Mouse Models

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In the world of neuroscience research, the mouse reigns supreme: in the US alone, tens of millions of mice are studied as a proxy for the human brain in labs. They’re small, they breed quickly, and they’re relatively easy to genetically manipulate, making mice ubiquitous in biomedical science. When studying something fundamental to biology, like how individual cells work, the leap from mouse to human doesn’t feel egregious. But when mice are used to study distinctly human conditions like autism, the parallels start to break down.

Fifteen years ago, researchers introduced the first two mouse models of autism, each carrying a genetic mutation linked to autism in humans. They claimed that these mice behaved like autistic humans, unusually preferring solitude over meeting new mice, and squeaking only around half as often as their non-autistic littermates.

Their results made major waves, inspiring researchers to experiment with other autism-related genes. Since the late 2000s, neuroscientists have bred over 20 types of mouse models with motor problems, sensory sensitivities, and repetitive behaviors. These each capture some hallmark of human autism — provided you buy that a mouse burying marbles is the same as, for example, an autistic child insisting on eating the same food every day.

As a freshly minted PhD working at the National Institute of Mental Health in the late 2000s, Jill Silverman ran experiments on mice missing part of their SHANK3 gene, a mutation found in about 1 in 100 autistic people. These SHANK3 mice seemed to show “autistic-like behaviors” like social discomfort and compulsive grooming, similar to the repetitive body movements, or stimming, seen in some humans with autism.

Silverman, now a principal investigator at the UC Davis Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, still gets compliments on these mice — even though many of her original findings couldn’t be reproduced in future experiments. “They’ll say all this amazing stuff praising it,” she said. “And I’m like, that is the biggest mistake this field has ever made.”

Billions of dollars have been poured into autism research over the last decade, funding a staggering number of experiments — including over 1,500 studies in the US in 2020 alone. Many of these studies use animal models, especially mice.

Whether or not you believe that animal testing is ethical (many don’t), scientists in numerous research fields — especially neuroscience, genetics, and other areas of biology — run experiments on animals. To understand how cells in the brain communicate to form thoughts and guide behavior, you need a living brain connected to a living body. Millions of rodents are used — and nearly all killed — for science experiments every year, many of which are preclinical tests of new drugs and other treatments with potential public health benefits, including for autism.

And yet, all attempts to make drugs that help people manage some of the more challenging effects of autism, like sensory sensitivity or self-harm, have failed.

When I asked senior scientist Brigitta Gundersen, who manages Simons Foundation Autism Research Initiative (SFARI) funding for autism studies involving rodents, for an example of a tangible quality of life improvement that this line of research has given us, she paused. “I struggle to think of examples across all of psychiatry, frankly.”

“There’s this overall idea that understanding biology and understanding mechanisms will lead to better interventions,” she said. “But that hasn’t totally panned out.”

In theory, figuring out how autism manifests in the brain and body should help scientists develop better treatments for some of its more debilitating symptoms, like seizures, mobility challenges, and self-harm. Given how much we still have to learn about how the brain works, autistic or otherwise, this kind of research is “a really long game,” Gundersen said.

Mouse models of autism-related gene mutations may help uncover the underlying biology of autism in the long run. But autistic people understandably want tangible support now, and research serving that need is hugely underfunded. “It barely matters to us what a mouse model says,” said Sam Crane, an advocate for people with disabilities and a public member of the federal Interagency Autism Coordinating Committee (IACC), a group that helps policymakers decide what types of autism research to pay for.

Others, including the parents of autistic children with very high support needs, fear that deprioritizing biological research will leave their loved ones behind, turning attention away from developing potentially lifesaving treatments. Massive funding agencies like the US National Institutes of Health (NIH) are also wary of those trying to shift autism research away from genetics and neuroscience, arguing that scientific breakthroughs often come from long-term studies of fundamental biology — even when those studies don’t seem to offer real-world benefits in the short term.

Looking at the numbers, though, research exploring how to help autistic people navigate everyday life — the research many autistic people say they’d like to see — is still only getting about a quarter of the money allocated for autism research in the US. At a moment when autism diagnoses are on the rise — for reasons scientists still don’t fully understand — why are we spending so much on mice that might help humans eventually, and so little on services that could help humans now?

The history of autism research, briefly explained
Biologically speaking, autism — like the brain in general — is still poorly understood. In the 1950s and 1960s, medical professionals embraced the now-discredited “refrigerator mother” theory linking autism to cold, distant parenting, blaming mothers for their children’s condition. Later, psychologist Bernie Rimland presented evidence that autism is rooted in biology. Then, former physician Andrew Wakefield published a paper in 1998 incorrectly linking the measles, mumps, and rubella (MMR) vaccine to autism, fueling the modern anti-vaccination movement.

Today, most researchers believe that autism is strongly influenced by genetics. However, when symptoms can include everything from difficulty reading social cues to seizures to constipation, it’s hard to figure out what genes might be causing what — after all, over several decades of work, scientists have compiled a list of 100 or so genes that might be linked to autism.

To leaders at private funding agencies like SFARI, Autism Speaks, and the Autism Science Foundation (ASF), that complexity is precisely why we need basic research to explore the underlying biology and genetics of autism. The ultimate goal of these funders, several of whom have autistic children, is to find treatments for autism. Historically, some of these institutions even wanted to find “cures.”

But digging into the genetics of autism in the early aughts raised more questions than answers, forcing researchers to reconsider what autism even is. Meanwhile, in the absence of meaningful medical progress, some desperate parents turned to extreme DIY “cures” like making their autistic kids drink bleach.

“Despite the fact that they’re pointing in diametrically opposed directions, there’s a common theme with the refrigerator mother approach and the anti-vaccine approach,” said Ari Ne’eman, assistant professor at the Harvard School of Public Health and co-founder of the Autistic Self Advocacy Network (ASAN). “Namely, they both really emphasize the idea of causation as central to the business of autism advocacy.”

Framing autism as a disease that “happens” to otherwise-healthy children as a consequence of their parenting, genetics, or environment makes it feel like something that science can fix, or even prevent in the first place. For many diseases — think deadly cancers — this wouldn’t be controversial.

But many autistic adults believe the “causation” framing is hugely misguided. Efforts to pinpoint genetic markers of autism have raised serious concerns about eugenics — namely, that if parents could get a prenatal test for autism, many of them would choose not to have those children.

Prenatal tests for many diseases, like cystic fibrosis and sickle cell disease, already exist, and the fears of autism advocates are not unfounded. In Iceland, for example, nearly 100 percent of parents who get prenatal tests for Down syndrome — a chromosomal condition affecting as many as 6 million people worldwide, many of whom live long, healthy, fulfilling lives — choose to abort their pregnancy if the results are positive, causing the population of Down syndrome children to almost completely disappear there. Even in the US, where abortion is politically fraught, over two-thirds of parents choose not to give birth after finding out their child will have Down syndrome. Should it also be acceptable for parents to abort a pregnancy if they learn that their child will be autistic?

“Autism research was really built with the assumption that the goal is a world without autism,” Ne’eman said. But a growing number of people embrace the neurodiversity movement, proposing that autism is simply another way to move through the world. To them, the condition is not something to cure with medication or prevent with prenatal testing. This shift has led to significant controversy in the world of autism research. Autism Speaks came under fire in the mid-2010s for portraying autism as a devastating disease that ought to be stamped out, before denouncing that rhetoric in 2016.

For now, an effective prenatal test is not widely available — while autism does seem to be strongly influenced by genetics, there isn’t a single gene that flags autism. Prenatal tests and emerging gene-editing tools like CRISPR seem to work best for conditions caused by a single genetic mutation, like sickle cell disease.

However, scientists have listed about 100 genes that all seem related to someone’s likelihood of being diagnosed with autism, making a target for potential screenings, drugs, or other therapies much harder to pin down.

All considered, autism isn’t currently something that can be addressed by traditional drug development pipelines. Yet, funding for projects studying the biology of autism more than quadrupled since 2008, while funding for projects finding better ways to help autistic people in day-to-day life fell or remained stagnant.

Under the Combating Autism Act, which George W. Bush signed into law in 2006, Congress established the Interagency Autism Coordinating Committee. As the name suggests, the Combating Autism Act was focused on finding treatments to prevent or “cure” autism.

At the time, the vast majority of IACC members were not autistic — and their funding priorities were oriented accordingly. Their first set of recommendations, published in 2009, heavily skewed toward funding the search for causes and cures of autism. For example, they proposed spending $75 million on developing animal models of autism — nearly 50 times more than they suggested spending on studying everyday support services for autistic people.

Can biologists breed autistic mice? (Not really.)
In the world of biomedical research, where there are genetic risk factors, there are genetically altered mouse models. But by continuing to fall back on the rodents that they are so accustomed to studying, researchers are holding themselves back from fully understanding how autism manifests in humans.

Mice are small, reproduce quickly, and share about 85 percent of their functional genes with humans, making them desirable to geneticists hoping to study diseases outside of the human body. While non-animal models are slowly replacing animal testing in many areas of science, “you need a live animal to study a disorder that’s solely behavioral,” Silverman said. “Cells don’t behave.”

Mice behave, but their behavior is very different from ours. So, neuroscientists have had to stretch to draw parallels between the behavior of mice and autistic humans.

It also makes preclinical trials for new treatments, which are often conducted in animals, challenging to translate to humans. Many symptoms, especially those related to social interactions and communication, are distinctly human — so much so that they’re nearly impossible to reproduce in mice. “You know,” Gundersen said, “no mice talk.”

Today, more scientists are rejecting the idea that mice can actually exhibit autistic-like behaviors. “Nobody thinks that mice are people,” Gundersen told me. “Nobody thinks that mice are modeling autism.”

But the number of publications featuring “mouse model(s) of autism” in the title has steadily increased since they were first introduced in the mid-2000s. A cynic might wonder why scientists are continuing to pursue this line of research, when both autistic self-advocates and a growing number of leaders in biomedicine are saying that it doesn’t make any sense.

Ne’eman said that some people in the autistic community jokingly refer to autism research as a “geneticist’s Full Employment Act” — a parallel to the proposed Autism Full Employment Act, which would create incentives for workplaces to hire autistic people.

The grant application system is really competitive. To boost their chances of getting research funding, applicants increasingly have to twist their research proposals to align with whoever will give them money. A lab interested in studying how gene expression guides brain cells to form connections with each other, for example, could pitch it as an autism study to open up additional funding opportunities.

It also makes preclinical trials for new treatments, which are often conducted in animals, challenging to translate to humans. Many symptoms, especially those related to social interactions and communication, are distinctly human — so much so that they’re nearly impossible to reproduce in mice. “You know,” Gundersen said, “no mice talk.”

Today, more scientists are rejecting the idea that mice can actually exhibit autistic-like behaviors. “Nobody thinks that mice are people,” Gundersen told me. “Nobody thinks that mice are modeling autism.”

But the number of publications featuring “mouse model(s) of autism” in the title has steadily increased since they were first introduced in the mid-2000s. A cynic might wonder why scientists are continuing to pursue this line of research, when both autistic self-advocates and a growing number of leaders in biomedicine are saying that it doesn’t make any sense.

Ne’eman said that some people in the autistic community jokingly refer to autism research as a “geneticist’s Full Employment Act” — a parallel to the proposed Autism Full Employment Act, which would create incentives for workplaces to hire autistic people.

The grant application system is really competitive. To boost their chances of getting research funding, applicants increasingly have to twist their research proposals to align with whoever will give them money. A lab interested in studying how gene expression guides brain cells to form connections with each other, for example, could pitch it as an autism study to open up additional funding opportunities.

I asked Halladay what research she wanted to see, as the mother of an autistic daughter. She agreed that more investigations of conditions related to autism, like sensory sensitivity, would be incredibly helpful to families like her own. Halladay, like many other parents, doesn’t want her daughter’s autism to go away; she just wants more support — and possibly medicine — to help her child live the best life possible.

Autism research is torn between different visions
In general, Ne’eman thinks that “the average autistic person, as well as the average family member, doesn’t wake up in the morning thinking, ‘Have they found a better mouse model?’” They do think about whether they’ll be able to find a full-time caretaker who is covered by insurance, or what the newest adaptive communication devices will be capable of.

When autistic self-advocates were largely excluded from the decision-making process, funding for things that would help them immediately, like communication assistance or housing support, fell by the wayside.

That’s since changed — today, the IACC includes 23 non-autistic government employees and 22 public members, seven of whom are autistic themselves. Their budget priorities have shifted accordingly, centering research questions like “What services and supports are needed to maximize health and well-being?” in addition to basic biology studies.

At the same time, the gap between the committee’s proposed budget and how much funders actually spend has also grown. And while funding for services and support doubled between 2019 and 2020, it still only accounted for 8.4 percent of the money spent that year.

One big thing standing in the way of the IACC’s recommendations and reality: the biggest sources of science funding, public and private, weren’t really built to fund things other than biology research. Of the 28 organizations listed as funding autism-related projects between 2019 and 2020, the National Institutes of Health and SFARI — which only award grants for basic science and clinical research — together paid for over 80 percent of research.

Agencies like the Department of Education and the Administration for Community Living pay for projects studying interventions like how to help autistic adults avoid institutionalization and live as independently as possible — major priorities for autistic self-advocates. However, they only fund a tiny portion of autism research.

Solving this problem will likely require a major redistribution of funding, or a big overall increase in the pool of money available to everyone. “I’m not sure that you can totally fix it by just yelling at the NIH,” Crane said. In fact, she suspects that the Office of National Autism Coordination, housed within the NIH, knows that they’re supposed to be funding more studies about how to support autistic people — they’re just not receiving grant applications for them. The NIH did not respond to Vox’s requests for comment by the time of publication.

One solution the IACC recommended involves growing the overall pool of money set aside for autism research to $685 million by next year. They specifically highlighted three research areas that need the most additional resources: lifespan issues, evidence-based interventions and services, and the development of culturally responsive services.

If they could create autism in mice, viola they know what causes autism,
So who decided which parts of autism could be cured?

I don't relate to NT people, lying and stealing ideas that aren't yours, living off others misery for profit. But co-morbids getting me down, like finding job I really really like as opposed to settling for best jobs that manageable. Don't want a boyfriend, I battle to relate to friends.
Life was so hard, that I want full cure in that since we know what causes autism, it's preventable.

I thought rats were more clever and diversified to human diet than mice. But mice and rats are different. Heard we more closely related to apes,
Ye, so howecome don't test this on the apes before mice?

UK ban on animal experiments was found that animals provide little evidence, I think cloning mammary or something, probably some kind plastic shallow boob jobs. World makes me sick, sorry. I'm not a Barbie or tart and can and never will be.
Mostly in us during cancer research they had underground labs and experimented on homeless, or very poor subjects from poor countries!! S$$$$moral$$$_