A newborn and mother in the hospital - first touch. (© martin81/Shutterstock)
Today in Melrose, Massachusetts, Cora Stetson is the picture of good health, a bubbly precocious 2-year-old. But Cora has two separate mutations in the gene that produces a critical enzyme called biotinidase and her body produces only 40 percent of the normal levels of that enzyme.
In the last few years, the dream of predicting and preventing diseases through genomics, starting in childhood, is finally within reach.
That's enough to pass conventional newborn (heelstick) screening, but may not be enough for normal brain development, putting baby Cora at risk for seizures and cognitive impairment. But thanks to an experimental study in which Cora's DNA was sequenced after birth, this condition was discovered and she is being treated with a safe and inexpensive vitamin supplement.
Stories like these are beginning to emerge from the BabySeq Project, the first clinical trial in the world to systematically sequence healthy newborn infants. This trial was led by my research group with funding from the National Institutes of Health. While still controversial, it is pointing the way to a future in which adults, or even newborns, can receive comprehensive genetic analysis in order to determine their risk of future disease and enable opportunities to prevent them.
Some believe that medicine is still not ready for genomic population screening, but others feel it is long overdue. After all, the sequencing of the Human Genome Project was completed in 2003, and with this milestone, it became feasible to sequence and interpret the genome of any human being. The costs have come down dramatically since then; an entire human genome can now be sequenced for about $800, although the costs of bioinformatic and medical interpretation can add another $200 to $2000 more, depending upon the number of genes interrogated and the sophistication of the interpretive effort.
Two-year-old Cora Stetson, whose DNA sequencing after birth identified a potentially dangerous genetic mutation in time for her to receive preventive treatment.
(Photo courtesy of Robert Green)
The ability to sequence the human genome yielded extraordinary benefits in scientific discovery, disease diagnosis, and targeted cancer treatment. But the ability of genomes to detect health risks in advance, to actually predict the medical future of an individual, has been mired in controversy and slow to manifest. In particular, the oft-cited vision that healthy infants could be genetically tested at birth in order to predict and prevent the diseases they would encounter, has proven to be far tougher to implement than anyone anticipated.
But in the last few years, the dream of predicting and preventing diseases through genomics, starting in childhood, is finally within reach. Why did it take so long? And what remains to be done?
Great Expectations
Part of the problem was the unrealistic expectations that had been building for years in advance of the genomic science itself. For example, the 1997 film Gattaca portrayed a near future in which the lifetime risk of disease was readily predicted the moment an infant is born. In the fanfare that accompanied the completion of the Human Genome Project, the notion of predicting and preventing future disease in an individual became a powerful meme that was used to inspire investment and public support for genomic research long before the tools were in place to make it happen.
Another part of the problem was the success of state-mandated newborn screening programs that began in the 1960's with biochemical tests of the "heel-stick" for babies with metabolic disorders. These programs have worked beautifully, costing only a few dollars per baby and saving thousands of infants from death and severe cognitive impairment. It seemed only logical that a new technology like genome sequencing would add power and promise to such programs. But instead of embracing the notion of newborn sequencing, newborn screening laboratories have thus far rejected the entire idea as too expensive, too ambiguous, and too threatening to the comfortable constituency that they had built within the public health framework.
"What can you find when you look as deeply as possible into the medical genomes of healthy individuals?"
Creating the Evidence Base for Preventive Genomics
Despite a number of obstacles, there are researchers who are exploring how to achieve the original vision of genomic testing as a tool for disease prediction and prevention. For example, in our NIH-funded MedSeq Project, we were the first to ask the question: "What can you find when you look as deeply as possible into the medical genomes of healthy individuals?"
Most people do not understand that genetic information comes in four separate categories: 1) dominant mutations putting the individual at risk for rare conditions like familial forms of heart disease or cancer, (2) recessive mutations putting the individual's children at risk for rare conditions like cystic fibrosis or PKU, (3) variants across the genome that can be tallied to construct polygenic risk scores for common conditions like heart disease or type 2 diabetes, and (4) variants that can influence drug metabolism or predict drug side effects such as the muscle pain that occasionally occurs with statin use.
The technological and analytical challenges of our study were formidable, because we decided to systematically interrogate over 5000 disease-associated genes and report results in all four categories of genetic information directly to the primary care physicians for each of our volunteers. We enrolled 200 adults and found that everyone who was sequenced had medically relevant polygenic and pharmacogenomic results, over 90 percent carried recessive mutations that could have been important to reproduction, and an extraordinary 14.5 percent carried dominant mutations for rare genetic conditions.
A few years later we launched the BabySeq Project. In this study, we restricted the number of genes to include only those with child/adolescent onset that could benefit medically from early warning, and even so, we found 9.4 percent carried dominant mutations for rare conditions.
At first, our interpretation around the high proportion of apparently healthy individuals with dominant mutations for rare genetic conditions was simple – that these conditions had lower "penetrance" than anticipated; in other words, only a small proportion of those who carried the dominant mutation would get the disease. If this interpretation were to hold, then genetic risk information might be far less useful than we had hoped.
Suddenly the information available in the genome of even an apparently healthy individual is looking more robust, and the prospect of preventive genomics is looking feasible.
But then we circled back with each adult or infant in order to examine and test them for any possible features of the rare disease in question. When we did this, we were surprised to see that in over a quarter of those carrying such mutations, there were already subtle signs of the disease in question that had not even been suspected! Now our interpretation was different. We now believe that genetic risk may be responsible for subclinical disease in a much higher proportion of people than has ever been suspected!
Meanwhile, colleagues of ours have been demonstrating that detailed analysis of polygenic risk scores can identify individuals at high risk for common conditions like heart disease. So adding up the medically relevant results in any given genome, we start to see that you can learn your risks for a rare monogenic condition, a common polygenic condition, a bad effect from a drug you might take in the future, or for having a child with a devastating recessive condition. Suddenly the information available in the genome of even an apparently healthy individual is looking more robust, and the prospect of preventive genomics is looking feasible.
Preventive Genomics Arrives in Clinical Medicine
There is still considerable evidence to gather before we can recommend genomic screening for the entire population. For example, it is important to make sure that families who learn about such risks do not suffer harms or waste resources from excessive medical attention. And many doctors don't yet have guidance on how to use such information with their patients. But our research is convincing many people that preventive genomics is coming and that it will save lives.
In fact, we recently launched a Preventive Genomics Clinic at Brigham and Women's Hospital where information-seeking adults can obtain predictive genomic testing with the highest quality interpretation and medical context, and be coached over time in light of their disease risks toward a healthier outcome. Insurance doesn't yet cover such testing, so patients must pay out of pocket for now, but they can choose from a menu of genetic screening tests, all of which are more comprehensive than consumer-facing products. Genetic counseling is available but optional. So far, this service is for adults only, but sequencing for children will surely follow soon.
As the costs of sequencing and other Omics technologies continue to decline, we will see both responsible and irresponsible marketing of genetic testing, and we will need to guard against unscientific claims. But at the same time, we must be far more imaginative and fast moving in mainstream medicine than we have been to date in order to claim the emerging benefits of preventive genomics where it is now clear that suffering can be averted, and lives can be saved. The future has arrived if we are bold enough to grasp it.
Funding and Disclosures:
Dr. Green's research is supported by the National Institutes of Health, the Department of Defense and through donations to The Franca Sozzani Fund for Preventive Genomics. Dr. Green receives compensation for advising the following companies: AIA, Applied Therapeutics, Helix, Ohana, OptraHealth, Prudential, Verily and Veritas; and is co-founder and advisor to Genome Medical, Inc, a technology and services company providing genetics expertise to patients, providers, employers and care systems.
With the population of older people projected to grow dramatically, and the cost of healthcare with it, the future welfare of the country may depend on solving aging, writes philosopher Ingemar Patrick Linden.
There is a lack of political will and leadership on the issue, and the idea that we should seek to do something about aging is generally met with a great deal of suspicion and trepidation. In a large representative study conducted by the Pew Research Center in 2013, only 38% of the respondents said that they would want a treatment that could slow the aging process and allow them to live at least 120 years. Apparently, most people prefer, or at least do not mind, to age and die within a natural lifespan. This result has been confirmed by smaller studies and it is, I think, surprising. Are we not supposed to live in a youth-culture? Are people not supposed to want to stay young and alive forever? Is self-preservation not the strong drive we have always assumed it to be?
We are inundated and saturated with an ideology of death-acceptance.
In my book, The Case against Death, I suggest that we have been culturally conditioned to think that it is virtuous to accept aging and death. We are taught to believe that although aging and death seem gruesome, they are what is best for us, all things considered. This is what we are supposed to think, and the majority accept it. I call this the Wise View because death acceptance has been the dominant view of philosophers since the beginning. Socrates compared our earthly life to an illness and a prison and described death as a healer and a liberator. The Buddha taught that life is suffering and that the way to escape suffering is to end the cycle of birth, death and rebirth. Stoic philosophers from Zeno to Marcus Aurelius believed that everything that happens in accordance with nature is good, and that therefore we should not only accept death but welcome it as an aspect of a perfect totality.
Epicureans agreed with these rival schools and famously argued that death cannot harm us because where we are, death is not, and where death is we are not. We cannot be harmed if we are not, so death is harmless. The simple view that death actually can harm us greatly is one of the least philosophical views one can hold.
In The Case Against Death, philosopher Ingemar Patrick Linden argues that we frown on using science to prolong healthy life only because we're culturally conditioned to think that way.
Many of the stories we tell promote the Wise View. One of the earliest known pieces of literature, the Epic of Gilgamesh, follows Gilgamesh on a quest for eternal life ending with the wisdom that death is the destiny of man. Today we learn about the tedium of immortality from the children’s book Tuck Everlasting by Natalie Babbitt, and we are warned about the vice of wanting to resist death in other books and films such as J.K Rowling’s Harry Potter, where Voldemort must kill Harry as a step towards his own immortality; C.S. Lewis’ The Chronicles of Narnia where the White Witch has gained immortal youth and madness in equal measures; J.R.R. Tolkien’s Lord of the Rings trilogy where the ring extends the wearer’s life but can also destroy them, as exemplified by the creep Gollum; and Doctor Strange where life extension is the one magical power that is taboo. In Star Wars, Yoda, a stereotype of the sage, teaches us the wisdom handed down by philosophers and prophets: “Death is a natural part of life. Rejoice for those around you who transform into the Force. Mourn them do not. Miss them do not.”
We are inundated and saturated with an ideology of death-acceptance. Can the dear reader name one single story where the hero is pursuing anti-aging, longevity or immortality and the villain tries to stop her?
The Wise View resonates with us partly because we think that there is nothing we can do about aging and death, so we do not want to wish for what we cannot have. Youth and immortality are sour grapes to us. Believing that death is, all things considered, not such a bad thing, protects us from experiencing our aging and approaching death as a gruesome tragedy. This need to escape the thought that we are heading towards a personal catastrophe explains why many are so quick to accept arguments against radical life extension, despite their often glaring weaknesses.
One of the most common objections to radical life extension is that aging and death are natural. The problem with this argument is that many things that are natural are very bad, such as cancer, and other things that are not natural are very good, such as a cure for cancer. Why are we so sure that cancer is bad? Because we assume that it is bad to die. Indeed, nothing is more natural than wanting to live. We seem to need philosophers and story tellers to talk us out of it and, in the words of a distinguished bioethicist, “instruct and somewhat moderate our lust for life.”
Another standard objection is that we need a deadline, and that without death we could postpone every action forever. “Death brings urgency and seriousness to life,” say proponents of this view, but there are several problems with this argument. Even if our lives were endless, there would still be many things we would have to do at a certain time, and that could not be redone, for example, saving our planet from being destroyed, or becoming the first person on Venus. And if we prefer pleasant endless lives over unpleasant endless ones, we will have to exercise, eat right, keep our word, develop our talents, show up for time at work, pay our taxes by the due date, remember birthdays, and so on.
The Wise View provides us with a feel-good bromide for the anxiety created by the foreknowledge of our decay and death by telling us that these are not evils, but blessings in disguise. Once perhaps an innocuous delusion, today the view stands in the way of a necessary societal commitment to research that can prolong our healthy life.
Besides, even if we succeeded in ending aging, we would still die from other causes. Given the rate of accidental deaths we would be fortunate to live to age 2000 all things equal. So even if, contrary to what I have argued, we do need a deadline, we can still argue that the natural lifespan that we now labor under is inhuman and that it forces each human to limit her ambitions and to become only a fragment of all that she that could have been. Our tight time constraint imposes tragic choices and inflated opportunity costs. Death does not make life matter; it makes time matter.
The perhaps most awful argument against radical life extension is grounded in a pessimism that holds life in such little regard that it says that best of all is never to have born. This view was expressed by Ecclesiastes in the Hebrew Bible, by Sophocles and several other ancient Greeks, by the German philosopher Arthur Schopenhauer, and recently by, among others, the South African philosopher David Benatar who argues that it is wrong to bring children into the world and that we should euthanize all sentient life. Pessimism, one suspects, largely appeals to some for reasons having to do with personal temperament, but insofar as it is built on factual beliefs, they can be addressed by providing a less negatively biased understanding of the world, by pointing out that curing aging would decrease the badness that they are so hypersensitive to, and by reminding them that if life really becomes unbearable, they are free to quit at any time. Other means of persuasion could include recommending sleep, exercise and taking long brisk walks in nature.
The Wise View provides us with a feel-good bromide for the anxiety created by the foreknowledge of our decay and death by telling us that these are not evils, but blessings in disguise. Once perhaps an innocuous delusion, today the view stands in the way of a necessary societal commitment to research that can prolong our healthy life. We need abandon it and openly admit that aging is a scourge that deserves to be fought with the combined energies equaling those expended on fighting COVID-19, Alzheimer’s disease, cancer, stroke and all the other illnesses for which aging is the greatest risk factor. The fight to end aging transcends ordinary political boundaries and is therefore the kind of grand unifying enterprise that could re-energize a society suffering from divisiveness and the sense of a lack of a common purpose. It is hard to imagine a more worthwhile cause.
A worker tends to a rural farm in Hanoi, Vietnam, where technology is making it easier to harvest an ancient fern called Azolla. Some scientists and farmers view Azolla as a solution to our modern-day agricultural and environmental challenges.
This “Arctic Azolla event” had devastating impacts on marine life. To date, scientists are trying to figure out how it ended. But they documented that the extraordinary event cooled down the Arctic by at least 40 degrees Fahrenheit — effectively freezing the poles and triggering several cycles of ice ages. “This carbon dioxide sequestration changed the climate from greenhouse to white house,” says Jonathan Bujak, a paleontologist who has researched the Arctic through expeditions since 1973.
Some farmers and scientists, such as Bujak, are looking to this ancient fern, which manipulated the Earth’s climate around 49 million years ago with its insatiable appetite for carbon dioxide, as a potential solution to our modern-day agricultural and environmental challenges. “There is no other plant like Azolla in the world,” says Bujak.
Decoding the Azolla plant
Azolla lives in symbiosis with a cyanobacterium called Anabaena that made the plant’s leaf cavities its permanent home at an early stage in Earth's history. This close relationship with Anabaena enables Azolla to accomplish a feat that is impossible for most plants: directly splitting dinitrogen molecules that make up 78 percent of the Earth’s atmosphere.
A dinitrogen molecule consists of two nitrogen atoms tightly locked together in one of the strongest bonds in nature. The semi-aquatic fern’s ability to split nitrogen, called nitrogen-fixing, made it a highly revered plant in East Asia. Rice farmers used Azolla as a biofertilizer since the 11th century in Vietnam and China.
For decades, scientists have attempted to decode Azolla’s evolution. Cell biologist Francisco Carrapico, who worked at the University of Lisbon, has analyzed this distinctive symbiosis since the 1980s. To his amazement, in 1991, he found that bacteria are the third partner of the Azolla-Anabaena symbiosis.
“Azolla and Anabaena cannot survive without each other. They have co-evolved for 80 million years, continuously exchanging their genetic material with each other,” says Bujak, co-author of The Azolla Story, which he published with his daughter, Alexandra Bujak, an environmental scientist. Three different levels of nitrogen fixation take place within the plant, as Anabaena draws down as much as 2,200 pounds of atmospheric nitrogen per acre annually.
“Using Azolla to mitigate climate change might sound a bit too simple. But that is not the case,” Bujak says. “At a microscopic level, extremely complicated biochemical reactions are constantly occurring inside the plant’s cells that machines or technology cannot replicate yet.”
In 2018, researchers based in the U.S. managed to sequence Azolla’s complete genome — which is four times larger than the human genome — through a crowdfunded study, further increasing our understanding of this plant. “Azolla is a superorganism that works efficiently as a natural biotechnology system that makes it capable of doubling in size within three to five days,” says Carrapico.
Making Azolla mainstream again in agriculture
While scientific groups in the Global North have been working towards unraveling the tiny fern’s inner workings, communities in the Global South are busy devising creative ways to return to their traditional agricultural roots by tapping into Azolla’s full potential.
Pham Gia Minh, an entrepreneur living in Hanoi, Vietnam, is one such citizen scientist who believes that Azolla could be a climate savior. More than two decades after working in finance and business development, Minh is now focusing on continuing his grandfather’s legacy, an agricultural scientist who conducted Azolla research until the 1950s. “Azolla is our family’s heritage,” says Minh.
Pham Gia Minh, an entrepreneur and citizen scientist in Hanoi, Vietnam, believes that Azolla could be a climate savior
Pham Gia Minh
Since the advent of chemical fertilizers in the early 1900s, farmers in Asia abandoned Azolla to save on time and labor costs. But rice farmers in the country went back to cultivating Azolla during the Vietnam War after chemical trade embargoes made chemical fertilizers far too expensive and inaccessible.
By 1973, Azolla cultivation in rice paddy fields was established on half a million hectares in Vietnam. By injecting nitrogen into the soil, Azolla improves soil fertility and also increases rice yields by at least 27 percent compared to urea. The plants can also reduce a farm’s methane emissions by 40 percent.
“Unfortunately, after 1985, chemical fertilizers became cheap and widely available in Vietnam again. So, farmers stopped growing Azolla because of the time-consuming and labor-intensive cultivation process,” says Minh.
Minh has invested in a rural farm where he is proving that modern technology can make the process less burdensome. He uses a pump and drying equipment for harvesting Azolla in a small pond, and he deploys a drone for spraying insecticides and fertilizers on the pond at regular intervals.
As Azolla lacks phosphorus, farmers in developing countries still find it challenging to let go of chemical fertilizers completely. Still, Minh and Bujak say that farmers can use Azolla instead of chemical fertilizers after mixing it with dung.
In the last few years, the fern’s popularity has been growing in other developing countries like India, Palestine, Indonesia, the Philippines, and Bangladesh, where local governments and citizens are trying to re-introduce Azolla integrated farming by growing the ferns in small ponds.
Replacing soybeans with Azolla
In Ecuador, Mariano Montano Armijos, a former chemical engineer, has worked with Azolla for more than 20 years. Since 2008, he has shared resources and information for growing Azolla with 3,000 farmers in Ecuador. The farmers use the harvested plants as a bio-fertilizer and feed for livestock.
“The farmers do not use urea anymore,” says Armijos. “This goes against the conventional agricultural practices of using huge amounts of synthetic nitrogen on a hectare of rice or corn fields.”
He insists that Azolla’s greatest strength is that it is a rich source of proteins, making it highly nutritious for human beings as well. After growing Azolla on a small scale in ponds, Armijos and his business partner, Ivan Noboa, are now building a facility for cultivating the ferns as a superfood on an industrial scale.
According to Armijos, one hectare of Azolla in Ecuador can produce seven tons of proteins. Whereas soybeans produce only one ton of protein per hectare. “If we switch to Azolla, it could help in reducing deforestation in the Amazon. But taming Azolla and turning it into a crop is not easy,” he adds.
Henriette Schluepmann, a molecular plant biologist at Utrecht University in the Netherlands, believes that Azolla could replace soybeans and chemical fertilizers someday — only if researchers can achieve yield stability in controlled environments over long durations.
“In a country like the Netherlands that is surrounded by water with high levels of phosphates, it makes sense to grow Azolla as a substitute for soybeans,” says Schluepmann. “For that to happen, we need massive investments to understand these ferns’ reproductive system and how to replicate that within aquaculture systems on a large scale.”
Pollution control and carbon sequestration
Currently, Schluepmann and her team are growing Azolla in a plant nursery or closed system before transferring the ferns to flooded fields. So far, they have been able to continuously grow Azolla without any major setbacks for a total of 155 days. Taking care of these plants’ well-being is an uphill struggle.
Unlike most plants, Azolla does not grow from seeds because it contains female and male spores that tend to split instead of reproducing. To add to that, growing Azolla on a large scale in controlled environments makes the floating plants extremely vulnerable to insect infestations and fungi attacks.
“Even though it is easier to grow Azolla on a non-industrial scale, the long and tedious cultivation process is often in conflict with human rights,” she says. Farms in developing countries such as Indonesia sometimes use child labor for cultivating Azolla.”
History has taught us that the uncontrolled growth of Azolla plants deprives marine ecosystems of sunlight and chokes life underneath them. But researchers like Schluepmann and Bujak are optimistic that even on a much smaller scale, Azolla can put up a fight against human-driven climate change.
Schluepmann discovered an insecticide that can control Azolla blooms. But in the wild, this aquatic fern grows relentlessly in polluted rivers and lakes and has gained a notorious reputation as an invasive weed. Countries like Portugal and the UK banned Azolla after experiencing severe blooms in rivers that snuffed out local marine life.
“Azolla has been misunderstood as a nuisance. But in reality, it is highly beneficial for purifying water,” says Bujak. Through a process called phytoremediation, Azolla locks up pollutants like excess nitrogen and phosphorus and stops toxic algal blooms from occurring in rivers and lakes.
A 2018 study found that Azolla can decrease nitrogen and phosphorus levels in wastewater by 33 percent and 40.5 percent, respectively. While harmful algae like phytoplankton produce toxins and release noxious gases, Azolla automatically blocks any toxins that its cyanobacteria, Anabaena, might produce.
“In our labs, we observed that Azolla works effectively in treating wastewater,” explains Schluepmann. “Once we gain a better understanding of Azolla aquaculture, we can also use it for carbon capture and storage. But in Europe, we would have to use the entire Baltic Sea to make a difference.”
Planting massive amounts of these prehistoric ferns in any of the Northern great water bodies is out of the question. After all, history has taught us that the uncontrolled growth of Azolla plants deprives marine ecosystems of sunlight and chokes life underneath them. But researchers like Schluepmann and Bujak are optimistic that even on a much smaller scale, Azolla can put up a fight against human-driven climate change.
Traditional carbon capture and storage methods are not only expensive but also inefficient and could increase air pollution. According to Bujak’s estimates, Azolla can sequester 10 metric tonnes of carbon dioxide per hectare annually, which is 10 times the average capacity of grasslands.
“Anyone can set up their own DIY carbon capture and storage system by growing Azolla in shallow water. After harvesting and compressing the plants, carbon dioxide gets stored permanently,” says Bujak.
He envisions scaling up this process by setting up “Azolla hubs” in mega-cities where the plants are grown in shallow trays stacked on top of each other with vertical farming systems built within multi-story buildings. The compressed Azolla plants can then be converted into a biofuel, fertilizer, livestock feed, or biochar for sequestering carbon dioxide.
“Using Azolla to mitigate climate change might sound a bit too simple. But that is not the case,” Bujak adds. “At a microscopic level, extremely complicated biochemical reactions are constantly occurring inside the plant’s cells that machines or technology cannot replicate yet.”
Through Azolla, scientists hope to work with nature by tapping into four billion years of evolution.