A newborn and mother in the hospital - first touch. (© martin81/Shutterstock)
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.
Researchers have found that a mindfulness-based therapy, including savoring natural rewards, can help patients with chronic pain and opioid addiction.
Garland’s study focused on 250 adults who had received opioid therapy for chronic pain for 90 days or longer, randomly assigning them to eight weeks of either a standard psychotherapy support group or Mindfulness-Oriented Recovery Enhancement (MORE) therapy, which combines mindfulness training, cognitive-behavioral therapy (CBT) and positive psychology. Nine months after getting these treatments in primary care settings, 45 percent of patients in the MORE group were no longer misusing opioids, compared to 24 percent of those in group therapy. In fact, about a third of the patients in the MORE group were able to cut their opioid dose in half or reduce it even further.
Patients treated with MORE also experienced more significant pain relief than those in support groups, according to Garland. Conventional approaches to treating opioid addiction include 12-step programs and medically-assisted treatment using drugs like methadone and Suboxone, sometimes coupled with support groups. But patients with Opioid Use Disorder (OUD) – the official diagnosis for opioid addiction – have high relapse rates following treatment, especially if they have chronic pain.
While medically-assisted treatments help to control drug cravings, they do nothing to control chronic pain, which is where psychological therapies like MORE come in.
“For patients suffering from moderate pain and OUD, the relapse rate is three times higher than in patients without chronic pain; for those with severe chronic pain, the relapse rate is five times higher,” says Amy Wachholtz, PhD, Director of Clinical Health Psychology and associate professor at University of Colorado in Denver. “So if we don’t treat the chronic pain along with the OUD addiction simultaneously, we are setting patients up for failure.”
Unfortunately, notes Garland, the standard of care for patients with chronic pain who are misusing their prescribed painkillers is “woefully inadequate.” Many patients don’t meet the criteria for OUD, he says, but instead fall into a gray zone somewhere between legitimate opioid use and full-blown addiction. And while medically-assisted treatments help to control drug cravings, they do nothing to control chronic pain, which is where psychological therapies like MORE come in. But behavioral therapies are often not available in primary care settings, and even when clinicians do refer patients to behavioral health providers, they often prescribe CBT. A large scale study last year showed that CBT – without the added components of mindfulness training and positive psychology – reduced pain but not opioid misuse.
Psychotherapist Eric Garland teaches mindfulness.
University of Utah
Reward Circuitry Rewired
Opioids are highly physiologically addictive. Repeated and high-dose drug use causes the brain to become hypersensitive to stress, pain, and drug-related cues, such as the sight of one’s pill bottle, says Garland, while at the same time becoming increasingly insensitive to natural pleasures. “As an individual becomes more and more dependent on the opioids just to feel okay, they feel less able to extract a healthy sense of joy, pleasure and meaning out of everyday life,” he explains. “This drives them to take higher and higher doses of the opioid to maintain a dwindling sense of well-being.”
The changes are not just psychological: Chronic opioid use actually causes changes in the brain’s reward circuitry. “You can see on brain imaging,” says Garland. “The brain’s reward circuitry becomes more responsive when a person is viewing opioid related images than when they are viewing images of smiling babies, lovers holding hands, or sunsets over the beach.” MORE, he says, teaches “savoring” – a tenet of positive psychology – as a means of restructuring the reward processes in the brain so the patient becomes sensitive to pleasure from natural, healthy rewards, decreasing cravings for drug-related rewards.
Mindfulness and Addiction
Mindfulness, a form of meditation that teaches people to observe their feelings and sensations without judgement, has been increasingly applied to the treatment of addiction. By observing their pain and cravings objectively, for example, patients gain increased awareness of their responses to pain and their habits of opioid use. “They learn how to be with discomfort, whether emotional or physical, in a more compassionate way,” says Sarah Bowen, PhD, associate professor of psychology at Pacific University in Oregon. “And if your mind gives you a message like ‘Oh, I can’t handle that,’ to recognize that that’s a thought that might not be true.”
Bowen’s research is focused on Mindfulness-Based Relapse Prevention, which addresses the cravings associated with addiction. She has patients practice what she calls “urge surfing”: riding out a craving or urge rather than relying on a substance for immediate relief. “Craving will happen, so rather than fighting it, we look at understanding it better,” she says.
MORE differs from other forms of mindfulness-based therapy in that it integrates reappraisal and savoring training. Reappraisal is a technique often used in CBT in which patients learn to change negative thought patterns in order to reduce their emotional impact, while savoring helps to restructure the reward processes in the brain.
Mindfulness training not only helps patients to understand and gain control over their behavior in response to cravings and triggers like pain, says Garland, but also provides a means of pain relief. “We use mindfulness to zoom into pain and break it down into its subcomponents – feelings of heat or tightness or tingling – which reduces the impact that negative emotions have on pain processing in the brain.”
Eric Garland examines brain waves.
University of Utah
Powerful interventions
As the dangers of opioid addiction have become increasingly evident, some scientists are developing less addictive, non-opioid painkillers, but more trials are needed. Meanwhile, behavioral approaches to chronic pain relief have continued to gain traction, and researchers like Garland are probing the possibilities of integrative treatments to treat the addiction itself. Given that the number of people suffering from chronic pain and OUD have reached new heights during the COVID-19 pandemic, says Wachholtz, new treatment alternatives for patients caught in the relentless cycle of chronic pain and opioid misuse are sorely needed. “We’re trying to refine the techniques,” she says, “but we’re starting to realize just how powerful some of these mind-body interventions can be.”
