Medical geneticist Omar Abdul-Rahman had a hunch. He thought that the three-year-old boy with deep-set eyes, a rounded nose, and uplifted earlobes might have Mowat-Wilson syndrome, but he'd never seen a patient with the rare disorder before.
"If it weren't for the app I'm not sure I would have had the confidence to say 'yes you should spend $1000 on this test."
Rahman had already ordered genetic tests for three different conditions without any luck, and he didn't want to cost the family any more money—or hope—if he wasn't sure of the diagnosis. So he took a picture of the boy and uploaded the photo to Face2Gene, a diagnostic aid for rare genetic disorders. Sure enough, Mowat-Wilson came up as a potential match. The family agreed to one final genetic test, which was positive for the syndrome.
"If it weren't for the app I'm not sure I would have had the confidence to say 'yes you should spend $1000 on this test,'" says Rahman, who is now the director of Genetic Medicine at the University of Nebraska Medical Center, but saw the boy when he was in the Department of Pediatrics at the University of Mississippi Medical Center in 2012.
"Families who are dealing with undiagnosed diseases never know what's going to come around the corner, what other organ system might be a problem next week," Rahman says. With a diagnosis, "You don't have to wait for the other shoe to drop because now you know the extent of the condition."
A diagnosis is the first and most important step for patients to attain medical care. Disease prognosis, treatment plans, and emotional coping all stem from this critical phase. But diagnosis can also be the trickiest part of the process, particularly for rare disorders. According to one European survey, 40 percent of rare diseases are initially misdiagnosed.
Healthcare professionals and medical technology companies hope that facial recognition software will help prevent families from facing difficult disruptions due to misdiagnoses.
"Patients with rare diseases or genetic disorders go through a long period of diagnostic odyssey, and just putting a name to a syndrome or finding a diagnosis can be very helpful and relieve a lot of tension for the family," says Dekel Gelbman, CEO of FDNA.
Consequently, a misdiagnosis can be devastating for families. Money and time may have been wasted on fruitless treatments, while opportunities for potentially helpful therapies or clinical trials were missed. Parents led down the wrong path must change their expectations of their child's long-term prognosis and care. In addition, they may be misinformed regarding future decisions about family planning.
Healthcare professionals and medical technology companies hope that facial recognition software will help prevent families from facing these difficult disruptions by improving the accuracy and ease of diagnosing genetic disorders. Traditionally, doctors diagnose these types of conditions by identifying unique patterns of facial features, a practice called dysmorphology. Trained physicians can read a child's face like a map and detect any abnormal ridges or plateaus—wide-set eyes, broad forehead, flat nose, rotated ears—that, combined with other symptoms such as intellectual disability or abnormal height and weight, signify a specific genetic disorder.
These morphological changes can be subtle, though, and often only specialized medical geneticists are able to detect and interpret these facial clues. What's more, some genetic disorders are so rare that even a specialist may not have encountered it before, much less a general practitioner. Diagnosing rare conditions has improved thanks to genomic testing that can confirm (or refute) a doctor's suspicion. Yet with thousands of variants in each person's genome, identifying the culprit mutation or deletion can be extremely difficult if you don't know what you're looking for.
Facial recognition technology is trying to take some of the guesswork out of this process. Software such as the Face2Gene app use machine learning to compare a picture of a patient against images of thousands of disorders and come back with suggestions of possible diagnoses.
"This is a classic field for artificial intelligence because no human being can really have enough knowledge and enough experience to be able to do this for thousands of different disorders."
"When we met a geneticist for the first time we were pretty blown away with the fact that they actually use their own human pattern recognition" to diagnose patients, says Gelbman. "This is a classic field for AI [artificial intelligence], for machine learning because no human being can really have enough knowledge and enough experience to be able to do this for thousands of different disorders."
When a physician uploads a photo to the app, they are given a list of different diagnostic suggestions, each with a heat map to indicate how similar the facial features are to a classic representation of the syndrome. The physician can hone the suggestions by adding in other symptoms or family history. Gelbman emphasized that the app is a "search and reference tool" and should not "be used to diagnose or treat medical conditions." It is not approved by the FDA as a diagnostic.
"As a tool, we've all been waiting for this, something that can help everyone," says Julian Martinez-Agosto, an associate professor in human genetics and pediatrics at UCLA. He sees the greatest benefit of facial recognition technology in its ability to empower non-specialists to make a diagnosis. Many areas, including rural communities or resource-poor countries, do not have access to either medical geneticists trained in these types of diagnostics or genomic screens. Apps like Face2Gene can help guide a general practitioner or flag diseases they might not be familiar with.
One concern is that most textbook images of genetic disorders come from the West, so the "classic" face of a condition is often a child of European descent.
Maximilian Muenke, a senior investigator at the National Human Genome Research Institute (NHGRI), agrees that in many countries, facial recognition programs could be the only way for a doctor to make a diagnosis.
"There are only geneticists in countries like the U.S., Canada, Europe, Japan. In most countries, geneticists don't exist at all," Muenke says. "In Nigeria, the most populous country in all of Africa with 160 million people, there's not a single clinical geneticist. So in a country like that, facial recognition programs will be sought after and will be extremely useful to help make a diagnosis to the non-geneticists."
One concern about providing this type of technology to a global population is that most textbook images of genetic disorders come from the West, so the "classic" face of a condition is often a child of European descent. However, the defining facial features of some of these disorders manifest differently across ethnicities, leaving clinicians from other geographic regions at a disadvantage.
"Every syndrome is either more easy or more difficult to detect in people from different geographic backgrounds," explains Muenke. For example, "in some countries of Southeast Asia, the eyes are slanted upward, and that happens to be one of the findings that occurs mostly with children with Down Syndrome. So then it might be more difficult for some individuals to recognize Down Syndrome in children from Southeast Asia."
There is a risk that providing this type of diagnostic information online will lead to parents trying to classify their own children.
To combat this issue, Muenke helped develop the Atlas of Human Malformation Syndromes, a database that incorporates descriptions and pictures of patients from every continent. By providing examples of rare genetic disorders in children from outside of the United States and Europe, Muenke hopes to provide clinicians with a better understanding of what to look for in each condition, regardless of where they practice.
There is a risk that providing this type of diagnostic information online will lead to parents trying to classify their own children. Face2Gene is free to download in the app store, although users must be authenticated by the company as a healthcare professional before they can access the database. The NHGRI Atlas can be accessed by anyone through their website. However, Martinez and Muenke say parents already use Google and WebMD to look up their child's symptoms; facial recognition programs and databases are just an extension of that trend. In fact, Martinez says, "Empowering families is another way to facilitate access to care. Some families live in rural areas and have no access to geneticists. If they can use software to get a diagnosis and then contact someone at a large hospital, it can help facilitate the process."
Martinez also says the app could go further by providing greater transparency about how the program makes its assessments. Giving clinicians feedback about why a diagnosis fits certain facial features would offer a valuable teaching opportunity in addition to a diagnostic aid.
Both Martinez and Muenke think the technology is an innovation that could vastly benefit patients. "In the beginning, I was quite skeptical and I could not believe that a machine could replace a human," says Muenke. "However, I am a convert that it actually can help tremendously in making a diagnosis. I think there is a place for facial recognition programs, and I am a firm believer that this will spread over the next five years."
Brittany Trang was staring at her glass test tube, which suddenly turned opaque white. At first, she had thought that the chemical reaction she tested left behind some residue, but when she couldn’t clean it off, she realized that the reaction produced corrosive compounds that ate at the glass. That, however, was a good sign. It meant that the reaction, which she didn’t necessarily expect to work, was in fact, working. And Trang, who in 2020 was a Ph.D. researcher in chemistry at Northwestern University, had reasons to be skeptical. She was trying to break down the nearly indestructible molecules of per- and polyfluoroalkyl substances or PFAS—the forever chemicals called so because they resist heat, oil, stains, grease, and water, and thus don’t react or break down in the environment.
“The first time I ran this, I was like, oh, like there's a bunch of stuff stuck to the glass, but when I tried to clean it, it wasn’t coming off,” Trang says, recalling her original experiment and her almost-disbelief at the fact she managed to crack the notoriously stubborn and problematic molecules. “I was mostly just surprised that it worked in general.”
In the recent past, the world has been growing increasingly concerned about PFAS, the pollutants that even at low levels are associated with a litany of adverse health effects, including liver damage, thyroid disease, high cholesterol, pregnancy complications and several cancers. Used for decades in manufacturing and in various products such as fire retardant foam, water-repellant clothes, furniture fabrics, Teflon-coated pans, disposable plates, lunch containers and shoes, these super-stable compounds don’t degrade in the environment. The forever chemicals are now everywhere: in the water, in soil, in milk, and in produce.
As of June 2022, the Environmental Working Group, a nonprofit watchdog organization, found 2,858 locations in 50 states and two territories to be heavily contaminated with PFAS while many farmers had been forced to dump their milk or spinach because the levels of these compounds were in some cases up to 400 times greater than what’s considered safe. And because PFAS are so pervasive in the environment and the food we eat, they are in our bodies too. One study found some levels of PFAS in 97 to 100 percent of participants tested.
Because these compounds were made to be very stable, they are hard to destroy. So far, the only known way to break down PFAS has been to “cook” them under very harsh conditions. The process, known as pyrolysis, requires upwards of 500 degrees Centigrade, high pressure and absence of oxygen, which is energy expensive. It involves sophisticated equipment and the burning of fossil fuels. Trang, who worked in the laboratory of William Dichtel, managed to break PFAS at 120 degrees Centigrade (248 F) without using strong pressure. After she examined the results of her process with various techniques that help quantify the resulting compounds and confirmed that PFAS had indeed degraded into carbon and the corrosive fluorine that clouded her glass, she was thrilled that it worked in such simple conditions.
“That's really what differentiates our finding from everything else that's out there,” Dichtel said about their discovery at a press conference announcing the study last month. “When we're talking about low temperatures, we're at 120 degrees Celsius and sometimes even quite a bit lower than that, and especially ambient pressure.”
The process used by Trang’s team was the exact opposite of the typical organic synthesis method.
Trang’s journey into PFAS degradation began with a paper she read about the nuances of the chemicals’ molecular structure. A long molecule comprised primarily of carbon and fluorine atoms, along with oxygen and hydrogen, it has what Trang describes as a head and a tail. At the head sits a compound called carboxylic acid while the fluorine atoms make up the tail portion, with the atomic bonds so strong they aren’t possible to break without harsh treatment. But in early 2020, Trang read that a solvent called dimethylsulfoxide, or DMSO, commonly used in labs and industry, can make the carboxylic acid “pop off” its place. The DMSO doesn’t react with carboxylic acid but sort of displaces it, leaving the rest of the typically indestructible PFAS molecule vulnerable.
Trang found that its exposed fluorine tail would react with another common chemical compound, sodium hydroxide, causing a cascade of reactions that ultimately unravel the rest. “After you have decarboxylated the head, the hydroxide is able to react with the tail,” Trang says. “That's what sets off a cascade of reactions that degrades the rest of the molecule.”
That pathway took time to figure out. Trang was able to determine that the molecule carboxylic acid head popped off, but before she was able to figure out the rest, her lab and the entire Northwestern University went into lockdown in early March of 2020. “I was able to do three experiments before the shutdown,” she recalls. For the next few months, she sat at home, reading scientific literature to understand how to continue the degradation process. “I had read a bunch of literature and had a bunch of ideas for what may or may not work,” she says. By the time she could return to work, she had a plan. “I added sodium hydroxide in my batch of experiments when the lab reopened.”
The process used by Trang’s team was the exact opposite of the typical organic synthesis method. “Most organic chemists take two molecules and squish them together to make one big molecule. It’s like taking two Legos and putting them together to make one thing that was larger,” she says. “What we are doing is kind of smashing the Lego with two bits and looking at what was left to figure out how it fell apart.” The team published their discovery in the journal Science.
Although very promising, the process isn’t quite ready for industrial applications, and will take time to adapt, Trang says. For starters, it would have to be scaled up to continuously clean large quantities of water, sewage or other substances that can be contaminated with PFAS. The process will also have to be modified, particularly when it comes to removing PFAS from drinking water because as an industrial chemical, DMSO is not suitable for that. Water companies typically use activated carbon to filter out PFAS and other pollutants, so once that concentrated waste is accumulated, it would be removed and then treated with DMSO and hydroxide to break down the molecules. “That is what our method would likely be applied to,” Trang says—the concentrated waste rather than a reservoir because “you wouldn't want to mix DMSO with your drinking water.”
There are some additional limitations to the method. It only breaks down one class of forever chemicals, but there are others. For example, the molecules of perfluoroalkane sulfonic acids, or PFSA, don’t have a carboxylic head that DMSO can displace. Instead, PFSA have a sulphonic acid as their molecular head, which would require a different solvent that still needs to be discovered. “There is certainly the possibility of activating sulphonates in similar ways [to what] we've done [with] carboxylates,” Dichtel said, and he hopes this will happen in the future. Other forever chemical types may have their own Achilles’ heels, waiting to be discovered. “If we can knock that sulphonated headgroup off the molecule and get to the same intermediates we get to in this study,” Dichtel added, “it's very reasonable to assume that they'll degrade by very similar pathways.” Perhaps another team of inquisitive chemists will take on the challenge.
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend.
Here are the promising studies covered in this week's Friday Five:
- A new mask can detect Covid and send an alert to your phone
- More promising research for a breakthrough drug to treat schizophrenia
- AI tool can create new proteins
- Connections between an unhealthy gut and breast cancer
- Progress on the longevity drug, rapamycin
And an honorable mention this week: Certain exercises may benefit some types of memory more than others