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.
Why the Pope Should Officially Embrace Biotechnology
[Editor's Note: This essay is in response to our current Big Question series: "How can the religious and scientific communities work together to foster a culture that is equipped to face humanity's biggest challenges?"]
In May 2015, Pope Francis issued an encyclical with the subtitle "On Care for Our Common Home." The letter addressed various environmental issues, such as pollution and climate change, and it reminded all of us that we are to steward the Earth, not plunder it.
Without question, biotechnology has saved the lives of millions – perhaps billions – of people.
The Pope's missive demonstrates that he is both theologically sound and scientifically literate, a very rare combination. That is why he should now author an encyclical urging the world to embrace the life-giving promise of biotechnology.
Without question, biotechnology has saved the lives of millions – perhaps billions – of people. Arguably, vaccines were the most important invention in the history of mankind. It is thought that, in the 20th century alone, at least 300 million people were killed by smallpox. Today, the number is zero, thanks to vaccination. Other killers, such as measles, diphtheria, meningitis, and diarrhea, are kept at bay because of vaccines.
Biotechnology has also saved the lives of diabetics. At one time, insulin was extracted from pig pancreases, and there were fears that we would run out of it. Then, in the 1970s, crucial advances in biotechnology allowed for the gene that encodes human insulin to be expressed in bacteria. Today, diabetics can get extremely pure insulin thanks to this feat of genetic modification.
Likewise, genetic modification has improved the environment and the lives of farmers all over the world, none more so than those living in developing countries. According to a meta-analysis published in PLoS ONE, GMOs have "reduced chemical pesticide use by 37%, increased crop yields by 22%, and increased farmer profits by 68%."
Even better, GMOs also could help improve the lives of non-farmers. In poor parts of the world, malnutrition is still extremely common. People whose diets consist mostly of rice, for example, often suffer from vitamin A deficiency, which can lead to blindness. Golden Rice, which was genetically modified to contain a vitamin A precursor, was created and given away for free in an act of humanitarianism. Other researchers have created a genetically modified cassava to help combat iron and zinc deficiencies among children in Africa.
Despite these groundbreaking advances, the public is turning against biotechnology.
Biotechnology has also helped women with mitochondrial disease bear healthy children. Children inherit their mitochondria, the powerhouses of our cells, solely from their mothers. Mitochondrial defects can have devastating health consequences. Using what is colloquially called the "three-parent embryo technique," a healthy woman donates an egg. The nucleus of that egg is removed, and that of the mother-to-be is put in its place. Then, the egg is fertilized using conventional in vitro fertilization. In April 2016, the world's first baby was born using this technique.
Yet, despite these groundbreaking advances, the public is turning against biotechnology. Across America and Europe, anti-vaccine activists have helped usher in a resurgence of entirely preventable diseases, such as measles. Anti-GMO activists have blocked the implementation of Golden Rice. And other activists decry reproductive technology as "playing God."
Nonsense. These technologies improve overall welfare and save lives. Those laudable goals are shared by all the world's major religions as part of their efforts to improve the human condition. That is why it is vitally important, if science is to succeed in eradicating illness, that it gets a full-throated endorsement from powerful religious leaders.
In his 2015 encyclical, Pope Francis wrote:
Any technical solution which science claims to offer will be powerless to solve the serious problems of our world if humanity loses its compass, if we lose sight of the great motivations which make it possible for us to live in harmony, to make sacrifices and to treat others well.
He is correct. Indeed, when people are protesting life-saving vaccines, we have lost not only our moral compass but our intellect, too.
Imagine the impact he could have if Pope Francis issued an encyclical titled "On Protecting Our Most Vulnerable." He could explain that some children, stricken with cancer or suffering from an immunological disease, are unable to receive vaccines. Therefore, we all have a moral duty to be vaccinated in order to protect them through herd immunity.
Or imagine the potential impact of an encyclical titled "On Feeding the World," in which the Pope explained that rich countries have an obligation to poorer ones to feed them by all means necessary, including the use of biotechnology. If Muslim, Buddhist, and Hindu scholars throughout Asia and Africa also embraced the message, its impact could be multiplied.
In order to be successful, science needs religion; in order to be practical, religion needs science.
In order to be successful, science needs religion; in order to be practical, religion needs science.
Unfortunately, in discussions of the relationship between science and religion, we too often focus on the few areas in which they conflict. But this misses a great opportunity. By combining technological advances with moral authority, science and religion can work together to save the world.
[Ed. Note: Don't miss the other perspectives in this Big Question series, from a Rabbi/M.D. and a Reverend/molecular geneticist.]
Viv spent nearly an hour choosing her body.
She considered going as her eight year-old self. She would stand eye-to-eye with her father in his hospital bed, shedding tears and crying: please don't go, daddy. But that was too obvious. It would offend him.
He became data coursing through a network, able to embody any form, to outlive physical decay.
She considered her eighteen year-old self. She would lean over him, scrawny and tall, her lips trembling with anger: you're being selfish, dad. But that would lead to shouting.
She considered every form, even reviving people from the past: her mother, her grandfather, her little sister Mary. How would her father react to Mary walking in? He would think himself dead. She could whisper a message to him: Stay alive, dad. God commands it.
In the end, Viv chose the look of her last days as a biological person. Thirty-one years old, her auburn hair cut short, her black eyes full of longing. She watched the body print in silicon over robotic armature.
When it blinked to life, Viv stood in front of a mirror. Her face was appropriately somber, her mind in sync with her new muscles. Without thinking, she stretched her arms, arched her body, twirled on her tiptoes. She had forgotten the pleasure of sensation.
"I should do this…" The voice resonated through her. She could not help but smile. "I should do this more often… often… often." Every repetition thrilled her with sound. She began to sing an old favorite: "Times have changed… and we've often…"
But she stopped herself. This was not a day for singing.
Viv clothed her body in a blue dress, packed her tablet in a briefcase, stood in front of the mirror one last time. "I'll be there in five," she said aloud, though she did not need to.
A man's voice answered in her mind: I'm not coming.
"Gabe…"
There's no point, said the voice. We know what he'll say.
"We have to try."
I won't see him dying, Viv.
The clenching of her jaw felt like the old days. Her brother made a habit of last-minute decisions, without concern for how they affected other people, most often her.
She remembered the day he became an everperson. It was soon after their mother's death. They were supposed to visit their father in mourning, but Gabe disappeared without explanation. Viv took the full burden of solace on herself. She sat with her father in a small room, with an old Persian rug and stale furniture. His mustache was beginning to gray, his eyes beginning to wrinkle. "She's with your sister now," he said. "Your mom and Mary, I can…" He leaned in to whisper, "I can almost hear them, at night, laughing on the other side. They tell me to wait… they tell me to wait." Viv nodded for him, pretending to believe, wishing she could.
Gabe did not return her calls that evening. The next day, she began to worry. The day after, she began to look. He made no effort to hide, he simply neglected to tell her the new plan.
Gabe had taken the money from his inheritance, and booked himself an everence. It was something new back then. Viv did not understand the science, but she knew it was a destructive process. His physical brain was destroyed by lasers that scanned it neuron by neuron, creating a digital replica. He became data coursing through a network, able to embody any form, to outlive physical decay. He became an everperson.
It took three days to complete. Viv went to the facility, a converted warehouse by the Bay Bridge. She watched the new Gabe being printed over robotic armature, taking the form of his last biological self, to help with the transition. When he blinked to life, she did not know if he would be the same person, or an imperfect copy of an imperfect copy. But Gabe was totally oblivious to the pain he caused her by disappearing in that way. No robot, she thought, could be so callous.
When Viv made her own decision to everize, she deliberated for weeks, thinking through the consequences and conversations to come. Afterwards, she sat with her father in that same small room, with the Persian rug older, the furniture staler, a new cat purring at his feet.
"But it's suicide," he said.
"It's the opposite, dad. It's eternal life."
"You'd be a robot. You wouldn't be you."
"Gabe's the same as he ever was," she noted the resentment in her voice. "He's just not… physical, until he wants to be."
Her father exhaled an Arabic phrase he was using more often in his old age. La hawla wa la quwata illa billah. She had never learned his native tongue, but she looked up the phrase to understand him better. It meant something like: there is no power except in God. It was a sigh of resignation.
"Vivian," he said eventually, "Your soul is not your brain. Your soul lives on. If you kill yourself, you... it's unforgivable. Don't you want to see mom in heaven? Mary? Me?"
She wanted to believe. She wanted painfully. But when she spoke, it was barely a whisper. "I don't think that will happen, dad."
Fewer biological people meant little need for hospitals, or doctors. It would close soon.
It was the first she had ever confessed to him about God or Heaven. In as steady a voice as he could manage, her father said: "You're an adult, Viv. You do what you think is best."
She came to visit sometimes, as an everperson. He could not tell at first. But as the years went by, as his eyes wrinkled, and his hair grayed, he noticed that Viv never aged. One day he stopped talking to her. Another she stopped coming.
Now he was waiting out the last days of his life alone in a hospital bed. Viv did not want to say goodbye. It seemed such a waste.
You don't have to, Gabe spoke into her mind. Get him to sign, say anything, say it's for selling the house. Once we have full power of attorney, we can decide for him.
"It's not right." She noticed herself speaking aloud on the hoverbus. Nine nervous faces turned to her.
It's not right, she continued in her mind. Dad never forced us to pray, never forced us to —
That was mom.
But he loved her. He never changed her mind, he raised us to question, and he quietly believed. He has every right to live his way, just like we did.
To live. Not to die... When he's an everperson, he'll thank us.
That gave her pause. It might be true. She remembered her first moments as an everperson, suddenly linked to countless other minds, waking to the full expanse of human knowledge like sunlight through an open window, breathless and unexpected.
Still, she said, it's not right.
So you want him to die?
I want to convince him.
And what if you don't? There was panic in his voice. Gabe steadied himself. You brought your tablet, Viv. You know what it's for. Get him to sign.
And what if I don't?
I'll figure something out, with or without you. I won't let him die, Viv. Not this day and age.
Viv kept quiet the rest of her way there. She played memories in her mind, of every conversation she ever had with her father, every time he read her a verse or taught her a parable. She looked for a way to convince him, some doubt, some chink in his armor of belief. But she got distracted by the world outside.
It was strange to pass for a time through physical space. It took longer than she expected. Now watching the sunlight refract through the hoverbus window, she was mesmerized. Every sensation felt more real, more vivid than her memory. "I should do this more often," she said aloud.
The hospital smelled like death. It had fallen into disrepair since her mother's illness. Fewer biological people meant little need for hospitals, or doctors. It would close soon, she thought. Her footsteps echoed through the halls, along with the sounds of old televisions playing old films to keep the patients company.
The room she entered had no sound, except the whirring machines. No light, except an eerie glow filtering through the curtains. The figure on the bed was her father, his breathing strained, his skin cracked like the desert. She closed the door behind her.
When her father turned, she saw a flicker of joy in his eyes. It disappeared.
"La hawla wa la… I thought it was her."
"I am her."
He winced. "She died some twenty years ago."
Viv sat next to him. The machines whirred around them, keeping his body alive another day, or hour, or minute. "It doesn't look good, dad."
"I know."
"You broke a promise."
He held her gaze. "I did?"
"You said we'd see the bats in Australia."
"You were scared of bats."
"And you said they were cute in Oz, the giant bats, like upside down puppies chewing bananas."
He smiled, but that was a long time ago. "Your mom was alive then… Gabe… You were alive…"
"I'm alive now, dad. Look at me. I'm Viv. Vivian Fatema. Your daughter. Half mom, half you. I'm the same person I was."
His eyes shifted. She sensed he wanted to believe. She held his hand and squeezed it. She felt him squeezing back. "I want you to stay, dad."
"There's nothing for me here."
"I'm here."
"You don't love me, Viv. You're a robot."
His hand let go. "You're there… I don't know where. I have a lot to answer for, Viv. I pray. I pray every day, five times a day, sometimes more. I pray that God forgive you for what you did, forgive me for my part, forgive Gabriel... I wish I could stay, love, but… Everyone I love is on the other side."
It hurt her to say the next words: "It's not real, dad."
"Of course you'd say that." He turned his body away from her.
"Please, dad."
She listened to his breathing.
"I love you," she said.
"You don't love me, Viv. You're a robot."
She lowered her head against the bed. She kneeled for countless breaths. It took all her strength to stand up again.
Viv took her briefcase, pulled out her tablet. She stood tapping at the screen for some time. The clenching of her jaw felt like the old days.
"Before I go, I need you to sign something. It's a power of attorney for the house. We can't sell it without you."
"You're selling the house?"
She shrugged. "It's no use to a robot."
His bony finger signed the screen without reading it. She kissed his forehead goodbye.
"Viv?" She stopped. "Before you go, could you open the curtains?"
She did. Her last image of him was a frail old body gazing at the moving clouds.
On the hoverbus home, Viv turned against the window outside. She pressed the briefcase to her like a hug, her mechanical heart thumping against it. Every heartbeat brought a memory back of her biological life. "I should do this more…" She whispered to herself, not caring who might hear. The sunset turned violet.
You made him sign. Gabe sounded like triumph.
"I did."
You did the right thing.
"I know."
Let me see.
She pulled out her tablet and, with a touch, uploaded the file.
Where's my name? Gabe asked. I only see your name.
"I changed it."
What do you mean you "changed it"?
"I changed my mind last minute, Gabe. I didn't think to tell you."
That's funny, sis. Very funny.
"It's not funny at all, Gabe. It's dead serious. I have power of attorney. I'm going to bury him next to mom and Mary."
No… There's no way.
"It's my choice now."
I can't watch him go, Viv. I can't. Don't be selfish.
"I'll miss him." She felt a pain in her chest. "I'll miss him too." Her voice was different now. "But it's what he wanted."
Gabe left her. She heard nothing but her thoughts. Unbearable thoughts.
Viv turned to the darkening world outside. She found her reflection instead, her reflection in tears. She saw her father's eyes.