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.
Six Reasons Why Humans Should Return to the Moon
"That's one small step for man; one giant leap for mankind."
This July 20th marks fifty years since Neil Armstrong, mission commander of NASA's Apollo 11, uttered those famous words. Much less discussed is how Project Apollo shifted lunar science into high gear, ultimately teaching scientists just how valuable the Moon could become.
A lunar-based solar power system would actually be cheaper than Earth-based solar power implemented on a global scale.
During the six missions that landed humans on the lunar surface from 1969 to 1972, Apollo astronauts collected some 842 pounds of lunar rocks and dirt. Analysis of these materials has provided us with major clues about the origin of Earth's celestial companion 4.51 billion years ago, but also has revealed the Moon is a treasure trove. Lunar rock contains a plethora of minerals with high industrial value. So let's take a look at some prime examples of how humanity's expected return to the lunar surface in the years to come could help life here on Earth.
24/7 solar energy for Earth
During the 1970s, scientists began examining the Apollo lunar samples to study how the lunar surface could be used as a resource. One such scientist was physicist David Criswell, who has since shown that a lunar-based solar power system would actually be cheaper than Earth-based solar power implemented on a global scale. Whoa! How is that possible, given the high cost of launching people and machines into space?
The key is that it would be enormously expensive to scale up enough Earth-based solar power to supply all of humanity's electrical needs, since solar power on such a scale would require a lot of metal, glass, and cement.
But the Moon's lack of atmosphere and weather means that photovoltaic cells built by robots from lunar materials can be paper thin, in contrast with the heavy structures needed in Earth-based solar arrays. Ringing the Moon, such a system would be in perpetual sunlight, making it cheaper to collect solar power there and beam it down to Earth in the form of microwaves.
A source of helium-3 for clean, safe nuclear fusion power and other uses
The gas helium-3 is extremely rare on Earth, but plentiful on the Moon, and could be used in advanced nuclear fusion reactors. Helium-3 also has anti-terrorism and medical uses, especially in the diagnosis of various pulmonary diseases.
A place to offload industrial pollution
Since there are minerals and oxygen in lunar rocks and dust, and frozen water in certain locations, the Moon is an ideal home for factories. Thus, billionaire Jeff Bezos has proposed relocating large segments of heavy industry there, reducing the amount of pollution that is produced on Earth.
The Moon could be a place for colonists to get their space legs before humans put down roots on more distant locations like Mars.
Radio Astronomy without interference from Earth
Constructed on the Moon's far side (the side of the Moon that always faces away from Earth), radio telescopes advancing human knowledge of the Cosmos, and searching for signals from extraterrestrial civilizations, could operate with increased sensitivity and efficiency.
Lunar Tourism
Using the Moon as a destination for tourists may not sound helpful initially, given that only the very wealthy would be able to afford such journeys in the foreseeable future. However, the economic payoff could be substantial in terms of jobs that lunar tourism could provide on Earth. Furthermore, short of actual tourism, companies are gearing up to provide lunar entertainment to fun-seekers here on Earth in the form of mini lunar rovers that people could control from their living rooms, just for fun.
Lunar Colonies
Similar to lunar tourism, lunar colonization sounds initially like a development that would help only those people who go. But, located just three-days' travel from Earth, the Moon would be an excellent place for humanity to become a multi-planet species. The Moon could be a place for colonists to get their space legs before humans put down roots on more distant locations like Mars. With hundreds or thousands of humans thriving on the Moon, Earthlings might find some level of peace of mind knowing that humanity is in a position to outlive a planetary catastrophe.
Brittany Barreto first got the idea to make a DNA-based dating platform nearly 10 years ago when she was in a college seminar on genetics. She joked that it would be called GeneHarmony.com.
Pheramor and startups, like DNA Romance and Instant Chemistry, both based in Canada, claim to match you to a romantic partner based on your genetics.
The idea stuck with her while she was getting her PhD in genetics at Baylor College of Medicine, and in March 2018, she launched Pheramor, a dating app that measures compatibility based on physical chemistry and what the company calls "social alignment."
"I wanted to use genetics and science to help people connect more. Our world is so hungry for connection," says Barreto, who serves as Pheramor's CEO.
With the direct-to-consumer genetic testing market booming, more and more companies are looking to capitalize on the promise of DNA-based services. Pheramor and startups, like DNA Romance and Instant Chemistry, both based in Canada, claim to match you to a romantic partner based on your genetics. It's an intriguing alternative to swiping left or right in hopes of finding someone you're not only physically attracted to but actually want to date. Experts say the science behind such apps isn't settled though.
For $40, Pheramor sends you a DNA kit to swab the inside of your cheek. After you mail in your sample, Pheramor analyzes your saliva for 11 different HLA genes, a fraction of the more than 200 genes that are thought to make up the human HLA complex. These genes make proteins that regulate the immune system by helping protect against invading pathogens.
It takes three to four weeks to get the results backs. In the meantime, users can still download the app and start using it before their DNA results are ready. The app asks users to link their social media accounts, which are fed into an algorithm that calculates a "social alignment." The algorithm takes into account the hashtags you use, your likes, check-ins, posts, and accounts you follow on Facebook, Twitter, and Instagram.
The DNA test results and social alignment algorithm are used to calculate a compatibility percentage between zero and 100. Barreto said she couldn't comment on how much of that score is influenced by the algorithm and how much comes from what the company calls genetic attraction. "DNA is not destiny," she says. "It's not like you're going to swab and I'll send you your soulmate."
Despite its name, Pheramor doesn't actually measure pheromones, chemicals released by animals that affect the behavior of others of the same species. That's because human pheromones have yet to be identified, though they've been discovered throughout the animal kingdom in moths, mice, rabbits, pigs, and many other insects and mammals. The HLA genes Pheramor analyzes instead are the human version of the major histocompatibility complex (MHC), a gene group found in many species.
The connection between HLA type and attraction goes back to the 1970s, when researchers found that inbred male mice preferred to mate with female mice with a different MHC rather than inbred female mice with similar immune system genes. The researchers concluded that this mating preference was linked to smell. The idea is that choosing a mate with different MHC genes gives animals an evolutionary advantage in terms of immune system defense.
The couples who had more dissimilar HLA types reported a more satisfied sex life and satisfied partnership, but it was a small effect.
In the 1990s, Swiss scientists wanted to see if body odor also had an effect on human attraction. In a famous experiment known as the "sweaty T-shirt study", they recruited 49 women to sniff sweaty, unwashed T-shirts from 44 men and put each in a box with a smelling hole and describe the odors of every shirt. The study found that women preferred the scents of T-shirts worn by men who were immunologically different from them compared to men whose HLA genes were similar to their own.
"The idea is, if you are very similar with your partner in HLA type then your offspring is similar in terms of HLA. This reduces your resistance against pathogens," says Illona Croy, a psychologist at the Technical University of Dresden who has studied HLA type in relation to sexual attraction in humans.
In a 2016 study Pheramor cites on its website, Croy and her colleagues tested the HLA types of 250 couples—all of them university students—and asked them how satisfied they were with their partnerships, with their sex lives, and with the odors of their partners. The couples who had more dissimilar HLA types reported a more satisfied sex life and satisfied partnership, but Croy cautions that it was a small effect. "It's not like they were super satisfied or not satisfied at all. It's a slight difference," she says.
Croy says we're much more likely to choose a partner based on appearance, sense of humor, intelligence and common interests.
Other studies have reported no preference for HLA difference in sexual attraction. Tristram Wyatt, a zoologist at the University of Oxford in the U.K. who studies animal pheromones, says it's been difficult to replicate the original T-shirt study. And one of the caveats of the original study is that women who were taking birth control pills preferred men who were more immunologically similar.
"Certainly, we learn to really like the smell of our partners," Wyatt says. "Whether it's the reason for choosing them in the first place, we really don't know."
Wyatt says he's skeptical of DNA-based dating apps because there are many subtypes of HLA genes, meaning there's a fairly low chance that your HLA type and your romantic partner's would be an exact match, anyway. It's why finding a suitable match for a bone marrow transplant is difficult; a donor's HLA type has to be the same as the recipient's.
"What it means is that since we're all different, it's hard statistically to say who the best match will be," he says.
DNA-based dating apps haven't yet gone mainstream, but some people seem willing to give them a try. Since Pheramor's launch a little over a year ago, about 10,000 people have signed up to use the app, about half of which have taken the DNA test, Barreto says. By comparison, an estimated 50 million people use Tinder, which has been around since 2012, and about 40 million people are on Bumble, which was released in 2014.
In April, Barreto launched a second service, this one for couples, called WeHaveChemistry.com. A $139 kit includes two genetic tests, one for you and your partner, and a detailed DNA report on your sexual compatibility.
Unlike the Phermor app, WeHaveChemistry doesn't provide users with a numeric combability score but instead makes personalized recommendations based on your genetic results. For instance, if the DNA test shows that your HLA genes are similar, Barreto says, "We might recommend pheromone colognes, working out together, or not showering before bed to get your juices running."
Despite her own research on HLA and sexual compatibility, Croy isn't sure how knowing HLA type will help couples. However, some researchers are doing studies on whether HLA types are related to certain cases of infertility, and this is where a genetic test might be very useful, says Croy.
"Otherwise, I think it doesn't matter whether we're HLA compatible or not," she says. "It might give you one possible explanation about why your sexual life isn't as satisfactory as it could be, but there are many other factors that play a role."