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.
Could Your Probiotic Be Making You Sicker?
Mindy D. had suffered from constipation for years when her gastroenterologist advised her, at 38, to take a popular over-the-counter probiotic. Over the next two years, she experimented with different dosages, sometimes taking it three times a day. But she kept getting sicker—sometimes so ill she couldn't work.
"We shouldn't just presume probiotics are safe."
Her symptoms improved only after she traveled from Long Island to Georgia to see Satish S. C. Rao, a gastroenterologist at Augusta University. "The key thing was taking her off probiotics and treating her with antibiotics," he says.
That solution sounds bizarre, if, like many, you believe that antibiotics are bad and probiotics good. Millions of Americans take probiotics—live bacteria deemed useful—assuming there can be only positive effects. The truth is that you really don't know how any probiotic will affect you. To quote the American Gastroenterological Association Center for Gut Microbiome Research and Education, "It remains unclear what strains of bacteria at what dose by what route of administration are safe and effective for which patients."
"We shouldn't just presume probiotics are safe," says Purna Kashyap, a gastroenterologist from the Mayo Clinic, in Rochester, Minnesota, and a member of the Center's scientific advisory board. Neither the U.S. Food and Drug Administration or the European Food Safety Authority have approved probiotics as a medical treatment. Things can go very wrong in the ill: Among patients with severe acute pancreatitis, one study found that a dose of probiotics increased the chance of death. Even randomized controlled trials of probiotics rarely report harms adequately and the effect over the long-term has not been studied.
Many people pick up a product at a drug store or health store without ever telling a doctor. Doctors are fans, too: in a 2017 survey of healthcare providers at Stanford, more than 60 percent of the respondents said they prescribed probiotics. Many did so inconsistently, leaving the choice of which probiotic up to the patient. Healthy people take them for a range of unproven benefits, including protection from infections or heart disease or to sharpen their brains.
It's fine—unless it isn't. "Probiotics are capable of altering the microbiome in unpredictable ways," explains Leo Galland, an internist in New York who specializes in difficult digestions. "I've had patients who got gas and bloating, constipation or diarrhea from probiotics."
Your Microbiome Is Unique
The booming probiotic market has fed on excitement about the new science of the microbiome, the genetic material of all the microbes that live in our bodies and on our skin. Microbes make up 1 to 3 percent of every human being's body mass—you carry trillions of them, including more than a hundred species and thousands of strains. To identify a microbe, you need to know the genus, species and strain. For example, in Lactobacillus rhamnosus GG, the ingredient in the OTC probiotic Culturelle, Lactobacillus is the genus, rhamnosus is the species and GG is the strain designation.
Variations in your microbiome could help explain why you put on weight or suffer from Crohn's or depression. Each of us has our own unique mix.
A decade ago, the U.S. National Institute of Health (NIH) launched the Microbiome Project to establish a baseline description of health. Scientists sequenced the DNA in more than 2,200 strains, still a small fraction of the whole.
Within a couple of years, we had evidence that our microbiomes are distinctive. Another team used the NIH data set to look into the idea of microbial "fingerprints." A classic computer science algorithm allowed it to assign individuals "codes" defined by DNA sequences of their microbes—no human DNA required. Using information solely from the guts, "Eighty percent of individuals could still be uniquely identified up to a year later," they wrote.
That distinctiveness makes a difference when we try to change our mix by swallowing bacteria considered "pro." Even in healthy people, the reactions to probiotics vary widely, according to a study in Cell in September. The team examined the intestines of healthy volunteers who had taken a cocktail of eleven strains of probiotics for the experiment. Which took up residence in the intestinal lining? The answer depended on the person. Led by Eran Segal and colleagues at the Weizmann Institute of Science, in Rehovot, Israel, the authors concluded that effective supplements would have to be personalized.
Patients with "brain fog" improved dramatically when they were taken off their probiotics and given antibiotics as well.
To truly customize a probiotic, however, we'd have to know the state of an individual's gut microbiome, identify danger signs and link them to symptoms, isolate relevant strains of probiotics that might be needed, and get them into the gut lining effectively. Commercial tests are still at step one. Several companies claim to assess your microbiome based on a stool sample—but the Weizmann team has also shown that the differences between our gut linings aren't apparent from our stool. Galland has explored testing his patients looking for ways to help. "I've concluded that uBiome, American Gut Project, and others don't yield useful information," he observes.
Can A Probiotic Make Your Brain Foggy?
Besides taking her probiotic, Mindy D. had cut out gluten and upped her vegetables and fruits. But soon after she ate her seemingly healthy meals, she would begin to feel dizzy and sometimes even slurred her words, as if she were drunk. "It was such an intense feeling," she said.
A slender 5 ft. 2 inches, she dropped 20 pounds, becoming unhealthily thin. She traveled to see specialists in Minnesota and Connecticut and took two month-long medical leaves before she found Rao in Georgia.
In June, Rao created a stir when he and his coauthors reported that a cluster of his patients with "brain fog"—the "intense feeling" Mindy D. described—improved dramatically when they were taken off their probiotics and given antibiotics as well.
His idea was that lactobacilli and other bacteria colonized their small intestines, rather than making it to the colon as intended—a condition known as "small intestinal bacteria overgrowth" (SIB0) that some gastroenterologists treat with antibiotics. In this group, he argues, the small intestine produced the brain fog symptoms as a consequence of D-lactic acidosis, a phenomenon usually associated with damaged intestines. "If you have brain fogginess along with gas and bloating, please don't take probiotics," Rao says.
The paper prompted a rebuttal at the end of September from Eamonn Quigley, a gastroenterologist at Houston Methodist, who criticized the methodology in detail. Kashyap, of the Mayo Clinic, is skeptical as well. "People were picked for their brain fogginess and they were taking probiotics. Probiotics could be an innocent bystander," he says.
"It's hard for me to imagine the mechanism of say, Culturelle, causing SIB0," says Shira Doron, a specialist in infectious diseases and associate professor at Tufts University School of Medicine who studies probiotics. "The vast majority of people will never suffer a side effect from a probiotic. But probiotics are a live organism so they have a unique set of potential risks that other supplements don't have. They can give you a severe infection in very rare circumstances."
The larger point is that probiotics should be used under a doctor's care. In April, a panel of 14 experts on behalf of the European Society for Primary Care Gastroenterology concluded that "specific probiotics are beneficial in certain lower GI problems." That does not mean any over-the-counter probiotic is likely to help you because it helped your cousin.
"Even your doctor may be going by anecdotal experience, rather than hard science."
Both Galland and Rao use probiotics in their practice, but carefully. "We advise caution against excessive and indiscriminate use of probiotics especially without a well-defined medical indication, and particularly in patients with gastrointestinal dysmotility," when the muscles of the digestive system don't work normally, Rao's team wrote.
"Because there are so many studies out there that are poorly done, that aren't looking at side effects, the science is murky. Even your doctor may be going by anecdotal experience, rather than hard science," Doron adds. Your doctor may tell you that many of his patients report a great experience with probiotics. As Doron points out, however, with disorders like irritable bowel syndrome, the most common gastrointestinal diagnosis, the placebo effect is very strong. Many patients could "respond to anything if they believe it works," she says.
Advances Bring First True Hope to Spinal Cord Injury Patients
Seven years ago, mountain biking near his home in Whitefish, Montana, Jeff Marquis felt confident enough to try for a jump he usually avoided. But he hesitated just a bit as he was going over. Instead of catching air, Marquis crashed.
Researchers' major new insight is that recovery is still possible, even years after an injury.
After 18 days on a ventilator in intensive care and two-and-a-half months in a rehabilitation hospital, Marquis was able to move his arms and wrists, but not his fingers or anything below his chest. Still, he was determined to remain as independent as possible. "I wasn't real interested in having people take care of me," says Marquis, now 35. So, he dedicated the energy he formerly spent biking, kayaking, and snowboarding toward recovering his own mobility.
For generations, those like Marquis with severe spinal cord injuries dreamt of standing and walking again – with no realistic hope of achieving these dreams. But now, a handful of people with such injuries, including Marquis, have stood on their own and begun to learn to take steps again. "I'm always trying to improve the situation but I'm happy with where I'm at," Marquis says.
The recovery Marquis and a few of his fellow patients have achieved proves that our decades-old understanding of the spinal cord was wrong. Researchers' major new insight is that recovery is still possible, even years after an injury. Only a few thousand nerve cells actually die when the spinal cord is injured. The other neurons still have the ability to generate signals and movement on their own, says Susan Harkema, co-principal investigator at the Kentucky Spinal Cord Injury Research Center, where Marquis is being treated.
"The spinal cord has much more responsibility for executing movement than we thought before," Harkema says. "Successful movement can happen without those connections from the brain." Nerve cell circuits remaining after the injury can control movement, she says, but leaving people sitting in a wheelchair doesn't activate those sensory circuits. "When you sit down, you lose all the sensory information. The whole circuitry starts discombobulating."
Harkema and others use a two-pronged approach – both physical rehabilitation and electrical stimulation – to get those spinal cord circuits back into a functioning state. Several research groups are still honing this approach, but a few patients have already taken steps under their own power, and others, like Marquis, can now stand unassisted – both of which were merely fantasies for spinal cord injury patients just five years ago.
"This really does represent a leap forward in terms of how we think about the capacity of the spinal cord to be repaired after injury," says Susan Howley, executive vice president for research for the Christopher & Dana Reeve Foundation, which supports research for spinal cord injuries.
Jeff Marquis biking on a rock before his accident.
This new biological understanding suggests the need for a wholesale change in how people are treated after a spinal cord injury, Howley says. But today, most insurance companies cover just 30-40 outpatient rehabilitation sessions per year, whether you've sprained your ankle or severed your spinal cord. To deliver the kind of therapy that really makes a difference for spinal cord injury patients requires "60-80-90 or 150 sessions," she says, adding that she thinks insurance companies will more than make up for the cost of those therapy sessions if spinal cord injury patients are healthier. Early evidence suggests that getting people back on their feet helps prevent medical problems common among paralyzed people, including urinary tract infections, which can require costly hospital stays.
"Exercise and the ability to fully bear one's own weight are as crucial for people who live with paralysis as they are for able-bodied people," Howley notes, adding that the Reeve Foundation is now trying to expand the network of facilities available in local communities to offer this essential rehabilitation.
"Providing the right kind of training every day to people could really improve their opportunity to recover," Harkema says.
It's not entirely clear yet how far someone could progress with rehabilitation alone, Harkema says, but probably the best results for someone with a severe injury will also require so-called epidural electrical stimulation. This device, implanted in the lower back for a cost of about $30,000, sends an electrical current at varying frequencies and intensities to the spinal cord. Several separate teams of researchers have now shown that epidural stimulation can help restore sensation and movement to people who have been paralyzed for years.
Epidural stimulation boosts the electrical signal that is generated below the point of injury, says Daniel Lu, an associate professor and vice chair of neurosurgery at the UCLA School of Medicine. Before a spinal cord injury, he says, a neuron might send a message at a volume of 10 but after injury, that volume might drop to a two or three. The epidural stimulation potentially trains the neuron to respond to the lower volume, Lu says.
Lu has used such stimulators to improve hand function – "essentially what defines us" – in two patients with spinal cord injuries. Both increased their grip strength so they now can lift a cup to drink by themselves, which they couldn't do before. He's also used non-invasive stimulation to help restore bladder function, which he says many spinal cord injury patients care about as much as walking again.
A closeup of the stimulator.
Not everyone will benefit from these treatments. People whose injury was caused by a cut to the spinal cord, as with a knife or bullet, probably can't be helped, Lu says, adding that they account for less than 5 percent of spinal cord injuries.
The current challenge Lu says is not how to stimulate the spinal cord, but where to stimulate it and the frequency of stimulation that will be most effective for each patient. Right now, doctors use an off-the-shelf stimulator that is used to treat pain and is not optimized for spinal cord patients, Harkema says.
Swiss researchers have shown impressive results from intermittent rather than continuous epidural stimulation. These pulses better reflect the way the brain sends its messages, according to Gregoire Courtine, the senior author on a pair of papers published Nov. 1 in Nature and Nature Neuroscience. He showed that he could get people up and moving within just a few days of turning on the stimulation. Three of his patients are walking again with only a walker or minimal assistance, and they also gained voluntary leg movements even when the stimulator was off. Continuous stimulation, this research shows, actually interferes with the patients' perception of limb position, and thus makes it harder for them to relearn to walk.
Even short of walking, proper physical rehabilitation and electrical stimulation can transform the quality of life of people with spinal cord injury, Howley and Harkema say. Patients don't need to be able to reach the top shelf or run a marathon to feel like they've been "cured" from their paralysis. Instead, recovering bowel, bladder and sexual functions, the ability to regulate their temperature and blood pressure, and reducing the breakdown of skin that can lead to a life-threatening infection can all be transformative – and all appear to improve with the combination of rehabilitation and electrical stimulation.
Howley cites a video of one of Harkema's patients, Stefanie Putnam, who was passing out five to six times a day because her blood pressure was so low. She couldn't be left alone, which meant she had no independence. After several months of rehabilitation and stimulation, she can now sit up for long periods, be left alone, and even, she says gleefully, cook her own dinner. "Every time I watch it, it brings me to tears," Howley says of the video. "She's able to resume her normal life activity. It's mind-boggling."
The work also suggests a transformation in the care of people immediately after injury. They should be allowed to stand and start taking steps as soon as possible, even if they cannot do it under their own power, Harkema says. Research is also likely to show that quickly implanting a stimulator after an injury will make a difference, she says.
There may be medications that can help immediately after an injury, too. One drug currently being studied, called riluzole, has already been approved for ALS and might help limit the damage of a spinal cord injury, Howley says. But testing its effectiveness has been a slow process, she says, because it needs to be given within 12 hours of the initial injury and not enough people get to the testing sites in time.
Stem cell therapy also offers promise for spinal cord injury patients, Howley says – but not the treatments currently provided by commercial stem cell clinics both in the U.S. and overseas, which she says are a sham. Instead, she is carefully following research by a California-based company called Asterias Biotherapeutics, which announced plans Nov. 8 to merge with a company called BioTime.
Asterias and a predecessor company have been treating people since 2010 in an effort to regrow nerves in the spinal cord. All those treated have safely tolerated the cells, but not everyone has seen a huge improvement, says Edward Wirth, who has led the trial work and is Asterias' chief medical director. He says he thinks he knows what's held back those who didn't improve much, and hopes to address those issues in the next 3- to 4-year-long trial, which he's now discussing with the U.S. Food and Drug Administration.
So far, he says, some patients have had an almost complete return of movement in their hands and arms, but little improvement in their legs. The stem cells seem to stimulate tissue repair and regeneration, he says, but only around the level of the injury in the spinal cord and a bit below. The legs, he says, are too far away to benefit.
Wirth says he thinks a combination of treatments – stem cells, electrical stimulation, rehabilitation, and improved care immediately after an injury – will likely produce the best results.
While there's still a long way to go to scale these advances to help the majority of the 300,000 spinal cord injury patients in the U.S., they now have something that's long been elusive: hope.
"Two or three decades ago there was no hope at all," Howley says. "We've come a long way."