Can Genetic Testing Help Shed Light on the Autism Epidemic?
A little boy standing by a window in contemplation. (© altanaka/Fotolia)
Autism cases are still on the rise, and scientists don't know why. In April, the Centers for Disease Control (CDC) reported that rates of autism had increased once again, now at an estimated 1 in 59 children up from 1 in 68 just two years ago. Rates have been climbing steadily since 2007 when the CDC initially estimated that 1 in 150 children were on the autism spectrum.
Some clinicians are concerned that the creeping expansion of autism is causing the diagnosis to lose its meaning.
The standard explanation for this increase has been the expansion of the definition of autism to include milder forms like Asperger's, as well as a heightened awareness of the condition that has improved screening efforts. For example, the most recent jump is attributed to children in minority communities being diagnosed who might have previously gone under the radar. In addition, more federally funded resources are available to children with autism than other types of developmental disorders, which may prompt families or physicians to push harder for a diagnosis.
Some clinicians are concerned that the creeping expansion of autism is causing the diagnosis to lose its meaning. William Graf, a pediatric neurologist at Connecticut Children's Medical Center, says that when a nurse tells him that a new patient has a history of autism, the term is no longer a useful description. "Even though I know this topic extremely well, I cannot picture the child anymore," he says. "Use the words mild, moderate, or severe. Just give me a couple more clues, because when you say autism today, I have no idea what people are talking about anymore."
Genetic testing has emerged as one potential way to remedy the overly broad label by narrowing down a heterogeneous diagnosis to a specific genetic disorder. According to Suma Shankar, a medical geneticist at the University of California, Davis, up to 60 percent of autism cases could be attributed to underlying genetic causes. Common examples include Fragile X Syndrome or Rett Syndrome—neurodevelopmental disorders that are caused by mutations in individual genes and are behaviorally classified as autism.
With more than 500 different mutations associated with autism, very few additional diagnoses provide meaningful information.
Having a genetic diagnosis in addition to an autism diagnosis can help families in several ways, says Shankar. Knowing the genetic origin can alert families to other potential health problems that are linked to the mutation, such as heart defects or problems with the immune system. It may also help clinicians provide more targeted behavioral therapies and could one day lead to the development of drug treatments for underlying neurochemical abnormalities. "It will pave the way to begin to tease out treatments," Shankar says.
When a doctor diagnoses a child as having a specific genetic condition, the label of autism is still kept because it is more well-known and gives the child access to more state-funded resources. Children can thus be diagnosed with multiple conditions: autism spectrum disorder and their specific gene mutation. However, with more than 500 different mutations associated with autism, very few additional diagnoses provide meaningful information. What's more, the presence or absence of a mutation doesn't necessarily indicate whether the child is on the mild or severe end of the autism spectrum.
Because of this, Graf doubts that genetic classifications are really that useful. He tells the story of a boy with epilepsy and severe intellectual disabilities who was diagnosed with autism as a young child. Years later, Graf ordered genetic testing for the boy and discovered that he had a mutation in the gene SYNGAP1. However, this knowledge didn't change the boy's autism status. "That diagnosis [SYNGAP1] turns out to be very specific for him, but it will never be a household name. Biologically it's good to know, and now it's all over his chart. But on a societal level he still needs this catch-all label [of autism]," Graf says.
"It gives some information, but to what degree does that change treatment or prognosis?"
Jennifer Singh, a sociologist at Georgia Tech who wrote the book Multiple Autisms: Spectrums of Advocacy and Genomic Science, agrees. "I don't know that the knowledge gained from just having a gene that's linked to autism," is that beneficial, she says. "It gives some information, but to what degree does that change treatment or prognosis? Because at the end of the day you have to address the issues that are at hand, whatever they might be."
As more children are diagnosed with autism, knowledge of the underlying genetic mutation causing the condition could help families better understand the diagnosis and anticipate their child's developmental trajectory. However, for the vast majority, an additional label provides little clarity or consolation.
Instead of spending money on genetic screens, Singh thinks the resources would be better used on additional services for people who don't have access to behavioral, speech, or occupational therapy. "Things that are really going to matter for this child in their future," she says.
Do New Tools Need New Ethics?
Symbols of countries on a chessboard.
Scarcely a week goes by without the announcement of another breakthrough owing to advancing biotechnology. Recent examples include the use of gene editing tools to successfully alter human embryos or clone monkeys; new immunotherapy-based treatments offering longer lives or even potential cures for previously deadly cancers; and the creation of genetically altered mosquitos using "gene drives" to quickly introduce changes into the population in an ecosystem and alter the capacity to carry disease.
The environment for conducting science is dramatically different today than it was in the 1970s, 80s, or even the early 2000s.
Each of these examples puts pressure on current policy guidelines and approaches, some existing since the late 1970s, which were created to help guide the introduction of controversial new life sciences technologies. But do the policies that made sense decades ago continue to make sense today, or do the tools created during different eras in science demand new ethics guidelines and policies?
Advances in biotechnology aren't new of course, and in fact have been the hallmark of science since the creation of the modern U.S. National Institutes of Health in the 1940s and similar government agencies elsewhere. Funding agencies focused on health sciences research with the hope of creating breakthroughs in human health, and along the way, basic science discoveries led to the creation of new scientific tools that offered the ability to approach life, death, and disease in fundamentally new ways.
For example, take the discovery in the 1970s of the "chemical scissors" in living cells called restriction enzymes, which could be controlled and used to introduce cuts at predictable locations in a strand of DNA. This led to the creation of tools that for the first time allowed for genetic modification of any organism with DNA, which meant bacteria, plants, animals, and even humans could in theory have harmful mutations repaired, but also that changes could be made to alter or even add genetic traits, with potentially ominous implications.
The scientists involved in that early research convened a small conference to discuss not only the science, but how to responsibly control its potential uses and their implications. The meeting became known as the Asilomar Conference for the meeting center where it was held, and is often noted as the prime example of the scientific community policing itself. While the Asilomar recommendations were not sufficient from a policy standpoint, they offered a blueprint on which policies could be based and presented a model of the scientific community setting responsible controls for itself.
But the environment for conducting science changed over the succeeding decades and it is dramatically different today than it was in the 1970s, 80s, or even the early 2000s. The regime for oversight and regulation that has provided controls for the introduction of so-called "gene therapy" in humans starting in the mid-1970s is beginning to show signs of fraying. The vast majority of such research was performed in the U.S., U.K., and Europe, where policies were largely harmonized. But as the tools for manipulating humans at the molecular level advanced, they also became more reliable and more precise, as well as cheaper and easier to use—think CRISPR—and therefore more accessible to more people in many more countries, many without clear oversight or policies laying out responsible controls.
There is no precedent for global-scale science policy, though that is exactly what this moment seems to demand.
As if to make the point through news headlines, scientists in China announced in 2017 that they had attempted to perform gene editing on in vitro human embryos to repair an inherited mutation for beta thalassemia--research that would not be permitted in the U.S. and most European countries and at the time was also banned in the U.K. Similarly, specialists from a reproductive medicine clinic in the U.S. announced in 2016 that they had performed a highly controversial reproductive technology by which DNA from two women is combined (so-called "three parent babies"), in a satellite clinic they had opened in Mexico to avoid existing prohibitions on the technique passed by the U.S. Congress in 2015.
In both cases, genetic changes were introduced into human embryos that if successful would lead to the birth of a child with genetically modified germline cells—the sperm in boys or eggs in girls—with those genetic changes passed on to all future generations of related offspring. Those are just two very recent examples, and it doesn't require much imagination to predict the list of controversial possible applications of advancing biotechnologies: attempts at genetic augmentation or even cloning in humans, and alterations of the natural environment with genetically engineered mosquitoes or other insects in areas with endemic disease. In fact, as soon as this month, scientists in Africa may release genetically modified mosquitoes for the first time.
The technical barriers are falling at a dramatic pace, but policy hasn't kept up, both in terms of what controls make sense and how to address what is an increasingly global challenge. There is no precedent for global-scale science policy, though that is exactly what this moment seems to demand. Mechanisms for policy at global scale are limited–-think UN declarations, signatory countries, and sometimes international treaties, but all are slow, cumbersome and have limited track records of success.
But not all the news is bad. There are ongoing efforts at international discussion, such as an international summit on human genome editing convened in 2015 by the National Academies of Sciences and Medicine (U.S.), Royal Academy (U.K.), and Chinese Academy of Sciences (China), a follow-on international consensus committee whose report was issued in 2017, and an upcoming 2nd international summit in Hong Kong in November this year.
These efforts need to continue to focus less on common regulatory policies, which will be elusive if not impossible to create and implement, but on common ground for the principles that ought to guide country-level rules. Such principles might include those from the list proposed by the international consensus committee, including transparency, due care, responsible science adhering to professional norms, promoting wellbeing of those affected, and transnational cooperation. Work to create a set of shared norms is ongoing and worth continued effort as the relevant stakeholders attempt to navigate what can only be called a brave new world.
Short-Term Suspended Animation for Humans Is Coming Soon
A man gasps for air through deep ice, in a symbolic representation of human hibernation through induced hypothermia.
At 1 a.m., Tony B. is flown to a shock trauma center of a university hospital. Five minutes earlier, he was picked up unconscious with no blood pressure, having suffered multiple gunshot wounds with severe blood loss. Standard measures alone would not have saved his life, but on the helicopter he was injected with ice-cold fluids intravenously to begin cooling him from the inside, and given special drugs to protect his heart and brain.
Suspended animation is not routine yet, but it's going through clinical trials at the University of Maryland and the University of Pittsburgh.
A surgeon accesses Tony's aorta, allowing his body to be flushed with larger amounts of cold fluids, thereby inducing profound hypothermia -- a body temperature below 10° C (50° F). This is suspended animation, a form of human hibernation, but officially the procedure is called Emergency Preservation and Resuscitation for Cardiac Arrest from Trauma (EPR-CAT).
This chilly state, which constitutes the preservation component of Tony's care, continues for an hour as surgeons repair injuries and connect his circulation to cardiopulmonary bypass (CPB). This allows blood to move through the brain delivering oxygen at low doses appropriate for the sharply reduced metabolic rate that comes with the hypothermia, without depending on the heart and lungs. CPB also enables controlled, gradual re-warming of Tony's body as fluid and appropriate amounts of red blood cells are transfused into him.
After another hour or so, Tony's body temperature reaches the range of 32-34° C (~90-93° F), called mild hypothermia. Having begun the fluid resuscitation process already, the team stops warming Tony, switches his circulation from CPB to his own heart and lungs, and begins cardiac resuscitation with electrical jolts to his heart. With his blood pressure stable, his heart rate slow but appropriate for the mild hypothermia, Tony is maintained at this intermediate temperature for 24 hours; this last step is already standard practice in treatment of people who suffer cardiac arrest without blood loss trauma.
The purpose is to prevent brain damage that might come with the rapid influx of too much oxygen, just as a feast would mean death to a starvation victim. After he is warmed to a normal temperature of 37° C (~99° F), Tony is awakened and ultimately recovers with no brain damage.
Tony's case is fictional; EPR-CAT is not routine yet, but it's going through clinical trials at the University of Maryland and the University of Pittsburgh, under the direction of trauma surgeon Dr. Samuel Tisherman, who spent many years developing the procedure in dogs and pigs. In such cases, patients undergo suspended animation for a couple of hours at most, but other treatments are showing promise in laboratory animals, like the use of hydrogen sulfide gas without active cooling to induce suspended animation in mice. Such interventions could ultimately fuse with EPR-CAT, sending the new technology further into what's still the realm of science fiction – at least for now.
Consider the scenario of a 5-year-old girl diagnosed with a progressive, incurable, terminal disease.
Experts say that extended suspended animation – cooling patients in a stable state for months or years -- could be possible at some point, although no one can predict when the technology will be clinical reality, since hydrogen sulfide and other chemical tactics would have to move into clinical use in humans and prove safe and effective in combination with EPR-CAT, or with a similar cooling approach.
How Could Long-Term Suspended Animation Impact Humanity?
Consider the scenario of a 5-year-old girl diagnosed with a progressive, incurable, terminal disease. Since available treatments would only lengthen the projected survival by a year, she is placed into suspended animation. She is revived partially every few years, as new treatments become available that can have a major impact on her disease. After 35 years of this, she is revived completely as treatments are finally adequate to cure her condition, but biologically she has aged only a few months. Physically, she is normal now, though her parents are in their seventies, and her siblings are grown and married.
Such hypothetical scenarios raise many issues: Where will the resources come from to take care of patients for that long? Who will pay? And how will patients adapt when they emerge into a completely different world?
"Heavy resource utilization is a factor if you've got people hibernating for years or decades," says Bradford Winters, an associate professor of anesthesiology and critical care medicine, and assistant professor of neurological surgery at Johns Hopkins.
Conceivably, special high-tech facilities with robots and artificial intelligence watching over the hibernators might solve the resource issue, but even then, Winters notes that long-term hibernation would entail major disparities between the wealthy and poor. "And then there is the psychological effect of being disconnected from one's family and society for a generation or more," he says. "What happens to that 5-year-old waking to her retired parents and married siblings? Will her younger sister adopt her? What would that be like?"
Probably better than dying is one answer.
Back on Earth, human hibernation would raise daunting policy questions that may take many years to resolve.
Outside of medicine, one application of human hibernation that has intrigued generations of science fiction writers is in long-duration space travel. During a voyage lasting years or decades, space explorers or colonists not only could avoid long periods of potential boredom, but also the aging process. Considering that the alternative to "sleeper ships" would be multi-generation starships so large that they'd be like small worlds, human hibernation in spaceflight could become an enabling technology for interstellar flight.
Big Questions: It's Not Too Early to Ask
Back on Earth, the daunting policy questions may take many years to resolve. Society ought to be aware of them now, before human hibernation technology outpaces its dramatic implications.
"Our current framework of ethical and legal regulation is adequate for cases like the gunshot victim who is chilled deeply for a few hours. Short-term cryopreservation is currently part of the continuum of care," notes David N. Hoffman, a clinical ethicist and health care attorney who teaches at Columbia University, and at Yeshiva University's Benjamin N. Cardozo School of Law and Albert Einstein College of Medicine.
"But we'll need a new framework when there's a capability to cryopreserve people for many years and still bring them back. There's also a legal-ethical issue involving the parties that decide to put the person into hibernation versus the patient wishes in terms of what risk benefit ratio they would accept, and who is responsible for the expense and burdens associated with cases that don't turn out just right?"
To begin thinking about practical solutions, Hoffman characterizes long-term human hibernation as an extension of the ethics of cyro-preserved embryos that are held for potential parents, often for long periods of time. But the human hibernation issue is much more complex.
"The ability of the custodian and patient to enter into a meaningful and beneficial arrangement is fraught, because medical advances necessary to address the person's illness or injury are -- by definition -- unknown," says Hoffman. "It means that you need a third party, a surrogate, to act on opportunities that the patient could never have contemplated."
Such multigenerational considerations might become more manageable, of course, in an era when gene therapy, bionic parts, and genetically engineered replacement organs enable dramatic life extension. But if people will be living for centuries regardless of whether or not they hibernate, then developing the medical technology may be the least of the challenges.