Can Genetic Testing Help Shed Light on the Autism Epidemic?
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.
[Editor's Note: Welcome to Leaps of the Past, a new monthly column that spotlights the fascinating backstory behind a medical or scientific breakthrough from history.]
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Until about 40 years ago, ulcers were a mysterious – and sometimes deadly – ailment. Found in a person's stomach lining or intestine, ulcers are small sores that cause a variety of painful symptoms, such as vomiting, a burning or aching sensation, internal bleeding and stomach obstruction. Patients with ulcers suffered for years without a cure and sometimes even needed their stomachs completely removed to rid them from pain.
"To gastroenterologists, the concept of a germ causing ulcers was like saying the Earth is flat."
In the early 1980s, the majority of scientists thought that ulcers were caused by stress or poor diet. But a handful of scientists had a different theory: They believed that ulcers were caused by a corkscrew-shaped bacterium called Helicobacter pylori, or H. pylori for short. Robin Warren, a pathologist, and Barry Marshall, an internist, were the two pioneers of this theory, and the two teamed up to study H. pylori at the Royal Perth Hospital in 1981.
The pair started off by trying to culture the bacteria in the stomachs of patients with gastritis, an inflammation of the stomach lining and a precursor to developing an ulcer. Initially, the microbiologists involved in their clinical trial found no trace of the bacteria from patient samples – but after a few weeks, the microbiologists discovered that their lab techs had been throwing away the cultures before H. pylori could grow. "After that, we let the cultures grow longer and found 13 patients with duodenal ulcer," said Marshall in a later interview. "All of them had the bacteria."
Marshall and Warren also cultured H. pylori in the stomachs of patients with stomach cancer. They observed that "everybody with stomach cancer developed it on a background of gastritis. Whenever we found a person without Helicobacter, we couldn't find gastritis either." Marshall and Warren were convinced that H. pylori not only caused gastritis and peptic ulcers, but stomach cancer as well.
But when the team presented their findings at an annual meeting of the Royal Australasian College of Physicians in Perth, they were mostly met with skepticism. "To gastroenterologists, the concept of a germ causing ulcers was like saying the Earth is flat," Marshall said. "The idea was too weird."
Warren started treating his gastritis patients with antibiotics with great success – but other internists remained doubtful, continuing to treat their patients with antacids instead. Making matters more complicated, neither Warren nor Marshall could readily test their theory, since the pair only had lab mice at their disposal and H. pylori infects only humans and non-human primates, such as rhesus monkeys.
So Marshall took an unconventional approach. First, he underwent two tests to get a baseline reading of his stomach, which showed no presence of H. pylori. Then, Marshall took some H. pylori bacteria from a petri dish, mixed it with beef extract to create a broth, and gulped it down. If his theory was correct, a second gastric biopsy would show that his stomach was overrun with H. pylori bacteria, and a second endoscopy would show a painfully inflamed stomach – gastritis.
Less than a week later, Marshall started feeling sick. "I expected to develop an asymptomatic infection," he later said in an interview published in the Canadian Journal of Gastroenterology. "… [but] after five days, I started to have bloating and fullness after the evening meal, and my appetite decreased. My breath was bad and I vomited clear watery liquid, without acid, each morning."
At his wife's urging, Marshall started on a regimen of antibiotics to kill off the burgeoning bacteria, so a follow-up biopsy showed no signs of H. pylori. A follow-up endoscopy, however, showed "severe active gastritis" along with epithelial damage. This was the smoking gun other clinicians needed to believe that H. pylori caused gastritis and stomach cancer. When they began to treat their gastritis patients with antibiotics, the rate of peptic ulcers in the Australian population diminished by 70 percent.
Today, antibiotics are the standard of care for anyone afflicted with gastritis.
In 2005, Marshall and Warren were awarded the Nobel Prize in Physiology or Medicine for their discovery of H. Pylori and its role in developing gastritis and peptic ulcers. "Thanks to the pioneering discovery by Marshall and Warren, peptic ulcer disease is no longer a chronic, frequently disabling condition, but a disease that can be cured by a short regimen of antibiotics and acid secretion inhibitors," the Nobel Prize Committee said.
Today, antibiotics are the standard of care for anyone afflicted with gastritis – and stomach cancer has been significantly reduced in the Western world.
Would a Broad-Spectrum Antiviral Drug Stop the Pandemic?
The refocusing of medical research to COVID-19 is unprecedented in human history. Seven months ago, we barely were aware that the virus existed, and now a torrent of new information greets us each day online.
There are many unanswered questions about COVID-19, but perhaps the most fascinating is whether we even need to directly go after the virus itself.
Clinicaltrials.gov, the most commonly used registry for worldwide medical research, listed 1358 clinical trials on the disease, including using scores of different potential drugs and multiple combinations, when I first wrote this sentence. The following day that number of trials had increased to 1409. Laboratory work to prepare for trials presents an even broader and untabulated scope of activity.
Most trials will fail or not be as good as what has been discovered in the interim, but the hope is that a handful of them will yield vaccines for prevention and treatments to attenuate and ultimately cure the deadly infection.
The first impulse is to grab whatever drugs are on the shelf and see if any work against the new foe. We know their safety profiles and they have passed some regulatory hurdles. Remdesivir is the first to register some success against SARS-CoV-2, the virus behind the disease. The FDA has granted it expedited-use status, pending presentation of data that may lead to full approval of the drug.
Most observers see it as a treatment that might help, but not one that by itself is likely to break the back of the pandemic. Part of that is because it is delivered though IV infusion, which requires hospitalization, and as with most antiviral drugs, appears to be most beneficial when started early in disease. "The most effective products are going to be that ones that are developed by actually understanding more about this coronavirus," says Margaret "Peggy" Hamburg, who once led the New York City public health department and later the U.S. Food and Drug Administration.
Combination therapy that uses different drugs to hit a virus at different places in its life cycle have proven to work best in treating HIV and hepatitis C, and likely will be needed with this virus as well. Most viruses are simply too facile at evolving resistance to a single drug, and so require multiple hits to keep them down.
Laboratory work suggests that other drugs, both off-the-shelf and in development, particularly those to treat HIV and hepatitis, might also be of some benefit against SARS-CoV-2. But the number of possible drug combinations is mind-bogglingly large and the capacity to test them all right now is limited.
Broad-Spectrum Antivirals
Viruses are simple quasi-life forms. Effective treatments are more likely to be specific to a given virus, or at best its close relatives. That is unlike bacteria, where broad-spectrum antibiotics often can be used against common elements like the bacterial cell wall, or can disrupt quorum sensing signals that bacteria use to function as biofilms.
More than a decade ago, virologist Benhur Lee's lab at UCLA (now at Mt. Sinai in New York City) stumbled upon a broad-spectrum antiviral approach that seemed to work against all enveloped viruses they tested. The list ranged from the common flu to HIV to Ebola.
Other researchers grabbed this lead to develop a compound that worked quite well in cell cultures, but when they tried it in animals, a frustrating snag emerged; the compound needed to be activated by light. As the greatest medical need is to counter viruses deep inside the body, the research was put on the shelf. So Lee was surprised to learn recently that a company has inquired about rights to develop the compound not as a treatment but as a possible disinfectant. The tale illustrates both the unanticipated difficulties of drug development and that one never knows how knowledge ultimately might be put to use.
Remdesivir is a failed drug for Ebola that has found new life with SARS-CoV-2. It targets polymerase, an enzyme that the virus produces to use host cell machinery to replicate itself, and since the genetic sequence of polymerase is very similar among all of the different coronaviruses, scientists hope that the drug might be useful against known members of the family and others that might emerge in the future.
But nature isn't always that simple. Viral RNA is not a two-dimensional assemblage of genes in a flat line on a table; rather it is a three-dimensional matrix of twists and turns where a single atom change within the polymerase gene or another gene close by might change the orientation of the RNA or a molecular arm within it and block a drug from accessing the targeted binding site on the virus. One drug might need to bind to a large flat surface, while another might be able to slip a dagger-like molecular arm through a space in the matrix to reach its binding target.
That is why a broad-spectrum antiviral is so hard to develop, and why researchers continue to work on a wide variety of compounds that target polymerase as a binding site.
Additionally, it has taken us decades to begin to recognize the unintended consequences of broad-spectrum rather than narrowly targeted antibiotics on the gut microbiome and our overall health. Will a similar issue potentially arise in using a broad-spectrum antiviral?
"Off-target side effects are always of concern with drugs, and antivirals are no exception," says Yale University microbiologist Ben Chen. He believes that "most" bacteriophages, the viruses that infect bacteria and likely help to maintain stability in the gut microbial ecosystem, will shrug off such a drug. However, a few families of phages share polymerases that are similar to those found in coronaviruses. While the immediate need for treatment is great, we will have to keep a sharp eye out for unanticipated activity in the body's ecosystem from new drugs.
Is an Antiviral Needed?
There are many unanswered questions about COVID-19, but perhaps the most fascinating is whether we even need to directly go after the virus itself. Mounting evidence indicates that up to half the people who contract the infection don't seem to experience significant symptoms and their immune system seems to clear the virus.
The most severe cases of COVID-19 appear to result from an overactive immune response that damages surrounding tissue. Perhaps downregulating that response will be sufficient to reduce the disease burden. Several studies are underway using approved antibodies that modulate an overly active immune response.
One of the most surprising findings to date involves the monoclonal antibody leronlimab. It was originally developed to treat HIV infection and works modestly well there, but other drugs are better and its future likely will be mainly to treat patients who have developed resistance to those other drugs.
The response has been amazingly different in patients in the U.S. with COVID-19 who were given emergency access to leronlimab – two injections a week apart, though the company believes that four might be better. The immune response and inflammatory cytokines declined significantly, T cell counts were maintained, and surprisingly the amount of virus in the blood declined too. Data from the first ten patients is available in a preprint while the paper undergoes peer review for publication. Data from an additional fifty patients will be added.
"We got lucky and hit the bulls' eye from a mile away," says Jay Lalezari, the chief science officer of Cytodyn, the company behind leronlimab. Dr. Jay, as he is widely known in San Francisco, built an adoring fan base running many of the early-phase drug studies for treating HIV. While touting leronlimab, Lalezari suspects it might best be used as part of a combination therapy.
The small, under-capitalized firm is struggling for attention in the vast pool of therapies proposed to treat COVID-19. It faces the added challenge of gaining acceptance because it is based on a different approach and mechanism of action, which involves a signaling molecule important to immune cell migration, than what most researchers and the FDA anticipate as being relevant to counter SARS-CoV-2.
Common Issues
All of the therapeutics under development will face some common sets of issues. One is the pressure to have results yesterday, because people are dying. The rush to disseminate information "make me worry that certain things will become entrenched as truth, even in the scientific community, without the actual scientific documentation that ordinarily scientists would demand," says Hamburg.
"It is becoming increasingly clear that the biggest problem for drug and vaccine makers is not which therapeutics or vaccine platform to pursue."
Lack of standardization in assays and laboratory operations makes it difficult to compare results between labs studying SARS-CoV-2. In the long run, this will slow down the iterative process of research that builds upon what has gone before. And the shut down of supply chains, from chemicals to cell lines to animals to air shipment, has the potential to further hobble research.
Almost all researchers consult with the FDA in putting together their clinical trials. But the agency is overwhelmed with the surge of activity in the field, and is even less capable of handling novel approaches that fall outside of its standard guidance.
"It is becoming increasingly clear that the biggest problem for drug and vaccine makers is not which therapeutics or vaccine platform to pursue. It is that conventional clinical development paths are far too lengthy and cumbersome to address the current public health threat," John Hodgson wrote in Nature Biotechnology.
Another complicating factor with this virus is the broad range of organ and tissue types it can infect. That has implications for potential therapies, which often vary in their ability to enter different tissues. At a minimum, it complicates the drug development process.
Remdesivir has become the de facto standard of care. Ideally, clinical trials are conducted using the existing standard of care rather than a placebo as the control group. But shortages of the drug make that difficult and further inhibit learning what is the best treatment regimen for regular clinical care.
"Understandably, we all really want to respond to COVID-19 in a much, much more accelerated fashion," says Hamburg. But ultimately that depends upon "the reality of understanding the nature of the disease. And that is going to take a bit more time than we might like or wish."
[This article was originally published on June 8th, 2020 as part of a standalone magazine called GOOD10: The Pandemic Issue. Produced as a partnership among LeapsMag, The Aspen Institute, and GOOD, the magazine is available for free online.]