What will the $100 genome mean?
In May 2022, Californian biotech Ultima Genomics announced that its UG 100 platform was capable of sequencing an entire human genome for just $100, a landmark moment in the history of the field. The announcement was particularly remarkable because few had previously heard of the company, a relative unknown in an industry long dominated by global giant Illumina which controls about 80 percent of the world’s sequencing market.
Ultima’s secret was to completely revamp many technical aspects of the way Illumina have traditionally deciphered DNA. The process usually involves first splitting the double helix DNA structure into single strands, then breaking these strands into short fragments which are laid out on a glass surface called a flow cell. When this flow cell is loaded into the sequencing machine, color-coded tags are attached to each individual base letter. A laser scans the bases individually while a camera simultaneously records the color associated with them, a process which is repeated until every single fragment has been sequenced.
Instead, Ultima has found a series of shortcuts to slash the cost and boost efficiency. “Ultima Genomics has developed a fundamentally new sequencing architecture designed to scale beyond conventional approaches,” says Josh Lauer, Ultima’s chief commercial officer.
This ‘new architecture’ is a series of subtle but highly impactful tweaks to the sequencing process ranging from replacing the costly flow cell with a silicon wafer which is both cheaper and allows more DNA to be read at once, to utilizing machine learning to convert optical data into usable information.
To put $100 genome in perspective, back in 2012 the cost of sequencing a single genome was around $10,000, a price tag which dropped to $1,000 a few years later. Before Ultima’s announcement, the cost of sequencing an individual genome was around $600.
Several studies have found that nearly 12 percent of healthy people who have their genome sequenced, then discover they have a variant pointing to a heightened risk of developing a disease that can be monitored, treated or prevented.
While Ultima’s new machine is not widely available yet, Illumina’s response has been rapid. In September 2022, the company unveiled the NovaSeq X series, which it describes as its fastest most cost-efficient sequencing platform yet, capable of sequencing genomes at $200, with further price cuts likely to follow.
But what will the rapidly tumbling cost of sequencing actually mean for medicine? “Well to start with, obviously it’s going to mean more people getting their genome sequenced,” says Michael Snyder, professor of genetics at Stanford University. “It'll be a lot more accessible to people.”
At the moment sequencing is mainly limited to certain cancer patients where it is used to inform treatment options, and individuals with undiagnosed illnesses. In the past, initiatives such as SeqFirst have attempted further widen access to genome sequencing based on growing amounts of research illustrating the potential benefits of the technology in healthcare. Several studies have found that nearly 12 percent of healthy people who have their genome sequenced, then discover they have a variant pointing to a heightened risk of developing a disease that can be monitored, treated or prevented.
“While whole genome sequencing is not yet widely used in the U.S., it has started to come into pediatric critical care settings such as newborn intensive care units,” says Professor Michael Bamshad, who heads the genetic medicine division in the University of Washington’s pediatrics department. “It is also being used more often in outpatient clinical genetics services, particularly when conventional testing fails to identify explanatory variants.”
But the cost of sequencing itself is only one part of the price tag. The subsequent clinical interpretation and genetic counselling services often come to several thousand dollars, a cost which insurers are not always willing to pay.
As a result, while Bamshad and others hope that the arrival of the $100 genome will create new opportunities to use genetic testing in innovative ways, the most immediate benefits are likely to come in the realm of research.
Bigger Data
There are numerous ways in which cheaper sequencing is likely to advance scientific research, for example the ability to collect data on much larger patient groups. This will be a major boon to scientists working on complex heterogeneous diseases such as schizophrenia or depression where there are many genes involved which all exert subtle effects, as well as substantial variance across the patient population. Bigger studies could help scientists identify subgroups of patients where the disease appears to be driven by similar gene variants, who can then be more precisely targeted with specific drugs.
If insurers can figure out the economics, Snyder even foresees a future where at a certain age, all of us can qualify for annual sequencing of our blood cells to search for early signs of cancer or the potential onset of other diseases like type 2 diabetes.
David Curtis, a genetics professor at University College London, says that scientists studying these illnesses have previously been forced to rely on genome-wide association studies which are limited because they only identify common gene variants. “We might see a significant increase in the number of large association studies using sequence data,” he says. “It would be far preferable to use this because it provides information about rare, potentially functional variants.”
Cheaper sequencing will also aid researchers working on diseases which have traditionally been underfunded. Bamshad cites cystic fibrosis, a condition which affects around 40,000 children and adults in the U.S., as one particularly pertinent example.
“Funds for gene discovery for rare diseases are very limited,” he says. “We’re one of three sites that did whole genome sequencing on 5,500 people with cystic fibrosis, but our statistical power is limited. A $100 genome would make it much more feasible to sequence everyone in the U.S. with cystic fibrosis and make it more likely that we discover novel risk factors and pathways influencing clinical outcomes.”
For progressive diseases that are more common like cancer and type 2 diabetes, as well as neurodegenerative conditions like multiple sclerosis and ALS, geneticists will be able to go even further and afford to sequence individual tumor cells or neurons at different time points. This will enable them to analyze how individual DNA modifications like methylation, change as the disease develops.
In the case of cancer, this could help scientists understand how tumors evolve to evade treatments. Within in a clinical setting, the ability to sequence not just one, but many different cells across a patient’s tumor could point to the combination of treatments which offer the best chance of eradicating the entire cancer.
“What happens at the moment with a solid tumor is you treat with one drug, and maybe 80 percent of that tumor is susceptible to that drug,” says Neil Ward, vice president and general manager in the EMEA region for genomics company PacBio. “But the other 20 percent of the tumor has already got mutations that make it resistant, which is probably why a lot of modern therapies extend life for sadly only a matter of months rather than curing, because they treat a big percentage of the tumor, but not the whole thing. So going forwards, I think that we will see genomics play a huge role in cancer treatments, through using multiple modalities to treat someone's cancer.”
If insurers can figure out the economics, Snyder even foresees a future where at a certain age, all of us can qualify for annual sequencing of our blood cells to search for early signs of cancer or the potential onset of other diseases like type 2 diabetes.
“There are companies already working on looking for cancer signatures in methylated DNA,” he says. “If it was determined that you had early stage cancer, pre-symptomatically, that could then be validated with targeted MRI, followed by surgery or chemotherapy. It makes a big difference catching cancer early. If there were signs of type 2 diabetes, you could start taking steps to mitigate your glucose rise, and possibly prevent it or at least delay the onset.”
This would already revolutionize the way we seek to prevent a whole range of illnesses, but others feel that the $100 genome could also usher in even more powerful and controversial preventative medicine schemes.
Newborn screening
In the eyes of Kári Stefánsson, the Icelandic neurologist who been a visionary for so many advances in the field of human genetics over the last 25 years, the falling cost of sequencing means it will be feasible to sequence the genomes of every baby born.
“We have recently done an analysis of genomes in Iceland and the UK Biobank, and in 4 percent of people you find mutations that lead to serious disease, that can be prevented or dealt with,” says Stefansson, CEO of deCODE genetics, a subsidiary of the pharmaceutical company Amgen. “This could transform our healthcare systems.”
As well as identifying newborns with rare diseases, this kind of genomic information could be used to compute a person’s risk score for developing chronic illnesses later in life. If for example, they have a higher than average risk of colon or breast cancer, they could be pre-emptively scheduled for annual colonoscopies or mammograms as soon as they hit adulthood.
To a limited extent, this is already happening. In the UK, Genomics England has launched the Newborn Genomes Programme, which plans to undertake whole-genome sequencing of up to 200,000 newborn babies, with the aim of enabling the early identification of rare genetic diseases.
"I have not had my own genome sequenced and I would not have wanted my parents to have agreed to this," Curtis says. "I don’t see that sequencing children for the sake of some vague, ill-defined benefits could ever be justifiable.”
However, some scientists feel that it is tricky to justify sequencing the genomes of apparently healthy babies, given the data privacy issues involved. They point out that we still know too little about the links which can be drawn between genetic information at birth, and risk of chronic illness later in life.
“I think there are very difficult ethical issues involved in sequencing children if there are no clear and immediate clinical benefits,” says Curtis. “They cannot consent to this process. I have not had my own genome sequenced and I would not have wanted my parents to have agreed to this. I don’t see that sequencing children for the sake of some vague, ill-defined benefits could ever be justifiable.”
Curtis points out that there are many inherent risks about this data being available. It may fall into the hands of insurance companies, and it could even be used by governments for surveillance purposes.
“Genetic sequence data is very useful indeed for forensic purposes. Its full potential has yet to be realized but identifying rare variants could provide a quick and easy way to find relatives of a perpetrator,” he says. “If large numbers of people had been sequenced in a healthcare system then it could be difficult for a future government to resist the temptation to use this as a resource to investigate serious crimes.”
While sequencing becoming more widely available will present difficult ethical and moral challenges, it will offer many benefits for society as a whole. Cheaper sequencing will help boost the diversity of genomic datasets which have traditionally been skewed towards individuals of white, European descent, meaning that much of the actionable medical information which has come out of these studies is not relevant to people of other ethnicities.
Ward predicts that in the coming years, the growing amount of genetic information will ultimately change the outcomes for many with rare, previously incurable illnesses.
“If you're the parent of a child that has a susceptible or a suspected rare genetic disease, their genome will get sequenced, and while sadly that doesn’t always lead to treatments, it’s building up a knowledge base so companies can spring up and target that niche of a disease,” he says. “As a result there’s a whole tidal wave of new therapies that are going to come to market over the next five years, as the genetic tools we have, mature and evolve.”
This article was first published by Leaps.org in October 2022.
The Toxic Effects of Noise and What We’re Not Doing About It
Erica Walker had a studio in her Brookline, Mass. apartment where she worked as a bookbinder and furniture maker. That was until a family with two rowdy children moved in above her.
The kids ran amuck, disrupting her sleep and work. Ear plugs weren’t enough to blot out the commotion. Aside from anger and a sense of lost control, the noise increased her heart rate and made her stomach feel like it was dropping, she says.
That’s when Walker realized that noise is a public health problem, not merely an annoyance. She set up her own “mini study” on how the clamor was affecting her. She monitored sound levels in her apartment and sent saliva samples to a lab to measure her stress levels.
Walker ultimately sold her craft equipment and returned to school to study public health. Today she is assistant professor of epidemiology and director of the Community Noise Lab at the Brown University School of Public Health. “We treat noise like a first world problem—like a sacrifice we should have to make for modern conveniences. But it’s a serious environmental stressor,” she asserts.
Our daily soundscape is a cacophony of earsplitting jets, motorcycles, crying babies, construction sites or gunshots if you’re in the military. Noise exposure is the primary cause of preventable hearing loss. Researchers have identified links between excessive noise and a heightened risk of heart disease, metabolic disorders, anxiety, depression, sleep disorders, and impaired cognition. Even wildlife suffers. Blasting oil drills and loud shipping vessels impede the breeding, feeding and migration of whales and dolphins.
At one time, the federal government had our back… and our ears. Congress passed the Noise Control Act in 1972. The Environmental Protection Agency set up the Office of Noise Abatement and Control (ONAC) to launch research, explore solutions and establish noise emission standards. But ONAC was defunded in 1981 amidst a swirl of antiregulatory sentiment.
Impossibly Loud and Unhealthy
Daniel Fink. a physician, WHO consultant, and board chair of The Quiet Coalition, a program of the nonprofit Quiet Communities, likens the effect of noise to the invisible but cumulative harm of second-hand smoke. About 1 in 4 adults in the U.S. who report excellent to good hearing already have some hearing loss. The injury can happen after one loud concert or from years with a blaring TV. Some people are more genetically susceptible to noise-related hearing loss than others.
“People say noise isn’t a big deal but it bothers your body whether you realize it or not,” says Ted Rueter, director of Noise Free America: A Coalition to Promote Quiet. Noise can chip away at your ears or cardiovascular system even while you’re sleeping. Rueter became a “quiet advocate” while a professor at UCLA two decades ago. He was plagued by headaches, fatigue and sleep deprivation caused by the hubbub of Los Angeles, he says.
The louder a sound is, and the longer you are exposed to it, the more likely it will cause nerve damage and harmful fluid buildup in your inner ear. Normal speech is 50-60 decibels (dBs). The EPA recommends that 24-hour exposure to noise should be no higher than 70 weighted decibels over 24 hours (weighted to approximate how the human ear perceives the sound) to prevent hearing loss but a 55 dB limit is recommended to protect against other harms from noise, too.
The decibel scale is logarithmic. That means 80 dB is 10 times louder than 70 dB. Trucks and motorcycles run 90 dBs. A gas-powered leaf blower, jackhammer or snow blower will cost you 100 dBs. A rock concert is in the 110 dB range. Aircraft takeoffs or sirens? 120 dBs.
Walker, the Brown professor, says that sound measurements often use misleading metrics, though, because they don’t include low frequency sound that disturb the body. The high frequency of a screeching bus will register in decibels but the sound that makes your chest reverberate is not accounted for, she explains. ‘How loud?’ is a superficial take when it comes to noise, Walker says.
After realizing the impact of noise on her own health, Erica Walker was inspired to change careers and become director of the Community Noise Lab at the Brown University School of Public Health.
Erica Walker
Fink adds that the extent to which noise impairs hearing is underestimated. People assume hearing loss is due to age but it’s not inevitable, he says. He cites studies of older people living in quiet, isolated areas who maintain excellent hearing. Just like you can prevent wrinkles by using sunscreen, you can preserve hearing by using ear plugs when attending fireworks or hockey games.
You can enable push notifications on a Smart Watch to alert you at a bar exceeding healthy sound levels. Free apps like SoundPrint, iHEARu, or NoiseTube can do decibel checks, too, but you don’t need one, says Fink. “If you can’t carry a conversation at normal volume, it’s too loud and your auditory health is at risk,” he says.
About 40 million U.S. adults, ages 20-69, have noise-induced hearing loss. Fink is among them after experiencing tinnitus (ringing or buzzing in the ears) on leaving a raucous New Year’s Eve party in 2007. The condition is permanent and he wears earplugs now for protection.
Fewer are aware of the link between noise pollution and heart disease. Piercing noise is stressful, raising blood pressure and heart rate. If you live near a freeway or constantly barking dog, the chronic sound stress can trigger systemic inflammation and the vascular changes associated with heart attacks and stroke.
Researchers at Rutgers University’s Robert Wood Johnson Medical School, working with data from the state’s Bureau of Transportation, determined that 1 in 20 heart attacks in New Jersey during 2018 were due to noise from highways, trains and air traffic. That’s 800 heart attack hospitalizations in the state that year.
Another study showed that incidence of hypertension and hardening arteries decreased during the Covid-19 air lockdown among Poles in Krakow routinely exposed to aircraft noise. The authors, comparing their pre-pandemic 2015 results to 2020 data, concluded it was no coincidence.
Mental health takes a hit, too. Chronic noise can provoke anxiety, depression and violence. Cognitively, there is ample evidence that noise disturbance lowers student achievement and worker productivity, and hearing loss among older people can speed up cognitive decline.
Noise also contributes to health disparities. People in neighborhoods with low socioeconomic status and a higher percentage of minority residents bear the brunt of noise. Affluent people have the means to live far from airports, factories, and honking traffic.
Out, Out, Damn Noise
Europe is ahead of the U.S. in tackling noise pollution. The World Health Organization developed policy guidelines used by the European Environment Agency to establish noise regulations and standards, and progress reports are issued.
Americans are relying too much on personal protective equipment (PPE) instead of eliminating or controlling noise. The Centers of Disease Control and Prevention rank PPE as the least useful response. Earplugs and muffs are effective, says Walker, but these devices are “a band-aid on a waterfall.”
Editing out noise during product design is the goal. Engineers have an arsenal of techniques and know-how for that. The problem is that these solutions aren’t being applied.
A better way to lower the volume is by maintaining or substituting equipment intended for common use. Piercing building alarms can be replaced with visual signals that flash alerts. Clanking chain and gear drives can be swapped out with belt drives. Acoustical barriers can wall off highway noise. Hospitals can soften beeping monitors and limit loudspeaker blasts. Double paned windows preserve quiet.
Editing out noise during product design is the goal. Engineers have an arsenal of techniques and know-how for that. The problem is that these solutions aren’t being applied, says Jim Thompson, an engineer and editor of the Noise Control Engineering Journal, published by the Institute of Noise Control Engineering of the USA
Engineers have materials to insulate, absorb, reflect, block, seal or diffuse noise. Building walls can be padded. Metal gears and parts can be replaced with plastic. Clattering equipment wheels can be rubberized. In recent years, building certifications such as LEED have put more emphasis on designs that minimize harmful noise.
Walker faults urban planners, too. A city’s narrow streets and taller buildings create a canyon effect which intensifies noise. City planners could use bypasses, rerouting, and other infrastructure strategies to pump down traffic volume. Sound-absorbing asphalt pavement exists, too.
Some municipalities are taking innovative measures on their own. Noise cameras have been installed in Knoxville, Miami and New York City this year and six California cities will join suit next year. If your muffler or audio system registers 86 dB or higher, you may receive a warning, fine or citation, similar to how a red-light camera works. Rueter predicts these cameras will become commonplace.
Based on understanding how metabolic processes affect noise-induced hearing loss in animal models, scientists are exploring whether pharmacological interventions might work to inhibit cellular damage or improve cellular defenses against noise.
Washington, DC, and the University of Southern California have banned gas-powered leaf blowers in lieu of quieter battery-powered models to reduce both noise and air pollution. California will be the first state to ban the sale of gas-powered lawn equipment starting 2024.
New York state legislators enacted the SLEEP (Stop Loud and Excessive Exhaust Pollution) Act in 2021. This measure increases enforcement and fines against motorists and repair shops that illegally modify mufflers and exhaust systems for effect.
“A lot more basic science and application research is needed [to control noise],” says Thompson, noting that funding for this largely dried up after the 1970s. Based on understanding how metabolic processes affect noise-induced hearing loss in animal models, scientists are exploring whether pharmacological interventions might work to inhibit cellular damage or improve cellular defenses against noise.
Studying biochemical or known genetic markers for noise risk could lead to other methods for preventing hearing loss. This would offer an opportunity to identify people with significant risk so those more susceptible to hearing loss could start taking precautions to avoid noise or protect their ears in childhood.
These efforts could become more pressing in the near future, with the anticipated onslaught of drones, rising needs for air conditioners, and urban sprawl boding poorly for the soundscape. This, as deforestation destroys natural carbon absorption reservoirs and removes sound-buffering trees.
“Local and state governments don’t have a plan to deal with [noise] now or in the future,” says Walker. “We need to think about this with intentionality.”
A new way to help kids with ADHD: Treat adult ADHD
When a child is diagnosed with attention deficit hyperactivity disorder (ADHD), it can often be a surprise to the parents that one of them has ADHD as well. They may have experienced some of the symptoms but never had the condition diagnosed.
Physicians, however, are usually less surprised because they know that ADHD is a very heritable disorder. According to a 2015 study, if a parent has ADHD, the child has up to a 57 percent chance of having it, and the child’s risk is 32 percent if their sibling has it.
“There have been 20 to 30 twin studies that show that the heritability of ADHD is about 70 percent,” meaning that both twins have it, says Stephen Faraone, distinguished professor and vice chair for research at SUNY Upstate Medical University. “It is as heritable as schizophrenia, bipolar disorder, autism or other psychiatric disorders that people tend to think are more biological than ADHD for some reason.”
More attention needed for adult ADHD
Brad McAlister, CMSE, executive director of the American Professional Society of ADHD & Related Disorders, or APSARD, explains that the consequences of untreated ADHD in adults are very well documented. The prevalence of ADHD in U.S. adults is 4.4 percent or about 11 million people.
Many adults go undiagnosed for decades or are misdiagnosed by providers. McAlister says that 75 percent are not receiving treatment. “The U.S. economic burden of adult ADHD is $105 to $194 billion annually,” he says. “The negative consequences on peoples’ lives include higher risks of dropping out of school, losing jobs, financial debt, divorce, fractured relationships, substance use disorders, and co-occurring depression/anxiety.”
One of the negative impacts of undiagnosed ADHD in adults is the effect that it can have on their children who have ADHD.
Adult ADHD is currently treated by a broad range of health care providers with different educational backgrounds and in different practice settings. In August, APSARD published the first U.S. guidelines for adult ADHD. “The creation of guidelines for ADHD in adults will allow all practitioners to benefit from the best evidence about diagnosing and treating the disorder,” McAlister says.
Faraone explains that the guidelines are intended to help practitioners understand the best practices for adults with ADHD, including screening and other ways of evaluating whether someone has it. He recently completed a study of what he calls the Metrics of Quality Care for adults with ADHD.
“We looked at a sizable group of primary care practices in the U.S., and we learned that although quality care for adults with ADHD has been gradually improving over the past decade, there are many areas where it is still far behind where it needs to be,” he says. “That’s consistent with other studies that show that in primary care for adults, ADHD is not treated nearly as well as it is treated in specialty and psychiatry care.”
How kids with ADHD are affected
One of the negative impacts of undiagnosed ADHD in adults is the effect that it can have on their children who have ADHD because their ability to care for that child’s special needs may be impaired.
“The treatments that are most effective in treating children with ADHD are medication and behavioral interventions as their reward bait, and at home, it’s the parent that administers them,” says Mark A. Stein, director of the ADHD and Related Disorders Program at Seattle Children’s Hospital. “Adults with ADHD have difficulties with time management and organization skills, so they will have a hard time making sure their child is ready for school, has breakfast, has their medications, etcetera.”
Even more challenging than getting a prescription, Stein adds, is finding a psychologist or therapist who is skilled in evaluating and working with children with ADHD and their parents. If left undiagnosed and untreated, adult ADHD may also interfere with getting a good evaluation for the child.
“If you have ADHD and your mind is wandering and you don’t have all of the forms from the school for your provider, and you’re focused on the bad day you’re having rather than giving a history of your child, all of that is going to delay getting an effective treatment for your child,” Stein says. “So that’s why it’s important to identify ADHD in parents.”
Promising research and training
After delays due to the pandemic, Stein and his colleague Andrea Chronis-Tuscano, professor and director of the Maryland ADHD Program at the University of Maryland, are now about two years into what they anticipate will be a six-year study that involves treating parents who have children with untreated ADHD symptoms. The goal is to see whether treating the parent first with medication and training, or just the training, helps the child’s symptoms due to improved parenting. They are also studying whether they can postpone the need for medication until children are older, when it’s more effective.
“Pediatricians are more aware of ADHD in parents because of our study,” Stein says. “They’re also more aware of the shortcomings in our healthcare delivery system in terms of how hard it is to find providers who are comfortable treating adult ADHD.”
“Besides depression, ADHD is the other disorder that parents have that really impacts kids significantly," Stein says. “With treatment, many people with ADHD do very well."
That said, he’s seen a significant improvement in the past decade with increased recognition of ADHD in adults. “It started with pediatricians recognizing that post-partum depression impacted the mother’s ability to care for her children and making it routine to screen for depression in parents of kids,” he says. “Besides depression, ADHD is the other disorder that parents have that really impacts kids significantly, so it’s important for them to be aware of characteristics of [ADHD in] parents and have resources they can give parents to help them.”
Stein emphasizes that even if someone displays symptoms of ADHD, that does not mean that they have it. They should seek a physician’s evaluation to confirm a diagnosis, which would enable them to get the medication and behavioral treatment they need.
The medication can take effect in parents within an hour. Meanwhile, when parents participate in the behavioral parent training courses, their kids with ADHD start showing significant improvement within about four to five weeks, according to Stein.
“With treatment, many people with ADHD do very well,” he says. “Especially if they get through formal schooling, find the right fit with their job, and if they make the right choices with their relationships, those three things can go a long way to make their ADHD fade into the background.”