Genetically Sequencing Healthy Babies Yielded Surprising Results
Today in Melrose, Massachusetts, Cora Stetson is the picture of good health, a bubbly precocious 2-year-old. But Cora has two separate mutations in the gene that produces a critical enzyme called biotinidase and her body produces only 40 percent of the normal levels of that enzyme.
In the last few years, the dream of predicting and preventing diseases through genomics, starting in childhood, is finally within reach.
That's enough to pass conventional newborn (heelstick) screening, but may not be enough for normal brain development, putting baby Cora at risk for seizures and cognitive impairment. But thanks to an experimental study in which Cora's DNA was sequenced after birth, this condition was discovered and she is being treated with a safe and inexpensive vitamin supplement.
Stories like these are beginning to emerge from the BabySeq Project, the first clinical trial in the world to systematically sequence healthy newborn infants. This trial was led by my research group with funding from the National Institutes of Health. While still controversial, it is pointing the way to a future in which adults, or even newborns, can receive comprehensive genetic analysis in order to determine their risk of future disease and enable opportunities to prevent them.
Some believe that medicine is still not ready for genomic population screening, but others feel it is long overdue. After all, the sequencing of the Human Genome Project was completed in 2003, and with this milestone, it became feasible to sequence and interpret the genome of any human being. The costs have come down dramatically since then; an entire human genome can now be sequenced for about $800, although the costs of bioinformatic and medical interpretation can add another $200 to $2000 more, depending upon the number of genes interrogated and the sophistication of the interpretive effort.
Two-year-old Cora Stetson, whose DNA sequencing after birth identified a potentially dangerous genetic mutation in time for her to receive preventive treatment.
(Photo courtesy of Robert Green)
The ability to sequence the human genome yielded extraordinary benefits in scientific discovery, disease diagnosis, and targeted cancer treatment. But the ability of genomes to detect health risks in advance, to actually predict the medical future of an individual, has been mired in controversy and slow to manifest. In particular, the oft-cited vision that healthy infants could be genetically tested at birth in order to predict and prevent the diseases they would encounter, has proven to be far tougher to implement than anyone anticipated.
But in the last few years, the dream of predicting and preventing diseases through genomics, starting in childhood, is finally within reach. Why did it take so long? And what remains to be done?
Great Expectations
Part of the problem was the unrealistic expectations that had been building for years in advance of the genomic science itself. For example, the 1997 film Gattaca portrayed a near future in which the lifetime risk of disease was readily predicted the moment an infant is born. In the fanfare that accompanied the completion of the Human Genome Project, the notion of predicting and preventing future disease in an individual became a powerful meme that was used to inspire investment and public support for genomic research long before the tools were in place to make it happen.
Another part of the problem was the success of state-mandated newborn screening programs that began in the 1960's with biochemical tests of the "heel-stick" for babies with metabolic disorders. These programs have worked beautifully, costing only a few dollars per baby and saving thousands of infants from death and severe cognitive impairment. It seemed only logical that a new technology like genome sequencing would add power and promise to such programs. But instead of embracing the notion of newborn sequencing, newborn screening laboratories have thus far rejected the entire idea as too expensive, too ambiguous, and too threatening to the comfortable constituency that they had built within the public health framework.
"What can you find when you look as deeply as possible into the medical genomes of healthy individuals?"
Creating the Evidence Base for Preventive Genomics
Despite a number of obstacles, there are researchers who are exploring how to achieve the original vision of genomic testing as a tool for disease prediction and prevention. For example, in our NIH-funded MedSeq Project, we were the first to ask the question: "What can you find when you look as deeply as possible into the medical genomes of healthy individuals?"
Most people do not understand that genetic information comes in four separate categories: 1) dominant mutations putting the individual at risk for rare conditions like familial forms of heart disease or cancer, (2) recessive mutations putting the individual's children at risk for rare conditions like cystic fibrosis or PKU, (3) variants across the genome that can be tallied to construct polygenic risk scores for common conditions like heart disease or type 2 diabetes, and (4) variants that can influence drug metabolism or predict drug side effects such as the muscle pain that occasionally occurs with statin use.
The technological and analytical challenges of our study were formidable, because we decided to systematically interrogate over 5000 disease-associated genes and report results in all four categories of genetic information directly to the primary care physicians for each of our volunteers. We enrolled 200 adults and found that everyone who was sequenced had medically relevant polygenic and pharmacogenomic results, over 90 percent carried recessive mutations that could have been important to reproduction, and an extraordinary 14.5 percent carried dominant mutations for rare genetic conditions.
A few years later we launched the BabySeq Project. In this study, we restricted the number of genes to include only those with child/adolescent onset that could benefit medically from early warning, and even so, we found 9.4 percent carried dominant mutations for rare conditions.
At first, our interpretation around the high proportion of apparently healthy individuals with dominant mutations for rare genetic conditions was simple – that these conditions had lower "penetrance" than anticipated; in other words, only a small proportion of those who carried the dominant mutation would get the disease. If this interpretation were to hold, then genetic risk information might be far less useful than we had hoped.
Suddenly the information available in the genome of even an apparently healthy individual is looking more robust, and the prospect of preventive genomics is looking feasible.
But then we circled back with each adult or infant in order to examine and test them for any possible features of the rare disease in question. When we did this, we were surprised to see that in over a quarter of those carrying such mutations, there were already subtle signs of the disease in question that had not even been suspected! Now our interpretation was different. We now believe that genetic risk may be responsible for subclinical disease in a much higher proportion of people than has ever been suspected!
Meanwhile, colleagues of ours have been demonstrating that detailed analysis of polygenic risk scores can identify individuals at high risk for common conditions like heart disease. So adding up the medically relevant results in any given genome, we start to see that you can learn your risks for a rare monogenic condition, a common polygenic condition, a bad effect from a drug you might take in the future, or for having a child with a devastating recessive condition. Suddenly the information available in the genome of even an apparently healthy individual is looking more robust, and the prospect of preventive genomics is looking feasible.
Preventive Genomics Arrives in Clinical Medicine
There is still considerable evidence to gather before we can recommend genomic screening for the entire population. For example, it is important to make sure that families who learn about such risks do not suffer harms or waste resources from excessive medical attention. And many doctors don't yet have guidance on how to use such information with their patients. But our research is convincing many people that preventive genomics is coming and that it will save lives.
In fact, we recently launched a Preventive Genomics Clinic at Brigham and Women's Hospital where information-seeking adults can obtain predictive genomic testing with the highest quality interpretation and medical context, and be coached over time in light of their disease risks toward a healthier outcome. Insurance doesn't yet cover such testing, so patients must pay out of pocket for now, but they can choose from a menu of genetic screening tests, all of which are more comprehensive than consumer-facing products. Genetic counseling is available but optional. So far, this service is for adults only, but sequencing for children will surely follow soon.
As the costs of sequencing and other Omics technologies continue to decline, we will see both responsible and irresponsible marketing of genetic testing, and we will need to guard against unscientific claims. But at the same time, we must be far more imaginative and fast moving in mainstream medicine than we have been to date in order to claim the emerging benefits of preventive genomics where it is now clear that suffering can be averted, and lives can be saved. The future has arrived if we are bold enough to grasp it.
Funding and Disclosures:
Dr. Green's research is supported by the National Institutes of Health, the Department of Defense and through donations to The Franca Sozzani Fund for Preventive Genomics. Dr. Green receives compensation for advising the following companies: AIA, Applied Therapeutics, Helix, Ohana, OptraHealth, Prudential, Verily and Veritas; and is co-founder and advisor to Genome Medical, Inc, a technology and services company providing genetics expertise to patients, providers, employers and care systems.
Cleaning has taken on a whole new meaning in Frank Mosco's household during the COVID-19 pandemic. There's a protocol for everything he and his two teenage daughters do.
Experts agree that over-disinfecting is better than inadequate disinfecting, especially during a pandemic.
"We wipe down every package that comes into the house and the items inside," says Mosco, a technologist and social justice activist in Hastings-on-Hudson, N.Y. "If it's a fruit or vegetable, I use vinegar and water, or water and soap. Then we throw out the boxes, clean up the table, and wash our hands." Only then do they put items away.
As the novel coronavirus continues to pose an invisible threat, parents of infants to adolescents are pondering how vigorously and frequently to clean and disinfect surfaces at home and apply hand sanitizer in public. They also fret over whether there can be too much of a good thing: Will making everything as seemingly germ-free as possible reduce immunity down the road?
Experts agree that over-disinfecting is better than inadequate disinfecting, especially during a pandemic. Every family should assess their particular risks. Factors to consider include pre-existing medical conditions, the number of people living in the same home, and whether anyone works in a hospital or other virus-prone environment, says Kari Debbink, assistant professor of biology at Bowie State University in Bowie, Maryland.
Constantly cleaning everything in sight isn't necessary, she explains, because coronavirus tends to spread mainly via immediate contact with respiratory droplets—catching it from surfaces is a less-likely scenario. The longer the virus stays on a surface, the less contagious it becomes.
Some parents worry that their children's growing bodies may become accustomed to an environment that is "too clean." Debbink, a virologist, offers a salient reminder: "The immune system comes into contact with many, many different antigens every day, and it is 'trained' from birth onwards to respond to pathogens. Doing a little more cleansing and disinfecting during the pandemic will not weaken the immune system."
Other experts agree. "There should be no negative outcome to properly washing your hands more frequently," says Stacey Schultz-Cherry, an infectious diseases specialist at St. Jude Children's Research Hospital in Memphis, Tennessee. "Even with enhanced disinfection, kids are still getting exposed to immune-boosting microbes from playing outside, having pets, etc."
"There's no reason why hand sanitizer would weaken anyone's immune system of any age."
Applying hand sanitizer consisting of at least 60 percent alcohol helps clean hands while outdoors, says Angela Rasmussen, associate research scientist and a virologist at Columbia University's Mailman School of Public Health in New York. "There's no reason why hand sanitizer would weaken anyone's immune system of any age," she adds, and recommends moisturizer so hands don't dry out from frequent use. Meanwhile, "cleaning and disinfecting at home also don't have an impact on antiviral immunity, in kids or adults."
With the coronavirus foremost in parents' minds, Patricia Garcia, a pediatric hospitalist, has fielded many questions about how thoroughly they should wipe, rub, scrub, or mop. As medical director of Connecticut Children's Healthy Homes Program in Hartford, which takes aim at toxins and other housing hazards, she reassures them with this mantra: "You're never going to get it perfectly sterilized, and that's okay."
To quell some of these concerns, in March the U.S. Environmental Protection Agency (EPA) released a list of products for household use. None of these products have been specifically tested against SARS-CoV-2, the novel coronavirus that causes COVID-19. But the agency expects these products to be effective because they have demonstrated efficacy against a different human coronavirus similar to SARS-CoV-2 or an even harder-to-kill virus.
Many products on the list contain isopropyl alcohol or hydrogen peroxide. "When using an EPA-registered disinfectant," the agency's website instructs, "follow the label directions for safe, effective use. Make sure to follow the contact time, which is the amount of time the surface should be visibly wet."
Bear in mind that not all cleaners actually disinfect, cautions Alan Woolf, a pediatrician at Boston Children's Hospital who directs its environmental health center and is a professor at Harvard Medical School. Some cleaners remove visible dirt, grease, and grime, but they don't kill viruses. Disinfectants by their nature inactivate both bacteria and viruses. "That's an important distinction," Woolf says.
Frequently touched surfaces—for instance, doorknobs, light switches, toilet-flushing levers, and countertops—should not only be cleaned, but also disinfected at least daily during a pandemic if someone in the household is sick. The objects one touches upon coming home are the ones most likely to become contaminated with viruses, experts say.
Before bringing items inside, "it might be good to clear off a counter space where they will be placed," says Debbink, the biology professor and virologist. "This way, they come into contact with as few items and surfaces as possible."
If space permits, another option would be to set aside nonperishable items. "I've heard of some families putting things in a 'mud room' and closing the door for 48 hours, some leaving things in their garage or car trunk," says Stephanie Holm, co-director of the Western States Pediatric Environmental Health Specialty Unit at the University of California, San Francisco. "Letting new purchases sit for 48 hours undisturbed would greatly reduce the number of viable viruses present."
Cleaning surfaces is recommended before disinfecting them. Holm suggests using unscented soap and microfiber cloths instead of paper towels, which can transmit bacteria and viruses from one area to another.
Soap has the power to eradicate viruses with at least 20 seconds of contact time. It attacks the coronavirus's protective coat, explains infectious diseases specialist Schultz-Cherry. "If you destroy the coat, the virus is no longer infectious. Influenza virus is also very sensitive to soap."
"The most important thing that parents should do for children's immune systems is make sure they are up to date on all their vaccines."
For cribs, toys, and other mouth-contact surfaces, sanitizing with soap and water, not disinfectants, is advisable, says pediatrician Woolf. Fresh fruits and vegetables also can be cleaned with soap, removing dirt and pesticide residue, he adds.
"Some parents are nervous about using disinfectant on toys, which is understandable, considering many toys end up in children's mouths, so soap and water can be an alternative," says pediatrician Garcia, who recommends using hot water.
While some toys can go in the washing machine and dryer or dishwasher, others need to be cleaned by hand, with dish soap or a delicate detergent, as indicated on their labels. But toys with electrical components cannot be submerged in water, in which case consulting the EPA's list of disinfectants may be a parent's best option, she says.
Labels on the back of cleaning and disinfecting products also contain specific instructions. Not allowing a liquid to sit on a surface for the recommended time results in exposure to chemicals without even accomplishing the intended purpose of disinfection. For most household bleach-containing agents, the advisable "dwell time" is 10 minutes. "Many people don't realize this," says Holm, the environmental health specialist who also trained as a physician.
Beware of combining any type of cleaners or disinfectants that aren't already premixed. Doing so can release harmful gases into the air, she cautions.
During the pandemic, Mosco and his daughters have been very conscientious about decontaminating whatever comes through their doors. Mosco says he doesn't believe the family is overusing cleaning and disinfecting products. Although he's fastidious, he says, "a completely sterile environment is not the goal."
His mother, who was a nurse, instilled in him that exposure to some bacteria is a good thing. In turn, he "always encouraged his kids to play with animals, and to have fun in sand and dirt, with plenty of sunlight to keep their immune systems strong."
Even though a vaccine for coronavirus currently doesn't exist, parents can take some comfort in the best weapon available today to protect kids from deadly pathogens: "The most important thing that parents should do for children's immune systems," says virologist Rasmussen, "is make sure they are up to date on all their vaccines."
In October 2006, Craig Mello received a strange phone call from Sweden at 4:30 a.m. The voice at the other end of the line told him to get dressed and that his life was about to change.
"We think this could be effective in [the early] phase, helping the body clear the virus and preventing progression to that severe hyperimmune response which occurs in some patients."
Shortly afterwards, he was informed that along with his colleague Andrew Fire, he had won the Nobel Prize in Physiology or Medicine.
Eight years earlier, biologists Fire and Mello had made a landmark discovery in the history of genetics. In a series of experiments conducted in worms, they had revealed an ancient evolutionary mechanism present in all animals that allows RNA – the structures within our cells that take genetic information from DNA and use it to make proteins – to selectively switch off genes.
At the time, scientists heralded the dawn of a new field of medical research utilizing this mechanism, known as RNA interference or RNAi, to tackle rare genetic diseases and deactivate viruses. Now, 14 years later, the pharmaceutical company Alnylam — which has pioneered the development of RNAi-based treatments over the past decade — is looking to use it to develop a groundbreaking drug for the virus that causes COVID-19.
"We can design small interfering RNAs to target regions of the viral genome and bind to them," said Akin Akinc, who manages several of Alnylam's drug development programs. "What we're learning about COVID-19 is that there's an early phase where there's lots of viral replication and a high viral load. We think this could be effective in that phase, helping the body clear the virus and preventing progression to that severe hyperimmune response which occurs in some patients."
Called ALN-COV, Alnylam's treatment hypothetically works by switching off a key gene in the virus, inhibiting its ability to replicate itself. In order to deliver it to the epithelial cells deep in the lung tissue, where the virus resides, patients will inhale a fine mist containing the RNAi molecules mixed in a saline solution, using a nebulizer.
But before human trials of the drug can begin, the company needs to convince regulators that it is both safe and effective in a series of preclinical trials. While early results appear promising - when mixed with the virus in a test tube, the drug displayed a 95 percent inhibition rate – experts are reserving judgment until it performs in clinical trials.
"If successful this could be a very important milestone in the development of RNAi therapies, but virus infections are very complicated and it can be hard to predict whether a given level of inhibition in cell culture will be sufficient to have a significant impact on the course of the infection," said Si-Ping Han, who researches RNAi therapeutics at California Institute of Technology and is not involved in the development of this drug.
So far, Alnylam has had success in using RNAi to treat rare genetic diseases. It currently has treatments licensed for Hereditary ATTR Amyloidosis and Acute Hepatic Porphyria. Another treatment, for Primary Hyperoxaluria Type 1, is currently under regulatory review. But its only previous attempt to use RNAi to tackle a respiratory infection was a failed effort to develop a drug for respiratory syncytial virus (RSV) almost a decade ago.
However, the technology has advanced considerably since then. "Back then, RNAi drugs had no chemical modifications whatsoever, so they were readily degraded by the body, and they could also result in unintended immune stimulation," said Akinc. "Since then, we've learned how to chemically modify our RNAi's to make them immunosilent and give them improved potency, stability, and duration of action."
"It would be a very important milestone in the development of RNAi therapies."
But one key challenge the company will face is the sheer speed at which viruses evolve, meaning they can become drug-resistant very quickly. Scientists predict that Alnylam will ultimately have to develop a series of RNAi drugs for the coronavirus that work together.
"There's been considerable interest in using RNAi to treat viral infections, as RNA therapies can be developed more rapidly than protein therapies like monoclonal antibodies, since one only needs to know the viral genome sequence to begin to design them," said David Schaffer, professor of bioengineering at University of California, Berkeley. "But viruses can evolve their sequences rapidly around single drugs so it is likely that a combinatorial RNAi therapy may be needed."
In the meantime, Alnylam is conducting further preclinical trials over the summer and fall, with the aim of launching testing in human volunteers by the end of this year -- an ambitious aim that would represent a breakneck pace for a drug development program.
If the approach does ultimately succeed, it would represent a major breakthrough for the field as a whole, potentially opening the door to a whole new wave of RNAi treatments for different lung infections and diseases.
"It would be a very important milestone in the development of RNAi therapies," said Han, the Caltech researcher. "It would be both the first time that an RNAi drug has been successfully used to treat a respiratory infection and as far as I know, the first time that one has been successful in treating any disease in the lungs. RNAi is a platform that can be reconfigured to hit different targets, and so once the first drug has been developed, we can expect a rapid flow of variants targeting other respiratory infections or other lung diseases."