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.
Probiotics seem to be everywhere these days. They are marketed for numerous health issues, from irritable bowel syndrome and vaginal yeast infections to life-threatening disorders like the bacterial infection Clostridium difficile.
The new probiotic drink is made of genetically engineered bacteria meant to help people feel better the day after drinking.
While the probiotic gummies that you'll find in supermarkets may not do much for you, good clinical evidence does support the C. difficile treatment, known as a fecal transplant, despite a recent setback, and there are always new probiotic regimens entering the scene. One emerging such treatment targets the hangover.
The Lowdown
You read that right – although "hangover" is a loaded term, according to ZBiotics, the company that's developing the product. The popular understanding of a hangover implies a collection of symptoms like a headache and fatigue, many of which result simply from dehydration and low-quality sleep. But those aren't the problems that the new product, a genetically engineered form of a common bacterial species, was developed to confront.
"Dehydration and poor sleep have actually always been pretty simple to deal with by having a good breakfast and some caffeine," notes ZBiotics founder and microbiologist Zack Abbott. Instead, the product targets acetaldehyde, a chemical that accumulates in the body if more than small amounts of alcohol are consumed.
Normally, body cells produce an enzyme that converts acetaldehyde into harmless acetic acid. But the enzyme becomes overwhelmed if you drink more than a little alcohol, or if you have a certain genetic deficiency.
A new probiotic drink aims to neutralize a chemical that builds up in the body after drinking alcohol.
(Zbiotics)
"I started ZBiotics with the hypothesis that if we used edible probiotic bacteria to make enzymes, and chose applications in which the enzymes these microbes make would be useful directly in the gut after you eat them, we could create all sorts of beneficial products," says Abbott. "I started with alcohol with the idea that we can augment the body's natural ability to digest its nasty byproduct, acetaldehyde, helping people feel better the day after drinking."
Next Steps
Based on the premise that the engineered bacteria augments a natural body function, ZBiotics had the product "sampled by thousands of beta-testers," including ZBiotics personnel, with "almost unanimously positive feedback," says Abbott.
"We are working on future scientifically controlled testing for publication."
ZBiotics is to set to launch on the market next week as a probiotic supplement, a category that does not require FDA approval. But some observers are troubled over whether the new product is attempting to serve a medical function without going through the standard drug testing process.
"I am skeptical of any new alternative product that is not FDA approved, has not undergone rigorous double-blind placebo control testing and adverse effects evaluation, and cites anecdotes as evidence of its efficacy," warns Heather Berlin, a cognitive neuroscientist and assistant professor of psychiatry at Icahn School of Medicine at Mount Sinai, in New York.
Abbott acknowledges that his product still needs to undergo rigorous study. "We are working on future scientifically controlled testing for publication," he says, noting that the company was "founded and [is] run by people with backgrounds in academic research."
Open Questions
Moving beyond the need for proper testing, Berlin has an additional concern: will a "hangover"-blocking substance cause people to drink more alcohol, or mask important physiological sensations like thirst?
"If that negative feeling is obscured, they may not [rehydrate], which can cause numerous adverse effects," Berlin says.
As for excessive drinking, there is a treatment on the market that does the opposite of Zbiotics. Disulfiram, commonly given to alcohol abusers, inhibits the very enzyme that ZBiotics supplements, causing acetaldehyde to accumulate especially fast. This makes drinking a pretty miserable experience.
But Abbott says his product would not interfere with disulfiram.
"[Zbiotics] is about enjoying the special moments in life where alcohol happens to be involved, but isn't the main focus."
"Disulfiram globally inhibits the enzyme throughout the entire body, including the liver, creating a massive amount of acetaldehyde at once, making the person ill immediately and forcing them to stop drinking right away," Abbott explains, whereas his product exerts its effects in the gut, and is really only helpful the next day. Thus, timing is everything; the probiotic would not change the experience at the moment of drinking.
"ZBiotics isn't about going out and ripping shots all night," Abbott says. "It's about enjoying the special moments in life where alcohol happens to be involved, but isn't the main focus. Weddings, celebrations, weekends with friends. And wanting to do that enjoyably while being safe and responsible at the same time."
I'll never forget the experience of having a child in the neonatal intensive care unit (NICU).
Now more than ever, we're working to remove the barriers between new parents and their infants.
It was another layer of uncertainty that filtered into my experience of being a first-time parent. There was so much I didn't know, and the wires attached to my son's small body for the first week of his life were a reminder of that.
I wanted to be the best mother possible. I deeply desired to bring my son home to start our lives. More than anything, I longed for a wireless baby whom I could hold and love freely without limitations.
The wires suggested my baby was fragile and it left me feeling severely unprepared, anxious, and depressed.
In recent years, research has documented the ways that NICU experiences take a toll on parents' mental health. But thankfully, medical technology is rapidly being developed to help reduce the emotional fallout of the NICU. Now more than ever, we're working to remove the barriers between new parents and their infants. The latest example is the first ever wireless monitoring system that was recently developed by a team at Northwestern University.
After listening to the needs of parents and medical staff, Debra Weese-Mayer, M.D., a professor of pediatric autonomic medicine at Feinberg School of Medicine, along with a team of materials scientists, engineers, dermatologists and pediatricians, set out to develop this potentially life-changing technology. Weese-Mayer believes wireless monitoring will have a significant impact for people on all sides of the NICU experience.
"With elimination of the cumbersome wires," she says, "the parents will find their infant more approachable/less intimidating and have improved access to their long-awaited but delivered-too-early infant, allowing them to begin skin-to-skin contact and holding with reduced concern for dislodging wires."
So how does the new system work?
Very thin "skin like" patches made of silicon rubber are placed on the surface of the skin to monitor vitals like heart rate, respiration rate, and body temperature. One patch is placed on the chest or back and the other is placed on the foot.
These patches are safer on the skin than previously used adhesives, reducing the cuts and infections associated with past methods. Finally, an antenna continuously delivers power, often from under the mattress.
The data collected from the patches stream from the body to a tablet or computer.
New wireless sensor technology is being studied to replace wired monitoring in NICUs in the coming years.
(Northwestern University)
Weese-Mayer hopes that wireless systems will be standard soon, but first they must undergo more thorough testing. "I would hope that in the next five years, wireless monitoring will be the standard in NICUs, but there are many essential validation steps before this technology will be embraced nationally," she says.
Until the new systems are ready, parents will be left struggling with the obstacles that wired monitoring presents.
Physical intimacy, for example, appears to have pain-reducing qualities -- something that is particularly important for babies who are battling serious illness. But wires make those cuddles more challenging.
There's also been minimal discussion about how wired monitoring can be particularly limiting for parents with disabilities and mobility aids, or even C-sections.
"When he was first born and I was recovering from my c-section, I couldn't deal with keeping the wires untangled while trying to sit down without hurting myself," says Rhiannon Giles, a writer from North Carolina, who delivered her son at just over 31 weeks after suffering from severe preeclampsia.
"The wires were awful," she remembers. "They fell off constantly when I shifted positions or he kicked a leg, which meant the monitors would alarm. It felt like an intrusion into the quiet little world I was trying to mentally create for us."
Over the last few years, researchers have begun to dive deeper into the literal and metaphorical challenges of wired monitoring.
For many parents, the wires prompt anxiety that worsens an already tense and vulnerable time.
I'll never forget the first time I got to hold my son without wires. It was the first time that motherhood felt manageable.
"Seeing my five-pound-babies covered in wires from head to toe rendered me completely overwhelmed," recalls Caila Smith, a mom of five from Indiana, whose NICU experience began when her twins were born pre-term. "The nurses seemed to handle them perfectly, but I was scared to touch them while they appeared so medically frail."
During the nine days it took for both twins to come home, the limited access she had to her babies started to impact her mental health. "If we would've had wireless sensors and monitors, it would've given us a much greater sense of freedom and confidence when snuggling our newborns," Smith says.
Besides enabling more natural interactions, wireless monitoring would make basic caregiving tasks much easier, like putting on a onesie.
"One thing I noticed is that many preemie outfits are made with zippers," points out Giles, "which just don't work well when your baby has wires coming off of them, head to toe."
Wired systems can pose issues for medical staff as well as parents.
"The main concern regarding wired systems is that they restrict access to the baby and often get tangled with other equipment, like IV lines," says Lamia Soghier, Medical Director of the Neonatal Intensive Care Unit at Children's National in Washington, D.C , who was also a NICU parent herself. "The nurses have to untangle the wires, which takes time, before handing the baby to the family."
I'll never forget the first time I got to hold my son without wires. It was the first time that motherhood felt manageable, and I couldn't stop myself from crying. Suddenly, anything felt possible and all the limitations from that first week of life seemed to fade away. The rise of wired-free monitoring will make some of the stressors that accompany NICU stays a thing of the past.