emerging Technologies Can Help Us Fight the New Coronavirus
In nature, few species remain dominant for long. Any sizable population of similar individuals offers immense resources to whichever parasite can evade its defenses, spreading rapidly from one member to the next.
Which will prove greater: our defenses or our vulnerabilities?
Humans are one such dominant species. That wasn't always the case: our hunter-gatherer ancestors lived in groups too small and poorly connected to spread pathogens like wildfire. Our collective vulnerability to pandemics began with the dawn of cities and trade networks thousands of years ago. Roman cities were always demographic sinks, but never more so than when a pandemic agent swept through. The plague of Cyprian, the Antonine plague, the plague of Justinian – each is thought to have killed over ten million people, an appallingly high fraction of the total population of the empire.
With the advent of sanitation, hygiene, and quarantines, we developed our first non-immunological defenses to curtail the spread of plagues. With antibiotics, we began to turn the weapons of microbes against our microbial foes. Most potent of all, we use vaccines to train our immune systems to fight pathogens before we are even exposed. Edward Jenner's original vaccine alone is estimated to have saved half a billion lives.
It's been over a century since we suffered from a swift and deadly pandemic. Even the last deadly influenza of 1918 killed only a few percent of humanity – nothing so bad as any of the Roman plagues, let alone the Black Death of medieval times.
How much of our recent winning streak has been due to luck?
Much rides on that question, because the same factors that first made our ancestors vulnerable are now ubiquitous. Our cities are far larger than those of ancient times. They're inhabited by an ever-growing fraction of humanity, and are increasingly closely connected: we now routinely travel around the world in the course of a day. Despite urbanization, global population growth has increased contact with wild animals, creating more opportunities for zoonotic pathogens to jump species. Which will prove greater: our defenses or our vulnerabilities?
The tragic emergence of coronavirus 2019-nCoV in Wuhan may provide a test case. How devastating this virus will become is highly uncertain at the time of writing, but its rapid spread to many countries is deeply worrisome. That it seems to kill only the already infirm and spare the healthy is small comfort, and may counterintuitively assist its spread: it's easy to implement a quarantine when everyone infected becomes extremely ill, but if carriers may not exhibit symptoms as has been reported, it becomes exceedingly difficult to limit transmission. The virus, a distant relative of the more lethal SARS virus that killed 800 people in 2002 to 2003, has evolved to be transmitted between humans and spread to 18 countries in just six weeks.
Humanity's response has been faster than ever, if not fast enough. To its immense credit, China swiftly shared information, organized and built new treatment centers, closed schools, and established quarantines. The Coalition for Epidemic Preparedness Innovations, which was founded in 2017, quickly funded three different companies to develop three different varieties of vaccine: a standard protein vaccine, a DNA vaccine, and an RNA vaccine, with more planned. One of the agreements was signed after just four days of discussion, far faster than has ever been done before.
The new vaccine candidates will likely be ready for clinical trials by early summer, but even if successful, it will be additional months before the vaccine will be widely available. The delay may well be shorter than ever before thanks to advances in manufacturing and logistics, but a delay it will be.
The 1918 influenza virus killed more than half of its victims in the United Kingdom over just three months.
If we faced a truly nasty virus, something that spreads like pandemic influenza – let alone measles – yet with the higher fatality rate of, say, H7N9 avian influenza, the situation would be grim. We are profoundly unprepared, on many different levels.
So what would it take to provide us with a robust defense against pandemics?
Minimize the attack surface: 2019-nCoV jumped from an animal, most probably a bat, to humans. China has now banned the wildlife trade in response to the epidemic. Keeping it banned would be prudent, but won't be possible in all nations. Still, there are other methods of protection. Influenza viruses commonly jump from birds to pigs to humans; the new coronavirus may have similarly passed through a livestock animal. Thanks to CRISPR, we can now edit the genomes of most livestock. If we made them immune to known viruses, and introduced those engineered traits to domesticated animals everywhere, we would create a firewall in those intermediate hosts. We might even consider heritably immunizing the wild organisms most likely to serve as reservoirs of disease.
None of these defenses will be cheap, but they'll be worth every penny.
Rapid diagnostics: We need a reliable method of detection costing just pennies to be available worldwide inside of a week of discovering a new virus. This may eventually be possible thanks to a technology called SHERLOCK, which is based on a CRISPR system more commonly used for precision genome editing. Instead of using CRISPR to find and edit a particular genome sequence in a cell, SHERLOCK programs it to search for a desired target and initiate an easily detected chain reaction upon discovery. The technology is capable of fantastic sensitivity: with an attomolar (10-18) detection limit, it senses single molecules of a unique DNA or RNA fingerprint, and the components can be freeze-dried onto paper strips.
Better preparations: China acted swiftly to curtail the spread of the Wuhan virus with traditional public health measures, but not everything went as smoothly as it might have. Most cities and nations have never conducted a pandemic preparedness drill. Best give people a chance to practice keeping the city barely functional while minimizing potential exposure events before facing the real thing.
Faster vaccines: Three months to clinical trials is too long. We need a robust vaccine discovery and production system that can generate six candidates within a week of the pathogen's identification, manufacture a million doses the week after, and scale up to a hundred million inside of a month. That may be possible for novel DNA and RNA-based vaccines, and indeed anything that can be delivered using a standardized gene therapy vector. For example, instead of teaching each person's immune system to evolve protective antibodies by showing it pieces of the virus, we can program cells to directly produce known antibodies via gene therapy. Those antibodies could be discovered by sifting existing diverse libraries of hundreds of millions of candidates, computationally designed from scratch, evolved using synthetic laboratory ecosystems, or even harvested from the first patients to report symptoms. Such a vaccine might be discovered and produced fast enough at scale to halt almost any natural pandemic.
Robust production and delivery: Our defenses must not be vulnerable to the social and economic disruptions caused by a pandemic. Unfortunately, our economy selects for speed and efficiency at the expense of robustness. Just-in-time supply chains that wing their way around the world require every node to be intact. If workers aren't on the job producing a critical component, the whole chain breaks until a substitute can be found. A truly nasty pandemic would disrupt economies all over the world, so we will need to pay extra to preserve the capacity for independent vertically integrated production chains in multiple nations. Similarly, vaccines are only useful if people receive them, so delivery systems should be as robustly automated as possible.
None of these defenses will be cheap, but they'll be worth every penny. Our nations collectively spend trillions on defense against one another, but only billions to protect humanity from pandemic viruses known to have killed more people than any human weapon. That's foolish – especially since natural animal diseases that jump the species barrier aren't the only pandemic threats.
We will eventually make our society immune to naturally occurring pandemics, but that day has not yet come, and future pandemic viruses may not be natural.
The complete genomes of all historical pandemic viruses ever to have been sequenced are freely available to anyone with an internet connection. True, these are all agents we've faced before, so we have a pre-existing armory of pharmaceuticals and vaccines and experience. There's no guarantee that they would become pandemics again; for example, a large fraction of humanity is almost certainly immune to the 1918 influenza virus due to exposure to the related 2009 pandemic, making it highly unlikely that the virus would take off if released.
Still, making the blueprints publicly available means that a large and growing number of people with the relevant technical skills can single-handedly make deadly biological agents that might be able to spread autonomously -- at least if they can get their hands on the relevant DNA. At present, such people most certainly can, so long as they bother to check the publicly available list of which gene synthesis companies do the right thing and screen orders -- and by implication, which ones don't.
One would hope that at least some of the companies that don't advertise that they screen are "honeypots" paid by intelligence agencies to catch would-be bioterrorists, but even if most of them are, it's still foolish to let individuals access that kind of destructive power. We will eventually make our society immune to naturally occurring pandemics, but that day has not yet come, and future pandemic viruses may not be natural. Hence, we should build a secure and adaptive system capable of screening all DNA synthesis for known and potential future pandemic agents... without disclosing what we think is a credible bioweapon.
Whether or not it becomes a global pandemic, the emergence of Wuhan coronavirus has underscored the need for coordinated action to prevent the spread of pandemic disease. Let's ensure that our reactive response minimally prepares us for future threats, for one day, reacting may not be enough.
This Dog's Nose Is So Good at Smelling Cancer That Scientists Are Trying to Build One Just Like It
Daisy wouldn't leave Claire Guest alone. Instead of joining Guest's other dogs for a run in the park, the golden retriever with the soulful eyes kept nudging Guest's chest, and stared at her intently, somehow hoping she'd get the message.
"I was incredibly lucky to be told by Daisy."
When Guest got home, she detected a tiny lump in one of her breasts. She dismissed it, but her sister, who is a family doctor, insisted she get it checked out.
That saved her life. A series of tests, including a biopsy and a mammogram, revealed the cyst was benign. But doctors discovered a tumor hidden deep inside her chest wall, an insidious malignancy that normally isn't detected until the cancer has rampaged out of control throughout the body. "My prognosis would have been very poor," says Guest, who is an animal behavioralist. "I was incredibly lucky to be told by Daisy."
Ironically, at the time, Guest was training hearing dogs for the deaf—alerting them to doorbells or phones--for a charitable foundation. But she had been working on a side project to harness dogs' exquisitely sensitive sense of smell to spot cancer at its earliest and most treatable stages. When Guest was diagnosed with cancer two decades ago, however, the use of dogs to detect diseases was in its infancy and scientific evidence was largely anecdotal.
In the years since, Guest and the British charitable foundation she co-founded with Dr. John Church in 2008, Medical Detection Dogs (MDD), has shown that dogs can be trained to detect odors that predict a looming medical crisis hours in advance, in the case of diabetes or epilepsy, as well as the presence of cancers.
In a proof of principle study published in the BMJ in 2004, they showed dogs had better than a 40 percent success rate in identifying bladder cancer, which was significantly better than random chance (14 percent). Subsequent research indicated dogs can detect odors down to parts per trillion, which is the equivalent of sniffing out a teaspoon of sugar in two Olympic size swimming pools (a million gallons).
American scientists are devising artificial noses that mimic dogs' sense of smell, so these potentially life-saving diagnostic tools are widely available.
But the problem is "dogs can't be scaled up"—it costs upwards of $25,000 to train them—"and you can't keep a trained dog in every oncology practice," says Guest.
The good news is that the pivotal 2004 BMJ paper caught the attention of two American scientists—Andreas Mershin, a physicist at MIT, and Wen-Yee Yee, a chemistry professor at The University of Texas at El Paso. They have joined Guest's quest to leverage canines' highly attuned olfactory systems and devise artificial noses that mimic dogs' sense of smell, so these potentially life-saving diagnostic tools are widely available.
"What we do know is that this is real," says Guest. "Anything that can improve diagnosis of cancer is something we ought to know about."
Dogs have routinely been used for centuries as trackers for hunting and more recently, for ferreting out bombs and bodies. Dogs like Daisy, who went on to become a star performer in Guest's pack of highly trained cancer detecting canines before her death in 2018, have shared a special bond with their human companions for thousands of years. But their vastly superior olfaction is the result of simple anatomy.
Humans possess about six million olfactory receptors—the antenna-like structures inside cell membranes in our nose that latch on to the molecules in the air when we inhale. In contrast, dogs have about 300 million of them and the brain region that analyzes smells is, proportionally, about 40 times greater than ours.
Research indicates that cancerous cells interfere with normal metabolic processes, prompting them to produce volatile organic compounds (VOCs), which enter the blood stream and are either exhaled in our breath or excreted in urine. Dogs can identify these VOCs in urine samples at the tiniest concentrations, 0.001 parts per million, and can be trained to identify the specific "odor fingerprint" of different cancers, although teaching them how to distinguish these signals from background odors is far more complicated than training them to detect drugs or explosives.
For the past fifteen years, Andreas Mershin of MIT has been grappling with this complexity in his quest to devise an artificial nose, which he calls the Nano-Nose, first as a military tool to spot land mines and IEDS, and more recently as a cancer detection tool that can be used in doctors' offices. The ultimate goal is to create an easy-to-use olfaction system powered by artificial intelligence that can fit inside of smartphones and can replicate dogs' ability to sniff out early signs of prostate cancer, which could eliminate a lot of painful and costly biopsies.
Andreas Mershin works on his artificial nose.
Trained canines have a better than 90 percent accuracy in spotting prostate cancer, which is normally difficult to detect. The current diagnostic, the prostate specific antigen test, which measures levels of certain immune system cells associated with prostate cancer, has about as much accuracy "as a coin toss," according to the scientist who discovered PSA. These false positives can lead to unnecessary and horrifically invasive biopsies to retrieve tissue samples.
So far, Mershin's prototype device has the same sensitivity as the dogs—and can detect odors at parts per trillion—but it still can't distinguish that cancer smell in individual human patients the way a dog can. "What we're trying to understand from the dogs is how they look at the data they are collecting so we can copy it," says Mershin. "We still have to make it intelligent enough to know what it is looking at—what we are lacking is artificial dog intelligence."
The intricate parts of the artificial nose are designed to fit inside a smartphone.
At UT El Paso, Wen-Yee Lee and her research team has used the canine olfactory system as a model for a new screening test for prostate cancer, which has a 92 percent accuracy in tests of urine samples and could be eventually developed as a kit similar to the home pregnancy test. "If dogs can do it, we can do it better," says Lee, whose husband was diagnosed with prostate cancer in 2005.
The UT scientists used samples from about 150 patients, and looked at about 9,000 compounds before they were able to zero in on the key VOCs that are released by prostate cancers—"it was like finding a needle in the haystack," says Lee. But a more reliable test that can also distinguish which cancers are more aggressive could help patients decide their best treatment options and avoid invasive procedures that can render them incontinent and impotent.
"This is much more accurate than the PSA—we were able to see a very distinct difference between people with prostate cancer and those without cancer," says Lee, who has been sharing her research with Guest and hopes to have the test on the market within the next few years.
In the meantime, Guest's foundation has drawn the approving attention of royal animal lovers: Camilla, the Duchess of Cornwall, is a patron, which opened up the charitable floodgates and helped legitimize MDD in the scientific community. Even Camilla's mother-in-law, Queen Elizabeth, has had a demonstration of these canny canines' unique abilities.
Claire Guest, and two of MDDs medical detection dogs, Jodie and Nimbus, meet with queen Elizabeth.
"She actually held one of my [artificial] noses in her hand and asked really good questions, including things we hadn't thought of, like the range of how far away a dog can pick up the scent or if this can be used to screen for malaria," says Mershin. "I was floored by this curious 93-year-old lady. Half of humanity's deaths are from chronic diseases and what the dogs are showing is a whole new way of understanding holistic diseases of the system."