For those who stopped reading after Wakefield, this is where the research on the causes of autism is going.

https://www.vox.com/science-and-health/2017/5/11/15508006/what-causes-autism-spectrum-disorder-vaccine-theory

Researchers have ditched the autism-vaccine hypothesis. Here’s what they think actually causes it.

Genes and the microbiome are some of the most promising leads.

By Julia Belluz@juliaoftoronto[email protected] Updated Apr 2, 2018, 10:37am EDT

Of all the issues doctors have explored in children’s health, none has been more exhaustively researched than the question of whether vaccines are linked to autism. After hundreds and hundreds of studies in thousands of children, “We can say with almost as much certainty than anybody could ever say that vaccines don’t cause autism,” Mayo Clinic autism researcher Dr. Sunil Mehta told me.

And yet the fear that they do remains stubbornly persistent, as a 2017 measles outbreak in Minnesota shows. The virus spread among unvaccinated children — in this case, Somali-Americans in Minneapolis, after anti-vaccine advocates targeted parents who were worried about autism with a misinformation campaign. By the end of the outbreak last August, 79 people, most of them children, came down with measles.

Today, about one in 68 US children has autism — a rate that’s remained unchanged since at least 1990, though there’s been a steady increase in awareness and diagnosis. And it’s the families of children with autism who are among the most vocal proponents of the vaccine-autism link. Many are confused, and searching for an explanation about why their children developed it.

It doesn’t help that doctors have long struggled to explain what exactly causes autism. Over the years, many medical theories have been debunked and then replaced by new ones.

But the medical community is now getting closer and closer to zeroing in on the cause. I recently talked to half a dozen researchers on the cutting edge of this work to find out what they see as the latest and best evidence for what might trigger autism. They were excited about their new understandings of the genetic basis for autism — what they view as the most promising area of research right now. They also talked about recent advances in grasping how particular genetic mutations change the biology of the brain in ways that cause autism symptoms.

More blurry is their research on the non-genetic (or environmental) contributors to autism, like pollution or medications. Here’s a quick rundown of what we know about the causes of autism — from most well-established to least well-established.

The strongest evidence of a cause: genetics

Autism spectrum disorder is a collection of close to 1,000 different conditions, with symptoms ranging from delayed speech development to asocial behavior and repetitive movements.

But “of all the causes of autism, the thing we know with the greatest certainty is that it’s a very genetic disorder,” said UCSF geneticist and autism researcher Stephan Sanders. “If you look at a child with autism, then look at their siblings, you’ll find the rate of autism is 10 times higher in those siblings than in the general population. This has been looked at in populations of millions.”

Researchers first recognized the genetic underpinnings of autism in the 1970s, with studies on twins involving at least one sibling with it. They found that monozygotic twins (with nearly identical genetics) were more likely to have autism in common than dizygotic (or non-identical) twins who shared less in common genetically.

Since then, large-scale population studies have uncovered the same pattern — and researchers have come to believe that shared genetic variants in families are probably more important than shared environments for triggering autism.

“The bottom line is that when you add up all of the genetic risks, it looks like genetics can account for 50 percent of the risk for autism, which is very high,” said David Amaral, an autism specialist at the UC Davis MIND Institute. To put that into context, compared to other common health problems — like heart attacks, or cancer — autism is much more genetic, with well over 100 genes now implicated.

The big question now is how these genes affect the brain in a way that leads to autism symptoms. So the next frontier in this area of autism research is understanding the biological effects of autism genes (or the genes where a mutation boosts a person’s risk of developing it).

“We anticipate some commonality in the effects of the [autism] genes, which we hope would reflect the most important aspects of autism biology,” Sanders said. Putting together the puzzle pieces on autism’s underlying biology will help researchers narrow in on potential treatments, he added.

To get there, researchers have been using whole-exome sequencing. The technique has been transformative for autism research since it allows researchers to sequence a person’s coding genes — or the small percentage of DNA in the genome that has translated into proteins to make functioning genes — and see how the exomes of people with autism differ from those without it.

Through exome sequencing, Sanders and his colleagues found that genetic variants in the gene SCN2A are linked with autism. Based on that discovery, they were able to uncover the “Rosetta Stone” of autism pathology: the particular genetic defects in an individual neuronal protein that lead to either epilepsy or autism, depending on how the mutations worked on the protein.

Narrowing in on how these single genetic mutations can lead to autism or other health problems opens the door to better understanding the biology, and how to treat it.

It’s worth noting that while there’s a robust conversation about finding ways to treat autism, there’s also a growing conversation in the autism community rejecting the language of “disorder” and “cure” and instead focusing on autism acceptance and neurodiversity.

Exposure to infections and certain medicines during pregnancy may be linked to autism

Not everyone with those genetic mutations has autism — and that’s because researchers believe it’s not mutations alone that cause it.

In many cases, you need that underlying genetic predisposition or mutation to collide with a range of potential environmental triggers. And finding those environmental risk factors is where things get murky pretty quickly.

Researchers have proposed dozens of potential environmental contributors to autism — including air pollution, pesticides, antidepressants, and viruses. And few of them have very robust science behind them, in large part because it’s much trickier to confirm the environmental causes of a disease.

“On the environmental side, nothing has come close to that level of confidence we have in the genetic causes of autism, partly because it’s so hard to do the experiments,” Sanders summed up.

In general, though, researchers have identified promising links between brain irregularities in children with autism and certain triggers during prenatal development.

For example, there is relatively strong evidence linking a mother’s infection with the rubella virus during pregnancy to an increased risk of autism in her baby. The evidence for other viruses — such as influenza, or herpes — is much less clear, however. “Some studies show some associations [between infections and autism] and others don’t,” explained Dr. Alice Kau, program director for research on autism at the National Institutes of Health. “The findings are mixed.”

There’s also pretty strong evidence that a mother’s use of the medicines thalidomide (originally used for morning sickness and now used to treat multiple myeloma and other diseases) and Valproic acid (for epilepsy and seizure control) seems to put babies at an increased risk of neurodevelopmental disorders, including autism.

But the evidence is again mixed on other drugs and supplements, such as SSRI antidepressants and folic acid.

It’s also mixed when it comes to stress. Researchers have long known that stress during pregnancy is linked with low birth rates and even preterm deliveries. They’re also exploring how exposure to stresses — a traumatic or extremely stressful life event during pregnancy — may contribute to autism, but they haven’t come to any definitive conclusions.

Despite all the claims to the contrary, the same is still true for heavy exposure to pesticides and air pollution. You can find research supporting and debunking these links and little agreement among researchers.

Part of the reason for the mixed results is that there’s not always a simple linear relationship between an exposure to a particular environmental trigger and a person’s autism risk. Genes also matter here. And in order to unpack exactly how pollution or pesticides may lead to autism (or not), researchers also need to understand how a person’s genetics determines how well their body metabolizes chemicals, responds to stress, and any number of other potential assaults.

That’s the next frontier in this area of autism research, said UCSF geneticist Lauren Weiss. For example, in a recent study, Weiss and her co-authors looked at whether genetics influences the levels of chemicals circulating in a mom’s blood during pregnancy and thus potentially her baby’s risk of autism.

“Some of the strongest links were between autism and lower levels of chemicals in [the mom’s] blood, and we think that suggests this is not a causal relationship,” Weiss explained. “It may be how well the body can handle chemicals that determines how much is circulating in pregnancy.”

In other words, a mother’s genetics influences how she responds to chemicals, and in turn, how they affect her fetus. And this is where the research is moving: “Autism studies will increasingly need to combine genetic data collection with estimates of environmental exposures,” said Amaral.

Researchers agree the MMR vaccine doesn’t cause autism — but the evidence is weak for other triggers after birth

Andrew Wakefield, the discredited British clinician who suggested a link between autism in children and the measles, mumps, and rubella vaccine based on fraudulent data. (Photo by Peter Macdiarmid/Getty Images)

Overall, the evidence for these prenatal exposures is stronger than the evidence for the range of postnatal causes that may trigger autism, said Amaral.

As he wrote in a recent review on the potential causes of autism, “Since autism is a neurological disorder that undoubtedly reflects altered brain function, it is possible that the insult to the brain occurs after birth.” But, he added: “There is currently very little evidence for this.”

One of the most popular theories — that the measles, mumps, rubella vaccine may cause autism — has been debunked by large-scale studiesinvolving thousands of participants in several countries.

Other popular potential postnatal causes, like profound social isolation among children, have also been disputed.

“Even though we’re still in this gray area of trying to find more certain specific causes of autism, virtually all the causes happen prenatally,” Amaral said. “If you have autism, you’re probably born with it.”

Boys are more likely to have autism than girls

There is one other important finding about autism: It seems to affect boys about four times more than girls.

Researchers have found it takes fewer genetic mutations for boys to get autism than girls, and they call this the “female protective effect.” It basically means that somehow girls with several autism-related genetic mutations would be able to adapt to that genetic hit — with no identifiable autism-like behaviors — whereas many boys can’t.

The research community doesn’t fully understand how this works. But scientists are trying to because it might help them identify biological treatments for autism.

There’s also some research that suggests autism may be harder to spot in girls, so women with it may be under-diagnosed. Autism researchers are working to unpack those subtle gender differences. Again, though, this isn’t a cause of the disease — just an association with the female sex.

The dearth of iron-clad autism triggers may be why people are vulnerable to the autism-vaccine hypothesis. It’s a much clearer explanation than suggesting it’s the result of some murky genetic-environmental interplay.

It’ll time take time for researchers to unlock the biology of autism, and how genetics and the environment work together to determine a person’s autism risk. There’s also increasing evidence that the gut microbiome interacts with the brain to contribute to the characteristics of autism, further complicating our understanding of autism, Amaral said. But scientists are quickly moving toward clearer answers — and maybe even biological treatments (for which there are currently none).

For now, vaccines are the wrong explanation for autism, and we should let the idea go. Autism researchers have. The more we hold onto it, the more outbreaks we’ll see like the measles epidemic in Minnesota, where autism fears gripped a community and pushed them away from a life-saving vaccine.