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.
Turning Algae Into Environmentally Friendly Fuel Just Got Faster and Smarter
Was your favorite beach closed this summer? Algae blooms are becoming increasingly the reason to blame and, as the climate heats up, scientists say we can expect more of the warm water-loving blue-green algae to grow.
"We have removed a significant development barrier to make algal biofuel production more efficient and smarter."
Oddly enough, the pesky growth could help fuel our carbon-friendly options.
This year, the University of Utah scientists discovered a faster way to turn algae into fuel. Algae is filled with lipids that we can feed our energy-hungry diesel engines. The problem is extracting the lipids, which usually requires more energy to transform than the actual energy we'd get – not achieving what scientists call "energy parity."
But now, the University of Utah team has discovered a new mix that is more efficient and much faster. We can now extract more power from algae with less waste materials after the fact. Paper co-author Dr. Leonard Pease says, "We have removed a significant development barrier to make algal biofuel production more efficient and smarter. Our method puts us much closer to creating biofuels energy parity than we were before."
Next Up
Algae has a lot going for it as an alternative fuel source. It grows fast and easily, absorbs carbon dioxide, does not compete with food crops for land, and could produce up to 60 times more oil than standard land-based energy crops, according to the U.S. Department of Energy. Yet the costs of algal biofuel production are still expensive for now.
According to Science Daily, only about five percent of total primary energy use in the United States came from algae and other biomass forms. By making the process more efficient, America and other nations could potentially begin relying on more plentiful resources – which, ironically, are more common now because of climate change.
Algae fuel efficiency is already a proven concept. A decade ago, Continental Airlines completed a 90-minute Boeing 737-800 flight with one engine split between biofuel and aircraft fuel. The biofuel was straight from algae. (Other flights were done based on nut fuel and other alternative sources.) The commercial airplane required no modification to the engine and the biofuel itself exceeded the standards of traditional jet fuel.
The problem, as noted at the time, is that biofuels derived from algae had yet to be proven as "commercially competitive."
The University of Utah's discovery could mean cheaper processing. At this point, it is less about if it works and more about if it is a practical alternative.
However, it's unclear how long it will take for algae to become more mainstream, if ever.
Open Questions
Higher efficiency and simpler transformations could mean lower prices and more business access. However, it's unclear how long it will take for algae to become more mainstream, if ever. The algae biofuel worked great for a relatively sophisticated Boeing 737 engine, but your family car, the cross-country delivery trucks and other less powerful machines may need to be modified – and that means the industry-at-large would have to revise their products in order to support the change.
Future-focused groups are already looking at how algae can fuel our space programs, especially if it is more renewable, safe and, potentially, cheaper than our traditional fuel choices. But first, it is worth waiting and seeing if corporations and, later, citizens are willing to take the plunge.
More Families Are Using Nanny Cams to Watch Elderly Loved Ones, Raising Ethical Questions
After Jackie Costanzo's mother broke her right hip in a fall, she needed more hands-on care in her assisted-living apartment near Sacramento, California. A social worker from her health plan suggested installing a video camera to help ensure those services were provided.
Without the camera, Costanzo wouldn't have a way to confirm that caregivers had followed through with serving meals, changing clothes, and fulfilling other care needs.
When Costanzo placed the device in May 2018, she informed the administrator and staff, and at first, there were no objections. The facility posted a sign on the apartment's front door, alerting anyone who entered of recording in progress.
But this past spring, a new management company came across the sign and threatened to issue a 30-day eviction notice to her 93-year-old mother, Louise Munch, who has dementia, for violating a policy that prohibits cameras in residents' rooms. With encouragement from California Advocates for Nursing Home Reform, Costanzo researched the state's regulations but couldn't find anything to support or deny camera use. She refused to remove the recording device and prevailed.
"In essence, my mom was 'grandfathered in' because she moved in under a management company that did not specify that residents could not have cameras," says Costanzo, 73, a retired elementary schoolteacher who lives a three-hour drive away, in Silicon Valley, and visits one day every two weeks. Without the camera, Costanzo, who is her mother's only surviving child, wouldn't have a way to confirm that caregivers had followed through with serving meals, changing clothes, and fulfilling other care needs.
As technological innovations enable next of kin to remain apprised of the elderly's daily care in long-term care facilities, surveillance cameras bring legal and privacy issues to the forefront of a complex ethical debate. Families place them overtly or covertly—disguised in a makeshift clock radio, for instance—when they suspect or fear abuse or neglect, so they can maintain a watchful eye, perhaps deterring egregious behavior. But the cameras also capture intimate caregiving tasks, such as bathing and toileting, as well as dressing and undressing, which may undermine the dignity of residents.
So far, laws or guidelines in eight states—Illinois, Maryland, New Mexico, Oklahoma, Texas, Utah, Virginia, and Washington—have granted families the rights to install cameras in a resident's room. In addition, about 15 other states have proposed legislation. Some states, such as Pennsylvania, have put forth regulatory compliance guidance, according to a column published in the July/August 2018 issue of Annals of Long-Term Care.
The increasing prevalence of this legislation has placed it on the radar of long-term care providers. It also suggests a trend to clarify responsible camera use in monitoring services while respecting privacy, says Victor Lane Rose, the column's editor and director of aging services at ECRI Institute, a health care nonprofit near Philadelphia, Pennsylvania.
In most cases, a resident's family installs a camera or instigates a request in hopes of sparing their loved one from the harms of abuse, says James Wright, a family physician who serves as the ethics committee's vice chair of the Society for Post-Acute and Long-Term Care Medicine in Columbia, Maryland. A camera also allows the family to check in on the resident from afar and remain on alert for a potential fall or agitated state, he says.
"It's rare that a facility will have 24-hour presence in a patient's room. You won't have a nurse in there all the time," says Wright, who is also medical director of two long-term care centers and one assisted-living facility around Richmond, Virginia. Particularly "with dementia, the family often wonders" if their loved one is safe.
While offering families peace of mind, he notes that video cameras can also help exonerate caregivers accused of abuse or theft. Hearing aids, which typically cost between $2,000 and $3,000 each, often go missing. By reviewing a video together, families and administrators may find clues to a device's disappearance. Conversely, Wright empathizes with the main counterargument against camera use, which is the belief that "invasion of privacy is also invasion of human dignity."
In respecting modesty, ethical questions abound over whether a camera should be turned off when a patient is in the midst of receiving personal care, such as dressing and undressing or using bedpans. Other ethical issues revolve around who may access the recordings, says Lori Smetanka, executive director of the National Consumer Voice for Quality Long-Term Care in Washington, D.C.
Video cameras, she contends, are only one tool in shielding residents from abuse. They are "not substitutes for personal involvement," she says. "People need to be very vigilant visiting their family members, and facilities have a responsibility to ensure that residents are free of abuse."
Lack of accountability perpetuates abuse in long-term care settings and stems in large part from systemic underfunding.
Educating employees in abuse prevention becomes paramount, and families should ask about staff training before placing their loved one in a long-term care facility, Smetanka says. Prior to installing a camera, she recommends consulting an attorney who is familiar with this issue.
But thoughts of a camera often don't occur to families until an adverse event affects their loved one, says Toby Edelman, a senior policy attorney at the Center for Medicare Advocacy, a nonprofit organization with headquarters in Washington, D.C., and Connecticut.
"These cameras can show exactly what's going on," she explains, noting that prosecutors have used the recordings in litigation. "When residents have injuries of unknown origin" and they can't verbalize what happened to them, "the cameras may document that yes, the resident was actually hit by somebody."
With a resident's safety and security being "the most important consideration," the American Health Care Association in Washington, D.C., which represents long-term and post-acute care providers, supports allowing states, clinicians, and patients to decide about camera use on a local level, says David Gifford, senior vice president of quality and regulatory affairs and chief medical officer.
"We've seen some success with tools such as permissive legislation, where residents and their loved ones have the ability to determine whether a camera is right for them while working with the center openly and ensuring the confidentiality of other residents," says Gifford, who practiced as a geriatrician. "It is important to note, however, that surveillance cameras are still only one element of the quality matrix. We can never hope to truly improve quality care by catching bad actors after the fact."
Lack of accountability perpetuates abuse in long-term care settings and stems in large part from systemic underfunding. Low wages and morale are tied to high turnover, and cameras don't address this overarching problem, says Clara Berridge, an assistant professor of social work at the University of Washington in Seattle, who has co-authored articles on surveillance devices in elder care.
Employees often don't perceive a nursing assistant position as a long-term career trajectory and may not feel vested in the workplace. Training in the recognition and reporting of abuse becomes ineffective when workers quit shortly thereafter. Many must juggle multiple jobs to make ends meet. Staffing shortages are endemic, leading to inadequate oversight of residents and voicing of abuse complaints, she says.
In Berridge's assessment, cameras may do more harm than good. Respondents to a survey she conducted of nursing homes and assisted-living facilities in the United States found that recording devices tend to fuel workers' anxiety amid a culture that further demoralizes and dehumanizes the care they provide.
Consent becomes particularly thorny in shared rooms, which are more common than not in nursing homes. States that permit in-room cameras mandate that roommates or their legal representative be made aware. Even if the camera is directed away from their bed, it will still capture conversations as well as movements that enter its scope. "Surveillance isn't the best way to protect adults in need of support," Berridge says. "Public investment in quality care is."
"The camera is invaluable. But there's no law that says you can have it automatically, so that's wrong."
In the one-bedroom assisted-living apartment where Costanzo's mother lives alone, consent from another resident wasn't needed. Without a roommate, the camera is much less intrusive, although Costanzo wishes she had put one in the living room, not just the bedroom, for more security.
Her safety concerns escalated when she read about a Texas serial killer who smothered victims after gaining access to senior care facilities by "masquerading as a maintenance man." She points to such horrifying incidents, although exceedingly rare, as further justification for permitting cameras to help guard the vulnerable against abuse in long-term care settings. And she hopes to advocate for an applicable law in California.
"The camera is invaluable," says Costanzo, who pays for monthly Wi-Fi service so she can see and interact with her mother, who turns 94 in October, any time of day or night. "But there's no law that says you can have it automatically, so that's wrong."