Month: November 2011

Fresh dispute about MMR ‘fraud’ ""

Andrew Wakefield's discredited theory linking vaccination and autism stirred public fears.Andrew Wakefield’s discredited theory linking vaccination and autism stirred public fears.L. MACGREGOR/REUTERS

It is one of the most serious allegations that could be made about a doctor: manipulating patients’ histories to make money. So it is no wonder that the charges, levied by editors of the British Medical Journal (BMJ) in January against medical researcher Andrew Wakefield, are still getting close scrutiny. Now an American whistleblower advocacy group has joined the fray over Wakefield, who in 1998 hypothesized a link, now scientifically disproven, between the measles, mumps and rubella vaccine (MMR) and autism.

On 9 November, David Lewis of the National Whistleblower’s Center in Washington DC published a letter in the BMJ ( arguing that Wakefield did not commit research fraud. Lewis told Nature that he thinks the combination of public charges and a slow, secretive investigation has left the public not knowing whom to believe and is unfair to the accused researcher. “[The system] throws people like Andy into a no-man’s-land,” Lewis says.

Wakefield was the lead author of a 1998 paper in The Lancet (A. J. Wakefield et al. Lancet 351, 637–641; 1998) reporting on the case histories of 12 children who had received the MMR vaccine and developed symptoms of autism or inflammatory bowel disease.

The paper inflamed public fears about vaccines, but it was retracted in 2010 after the UK General Medical Council (GMC) concluded that Wakefield had a charge of serious professional misconduct to answer, in part because it found that his team did not have proper ethical approval for tests performed on the children. Later in the year, the GMC found him guilty of the misconduct charge and revoked his licence to practice as a doctor. By then, more than 12 large-scale epidemiological studies had failed to find evidence of the hypothesized link (J. S. Gerber and P. A. Offit Clin. Infect. Dis. 48, 456–461; 2009) and the MMR vaccine is today regarded as safe.

But was the paper merely mistaken, or a deliberate fraud? Articles by medical journalist Brian Deer published in the BMJ in 2010 and 2011 accused Wakefield of reporting histories for the children that were not consistent with their records and their parents’ recollections, at a time when Wakefield was also being paid by lawyers intending to sue MMR manufacturers. Deer’s articles themselves did not allege fraud, but on their basis a BMJ editorial in January 2011 called the paper fraudulent.

Wakefield has always denied allegations of manipulating data or having a financial motive in the Lancet paper, but no institution has yet ruled on the matter. In March, University College London (UCL), which took over divisions of the Royal Free Hospital where Wakefield worked, said it had launched an investigation.

In the meantime, Lewis, a microbiologist and former whistleblower who says he was falsely accused of misconduct after alleging links between human illness and the spreading of sewage sludge, asked Wakefield for the chance to review his files. His claims are not likely to challenge the conclusion based on much other evidence that the vaccine does not trigger autism. But they could complicate the debates about Wakefield’s integrity and the UCL investigation.

The documents that Lewis reviewed include confidential forms describing biopsies from the guts of children. The forms were filled out by pathologists Andrew Anthony and Paul Dhillon, who worked with Wakefield at the Royal Free. These documents, Lewis says, are relevant to Deer’s charge that records he obtained do not support Wakefield’s claims in the Lancet paper that the children had nonspecific colitis, a supposed element of an MMR-induced syndrome. On sheets for three of the children graded by Anthony, the handwritten word “colitis” appears, and Dhillon checked a box labelled “non-specific” on 10 forms. Anthony’s sheets are dated after the Lancet publication, whereas Dhillon’s are dated before.

Lewis believes that the sheets show that Anthony and Dhillon were making good-faith diagnoses of colitis. Anthony, who has left UCL, could not be reached by Nature, and Dhillon indicated that UCL had told him not to comment. (Neither has been accused of manipulating data.)

Before publishing Lewis’s letter, the BMJ asked Ingvar Bjarnason, a gastroenterologist at King’s College Hospital, London, to review the materials. Bjarnason says he doesn’t believe they are sufficient to support claims in the Lancet paper of a new disease process. He also questions whether “non-specific” on the grading sheets refers to colitis, saying it could refer to any kind of gut changes. But he says that the forms don’t clearly support charges that Wakefield deliberately misinterpreted the records. “The data are subjective. It’s different to say it’s deliberate falsification,” he says.

Deer notes that he never accused Wakefield of fraud over his interpretation of pathology records. But he says that records read to him from the Royal Free pathology service clearly stated that the children’s gut biopsies were within normal limits, even though they were reported in the Lancet paper as having enterocolitis.



Fiona Godlee, the editor of the BMJ, says that the journal’s conclusion of fraud was not based on the pathology but on a number of discrepancies between the children’s records and the claims in the Lancet paper. She says she will be calling for a public inquiry into the matter, noting that it has been more than a year since she first informed UCL about concerns over Wakefield’s work.

Wakefield denies charges of data manipulation. He says that UCL has yet to officially request his response to any charges and he isn’t convinced that the inquiry will give him a fair hearing. A UCL spokesman says that the investigation will be “thorough, fair and wide-ranging”. But eight months after announcing its inquiry, the university is still looking for a suitable external chairman. 

See also Correspondence — ‘Scientific misconduct: Latest MMR ‘dispute’ is a straw man’



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US lawsuit extends thalidomide’s reach ""

In a new twist of a historic tragedy, 13 Americans who say they are survivors of thalidomide are suing four companies for producing and distributing the notorious drug. They say that the drug — used by pregnant women for morning sickness until it was discovered to cause severe birth defects — affected more people in the United States than thought, and caused a wider range of deformities. And, they say, the companies have done all they can to hide these facts.

Thalidomide’s devastating effects first came to light 50 years ago this month in the German newspaper Welt am Sonntag. In Europe, the drug was implicated in thousands of cases of malformed newborns, but in the United States the damage was limited because the Food and Drug Administration (FDA) refused to approve it for market. Until now, most US cases were thought to originate from thalidomide obtained abroad.

The lawsuit, filed in a Philadelphia court on 25 October, asserts that before thalidomide was pulled from markets around the world, samples were doled out to more than 1,200 physicians in the United States by three companies whose legal liabilities are now the property of Sanofi-Aventis US, based in Bridgewater, New Jersey. Separately, it alleges, citing an FDA memorandum that only came to light earlier this year, the company Smith, Kline & French, now GlaxoSmithKline (GSK), ran a clinical trial of the drug in the US involving 875 people, including pregnant women, in 1956–57. The suit claims that at least one malformed baby was born to a trial participant in 1958. (The German firm Grünenthal, based in Aachen, and Avantor Performance Materials, based in Center Valley, Pennsylvania, are also named in the suit.)

Sanofi-Aventis and Grünenthal say that they cannot comment on ongoing litigation.

Mary Anne Rhyne, a spokeswoman for GSK, says that the company “intends to vigorously defend itself against this lawsuit”. She notes that Smith Kline & French never manufactured or sold thalidomide and adds: “The Plaintiffs’ complaint is replete with scientific inaccuracies and misstatements.”

The company challenges the claim that thalidomide can cause limb defects that are confined to one side of the body, as seen in nine of the plaintiffs. Conventional wisdom has long held that thalidomide’s signature defect — a shortened, seal-like ‘flapper’ arm, known as phocomelia — affects both sides of the body.

The plaintiffs’ lawyers argue that this assumption is unproven. “There are no representative, controlled studies documenting the true spectrum of thalidomide injuries,” they write in the lawsuit. “A universe of thalidomide related injuries has been thereby excluded from diagnosis.” They further suggest that “recently available studies published in medical and scientific journals reveal the flaws in the orthodox medical opinion”.

When asked by Nature for relevant studies, the plaintiffs’ lawyers at Hagens Berman Sobol Shapiro in Seattle, Washington, pointed to work showing one-sided limb defects in chick embryos exposed to thalidomide and thalidomide analogues (C. Therapontos et al. Proc. Natl Acad. Sci. USA 106, 8573–8578; 2009). The paper’s senior author, Neil Vargesson of the School of Medical Sciences at the University of Aberdeen, UK, says that the one-sidedness was due to the physical orientation of the developing chick when the medication was injected into the egg.



Vargesson says his work does not confirm or deny that the plaintiffs’ defects are the result of thalidomide. “The biggest issue facing the lawyers is persuading authorities that thalidomide gave rise to a range of other defects, including unilateral limb defects — or that it caused other damage without apparent limb defects at all.” However, adds Vargesson, who has advised lawyers for potential plaintiffs in the United Kingdom who do not have apparent limb defects, “it’s pretty clear that this drug did an awful lot of things and they don’t always centre around limb defects”.

Lewis Holmes, an expert in birth defects at Massachusetts General Hospital in Boston, says that the plaintiffs will have an uphill struggle to support their argument from the scientific literature because of the lack of systematic studies that follow up the offspring of women who took thalidomide during pregnancy. Holmes also notes that the relative paucity of thalidomide births in the United States means that few researchers there can speak with authority on the drug’s effects. “None of us ever saw thalidomide-damaged children,” he says. 



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Aid organizations tap into social-science expertise ""

Oral rehydration is a cheap and simple life-saver.Oral rehydration is a cheap and simple life-saver.G. Pirozzi/Panos

Condoms. Breastfeeding. Hand washing. After a decade of ramped-up spending, the donors to global-health programmes are grappling with a thorny issue: why are some health-care interventions that are proven life-savers failing to save as many lives as they should in the field, even after unprecedented investment to support them?

The question topped the agenda at a meeting last week of industry executives, researchers, public-health workers and global-health campaigners convened by the Bill & Melinda Gates Foundation in Seattle, Washington. The foundation is looking to enlist insights from the behavioural and social sciences to help in two key areas: helping communities to adopt proven interventions, and scaling these measures up to help more people in poor countries.

In the past, the foundation has invested heavily in developing technological innovations but comparatively little on persuading people to embrace them. It is now changing that by commissioning reports on how to build social and behavioural research into future development programmes to make them more successful. Foundation officials say that they are also considering these issues at each step in programmes already under way. The changes were spurred by discouraging reports such as one published in September (R. Lozano et al. Lancet 378, 1139–1165; 2011). This found that only 9 out of 137 developing countries are on track to meet two ambitious targets under the United Nations’ Millennium Development Goals: to reduce maternal deaths by three-quarters and child deaths by two-thirds by 2015.

Many treatments, such as oral-rehydration therapy to treat diarrhoea, or ‘kangaroo mother’ care, in which premature infants are held in skin-to-skin contact with their carer, are inexpensive and simple, but cultural and behavioural factors have slowed their adoption. “There isn’t anything we do in global health that doesn’t have some component of social change,” Melinda Gates told delegates in her opening address. “We may have the best malarial bed net, but if people don’t sleep under it, it’s not going to make a difference.”

“We may have the best malarial bed net, but if people don’t sleep under it, it’s not going to make a difference.”

Participants at the meeting cited numerous examples of how common sense and local knowledge could help to overcome barriers. Rashad Massoud, director of the USAID Health Care Improvement Project in Bethesda, Maryland, described a programme in Niger that aimed to prevent deaths from post-partum haemorrhage using the drug oxytocin. The programme was failing because oxytocin, which must be refrigerated, was delivered at night, when health-centre pharmacies were closed and could not accept deliveries. Public-health workers urged local communities to come up with their own solutions, such as using coolers to store the medicine, and maternal deaths from haemorrhage plummeted.

“A lot of the solutions we’ve figured out have come from communities themselves,” noted Nana Twum-Danso, who directs African operations for the non-profit Institute for Healthcare Improvement in Cambridge, Massachusetts. She told the story of a project aimed at convincing women in Ghanaian villages to go to clinics to have their babies. Project leaders learned that women were reluctant to do this because it was perceived as cowardly. The villagers themselves came up with solutions to the problem, one of which was to fine men whose wives gave birth at home.



Gary Darmstadt, director of family health at the Gates Foundation, said that marketing expertise could also help. The private sector has experience in assessing markets’ openness to new products and finding ways to get consumers to demand those products, he says. Such an approach might help the foundation to achieve its goals in cases such as promoting use of the antiseptic chlorhexidine to cleanse a newborn’s umbilical cord to prevent infection. This has proved a challenge because many cultures have traditions surrounding the umbilical cord, such as smearing it with cow dung, oils or ash. “We’re looking at how we design a product that makes people want to buy it and put it on, and these are the kinds of things that public health really hasn’t done,” Darmstadt said.

At the meeting, Donald Berwick, head of the US Centers for Medicare and Medicaid Services, in Baltimore, Maryland, praised the foundation for focusing attention on how to scale up proven health-care interventions. This could inspire a worldwide change, even in developed countries such as the United States, whose own health-care system is in “crisis”, he said.

“If the Gates Foundation is interested in this, it will change the world,” Berwick said. 



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Palestinian membership puts UN projects at risk ""

UN agencies risk their budgets by voting for Palestinian membership.UN agencies risk their budgets by voting for Palestinian membership.Gao jing/Xinhua/Corbis

Concern is growing that United Nations bodies could face budget crises after the UN agency responsible for science suffered a drastic cut in contributions following a vote in which it admitted the Palestinian Authority as a member.

The vote on 31 October by the UN Educational, Scientific and Cultural Organization (UNESCO), based in Paris, caused the United States to pull its 22% share of the agency’s budget — some US$80 million a year. US law prevents the nation from funding any UN body that grants full membership to any organization or group that is not an internationally recognized state.

Following the vote, Irina Bokova, UNESCO’s director-general, said that she was “concerned by the potential challenges that may arise to the universality and financial stability of the Organization”. Other countries, such as Canada and Israel, have followed the United States in withdrawing funding; the cuts will put pressure on UNESCO-funded science and education projects.

The US Department of State has warned of a potential ‘cascade’ effect. As part of continuing attempts to win recognition as an independent state, the Palestinian Authority is reportedly set to apply to join other UN agencies, including the World Health Organization (WHO) in Geneva, Switzerland; the Inter­national Atomic Energy Agency (IAEA) in Vienna; and the Food and Agriculture Organization (FAO) in Rome. All of these groups get around one-fifth of their direct funding from the United States, and would lose it if they admitted a Palestinian state.

At UNESCO, 107 nations voted for Palestinian membership and only 14 against, with 52 abstentions. A similar selection of states are members of other UN bodies, so further Palestinian applications have a good chance of success. However, other bodies have different systems for granting membership.

UNESCO funds and runs many inter­national science projects, including a tsunami-warning system in the Indian Ocean, put in place after the 2004 disaster. It also runs science-policy and education programmes. “The present cuts will seriously reduce the good work currently in hand,” says Peter Fensham, emeritus professor of science education at Monash University in Melbourne, Australia, who has worked with UNESCO. He adds, “I also remember how handicapped UNESCO’s very good work in science education was when the United States and United Kingdom cut off funding in the Reagan and Thatcher eras.”

Jens Jørgen Gaardhøje, a physicist at the Niels Bohr Institute at the University of Copenhagen and a member of the Danish National Commission for UNESCO, says that UNESCO programmes are already “systematically” short of funding. “With a very significant reduction of the budget I fear that significant activities will have to be discontinued entirely and some very hard choices will have to be made,” he says.

As Nature went to press, the FAO, the WHO and the IAEA said that they had not received applications from the Palestinian Authority. The FAO and the IAEA would not comment on whether they have contingency plans to deal with a potential loss of US funding. A spokesperson for the WHO said that because it has not yet received a membership request, the organization has not reached the point of considering revised funding plans.



Kelley Lee, director of global health at Simon Fraser University in Burnaby, Canada, said that other countries might make up any shortfall in funding if the UNESCO situation was repeated at the WHO. “China is an obvious country to step in,” she says.

But a Palestinian membership attempt could be particularly problematic at the WHO. The agency is preoccupied with a huge internal reform driven by its director-general, Margaret Chan (see Nature 473, 430–431; 2011), so its members may resist Palestinian overtures. “Overall, my feeling is that it is unlikely to happen given the current and indeed long-standing financial austerity within the organization and Margaret Chan’s focus on protecting the organization’s financial and political standing,” says Lee. “Palestinian membership poses higher risks than I think the organization can bear at present.” 



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Smoking stokes cocaine cravings ""

girl smokingSmoking now may make you more susceptible to cocaine addiction later.Edyta Pawlowska/Glow Images

Nicotine causes changes in gene regulation that enhance the brain’s subsequent response to cocaine. The finding, in mice, provides the first clear evidence for a molecular mechanism supporting the idea of ‘gateway drugs’.

Epidemiologist Denise Kandel at Columbia University, New York, reported back in 1975 that drug-using adolescents had tended to start with cigarettes, which contain the addictive substance nicotine, and alcohol before progressing to more illicit substances such as cocaine1. The idea that smoking and alcohol act as a gateway, making teenagers more likely to experiment with other drugs, has proved controversial ever since.

Now Kandel has collaborated with her husband of 56 years, neurobiologist Eric Kandel, and other colleagues at Columbia, to probe the molecular biology underlying the gateway effect. In a study published today in Science Translational Medicine2, the team shows that, in mice at least, nicotine causes epigenetic changes — long-lasting changes in the control of gene expression — that subsequently boost the response to cocaine.

Hunt for a mechanism

Neurobiologists Eric Nestler and Alfred Robison of the Mount Sinai School of Medicine in New York suggested in a review published earlier this month that such gene priming is likely to be at work in drug addiction3. But their prediction was based on limited existing evidence. “This paper is exciting because it is one of the first well-defined characterizations of gene priming by a drug,” says Robison.

“Adolescence is a time when the brain is very malleable.”

Amir Levine
Columbia University

Amir Levine, a member of the Columbia team, acknowledges that there could be other reasons, such as social factors, for the progression from soft to hard drugs, but “adolescence is a time when the brain is very malleable”, he points out. “We wondered if drug-induced brain alterations could have long-term molecular impacts.”

To investigate, the researchers plied mice with nicotine, followed seven days later by cocaine. What they found was striking. Compared with mice on cocaine who had not previously received nicotine, the animals were 98% more active and 78% more likely to return to areas previously associated with the cocaine.

The reverse didn’t hold, however. Cocaine had no effect on nicotine-induced behaviour.

The chromatin connection

To determine how nicotine boosts cocaine’s impact, the researchers studied molecular markers of drug addiction, including the transcription of FosB, a gene implicated in addiction to many drugs of abuse, and the structural changes that regulate FosB expression.

“We found that nicotine works on the DNA-packaging system, known as chromatin,” says Levine. Nicotine loosens chromatin, a complex material in which DNA is packaged up by histones and other proteins, by enhancing a process called histone acetylation, catalyzed by acetylase enzymes. Acetylation effectively opens up the packaging, enabling greater transcription of the FosB gene, he says. Nicotine does this by inhibiting another enzyme involved in gene regulation, histone deacetylase, which has the opposite effect on chromatin.

The authors backed up their results with additional experiments showing, for example, that the drug suberoylanilide hydroxamine acid, which inhibits deacetylases, simulates the effect of nicotine.

New life for an old hypothesis

The team also re-evaluated existing epidemiological data on the drug use of 1,160 high school students and found that it confirmed that smoking increased the risk of cocaine dependency in people – consistent with the findings in mice.

The research promises to reinvigorate the gateway-drug hypothesis, which Levine says has gained a bad reputation. “People think it’s backed by conservative movements to make a case for making marijuana illegal, when it is simply the sequence of adolescent drug use as found in epidemiological studies,” he says.

Frances Leslie, a neuropharmacologist at the University of California at Irvine, who was not involved in the study, says that part of the problem is that people don’t want to believe that teenage smoking will sensitize them to other drugs. And because it’s difficult to tease out social factors in human studies, animal work has an important role. Her own group has shown that nicotine is associated with ‘risky’ behaviour, including an increase in self-administration of cocaine, in adolescent rats4.

The molecular mechanism revealed by the Columbia team’s work “is exciting because it may lead to therapeutic interventions”, says Leslie. “Hopefully this paper will make it less controversial to use the term ‘gateway drug’ in future papers and grants,” she adds.

The policy implications of the findings will undoubtedly be debated. Laura Bierut, a psychiatrist at Washington University in St Louis, Missouri, who focuses on the genetic epidemiology of addiction, says the Columbia study suggests that existing policies aimed at cutting smoking may be having a larger effect on public health than thought.



It should also help to guide epidemiological studies to tease apart the relationship between cocaine use and smoking, she says, including the effects of the age that someone starts smoking, how much they smoke, and what other drugs they take.

Levine and Eric Kandel now hope to determine whether alcohol and marijuana similarly prime the response to illicit drugs or have a different effect. “Is there a common gateway mechanism or a family of gateway mechanisms?” says Kandel. 

  • References

    1. Kandel, D. Science 190, 912-914 (1975). | Article | PubMed | ChemPort |
    2. Levine, A. et al. Sci. Transl. Med. 3, 107ra109a (2011). | Article |
    3. Robison, A. & Nestler, E. Nature Rev. Neurosci. 12, 623-636 (2011). | Article |
    4. Dao, J. M., McQuown, S. C., Loughlin, S. E., Belluzzi, J. D. & Leslie, F. M. Neuropsychopharmacology 36, 1319-1331 (2011). | Article | PubMed | ISI | ChemPort |



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The prevalence puzzle: Autism counts ""

When Leo Kanner first described autism in 1943, he based his observations on 11 children with severe communication problems, repetitive behaviours such as rocking and an acute lack of social interaction. The physician and psychiatrist at Johns Hopkins University in Baltimore, Maryland, predicted that there were probably many more cases than he or anyone else had noticed1. “These characteristics form a unique ‘syndrome’, not heretofore reported,” he wrote, “which seems to be rare enough, yet is probably more frequent than is indicated by the paucity of observed cases.”

Kanner’s prophecy has been more than fulfilled. An early study2, in 1966, examined eight- to ten-year-old schoolchildren in Middlesex, UK, and estimated a prevalence of 4.5 cases per 10,000 children. By 1992, 19 in every 10,000 six-year-old Americans were being diagnosed as autistic3.

Numbers skyrocketed in the first decade of the twenty-first century, according to data from the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia. Surveying what is now known as autism spectrum disorder (ASD), the CDC found that by 2006, more than 90 in 10,000 eight-year-olds in the United States had autism4. Put another way, autism was now affecting 1 in every 110 children — a figure that strengthened public fears that an ‘epidemic’ was afoot (see ‘Diagnosis: rising’).

For the most part, research into autism’s prevalence had explained away the increase. Studies attributed it to greater awareness of the condition, the wider diagnostic criteria for ASD, more frequent diagnosis of children with mental retardation as also having autism and diagnosis at younger ages. But by the mid-2000s, researchers started to note that these explanations were coming up short. “A true risk due to some, as yet to be identified, environmental risk factor cannot be ruled out”, read one study from 2005 (ref. 5).

That shift is important. If the rise in autism can be explained mainly by increased awareness, diagnosis and social factors, then the contributing environmental factors will always have been present — perhaps an ill-timed infection in pregnancy or some kind of nutritional deficit. If the increase can’t be explained away — and at least part of the rise is ‘real’ — then new factors must be causing it, and scientists urgently need to find them.

The subject is sensitive. Parents of children with autism agonize over whether they could have done something to prevent it. Researchers have been wary of invoking environmental triggers because that harkens back to a long-discarded idea that cold, unloving ‘refrigerator’ mothers were the source of their children’s problems. And the increase in prevalence has been used to support more recently debunked hypotheses such as the idea that vaccines cause autism.

Thomas Insel, director of the National Institute of Mental Health in Bethesda, Maryland, says it is time to get past these legacies. “This whole idea of whether the prevalence is increasing is so contentious for autism, but not for asthma, type 1 diabetes, food allergies — lots of other areas where people kind of accept the fact that there are more kids affected.” To him, it is clear that there is a real increase in autism, and researchers need more funding and encouragement to look at possible environmental causes. During the past decade, the US federal government has spent about US$1 billion researching the genetics of autism and only about $40 million on studies of possible environmental factors.

Not everyone agrees with Insel’s assessment. Some argue that the current data aren’t strong enough to say for certain that the increase in autism diagnoses represents a true change in its prevalence. “It feels like the numbers are going up. It really does,” says Richard Grinker, an anthropologist at George Washington University in Washington DC. But “when I look at the science, that doesn’t stand up”, he says. “You simply can’t take prevalence estimates of autism as if they are the kind of hard scientific evidence that you would get from mapping out the increase in a virus.”

Changing criteria

No one knows for sure what causes autism, although genes and environment both seem to be involved. The brain’s white matter may grow too fast in the first two years of life, leaving its networks jumbled. Synapses, the junctions between neurons, might not be functioning normally. Or other physiological processes could be involved: autism has been variously linked to epilepsy, digestive problems, immune or hormonal dysfunction, mitochondrial function and more.

“This whole idea of whether the prevalence is increasing is so contentious for autism.”

The diagnostic criteria for autism have changed over time. In 1952, autism defined by Kanner’s narrow description was diagnosed as ‘early-onset schizophrenia’; it was renamed ‘infantile autism’ in 1980 and then ‘autism disorder’ in 1987. In the past decade, the common name autism has covered a wider range of behavioural, communication and social disorders also referred to by the umbrella term ASD, which includes autistic disorder, Asperger’s syndrome and other related conditions.

Diagnoses of autism are also subjective. Social skills vary widely in the general population, as do other behaviours associated with autism. When does lack of spontaneity or an inability to make eye contact become a problem worthy of a medical label? And the frequency of diagnosis often reflects how eager parents are to receive one. When there’s a stigma attached, diagnoses are likely to fall; when public support rises, so will cases.

A diagnosis is mutable, says Grinker. “It is a framework for a set of symptoms. And it’s a framework that works at a particular point in time with a certain society and a certain health-care system and education system, and that will change as society changes.”

Such considerations help to explain the startlingly high prevalence of autism that Grinker found in South Korea in a study published this year6. In the 1980s, he had found Korean families generally unwilling to admit that anything might be wrong with their children, because of the stigma attached7. But when he undertook the latest study, attitudes had changed. Families in Ilsan, a stable, residential community on the outskirts of Seoul, welcomed information about autism, which in this study was offered confidentially. His team screened more than 55,000 children born between 1993 and 1999, and came up with an estimated prevalence for ASD of 1 in 38 (ref. 6). Grinker says that this is perhaps an overestimate, but it’s the best his team could produce.

Current US prevalence figures for autism are likely to be too low, Grinker says, because they don’t look at the entire population. Many US studies are based on diagnosed cases of autism, either in the California school district — the nation’s largest — or in the CDC’s Autism and Developmental Disabilities Monitoring Network. But the California data count only children old enough to be in school and disabled enough to get a diagnosis or need services. The CDC surveillance also only picks up children with a documented developmental disorder. These methods probably miss children at the milder end of the spectrum.

Some research suggests that the prevalence has always been high. In a study published this year8, a team led by Terry Brugha, a psychiatrist at the University of Leicester, UK, looked into autism’s past by counting adults with the disorder. His team knocked on more than 7,000 doors across England. And although Brugha expected to uncover a very low prevalence of autism in adults, he and his colleagues calculated it as 9.8 in 1,000 — close to the frequency found in US children.

“If it is an environmental cause contributing to an increase, we certainly want to find it.”

Brugha says that the research needs to be repeated in different groups, but the implication is that autism prevalence is stable. “If this is confirmed in other studies, it means we should also be looking for causes of autism that have always been there, and not just for causes that have developed in recent years or decades,” he says.

Christopher Gillberg, who studies child and adolescent psychiatry at the University of Gothenburg in Sweden, has been finding much the same thing since he first started counting cases of autism in the 1970s. He found a prevalence of autism of 0.7% among seven-year-old Swedish children in 1983 (ref. 9) and 1% in 1999 (ref. 10). “I’ve always felt that this hype about it being an epidemic is not really very likely,” he says.

Filling the gap

Nevertheless, with numbers rising fast, many expect to see some sort of smoking gun in the environment. Peter Bearman, a sociologist at Columbia University in New York, has been trying to figure out how much of the increase is driven by social forces. He analysed nearly 5 million California birth records and 20,000 records from the state’s department of developmental services. By linking birth with detailed diagnostic data he was able to generate a rich picture of the demographics and life history of those with autism, which yielded clues to the social factors that influence diagnosis.

So far, Bearman says, he can account for just more than 50% of the observed increase (see ‘Reasons: unclear’). Around 25% of the rise in autism over the past two decades can be attributed to what he calls “diagnostic accretion”. He could see from the medical records that some children who would have been diagnosed as mentally retarded a decade ago are now given a diagnosis of both mental retardation and autism11. Another 15% can be accounted for by the growing awareness of autism — more parents and paediatricians know about it12.

Geographic clustering accounts for 4%, Bearman says. The most fascinating cluster lies in and around the hills of Hollywood, California. Children living in a 900-square-kilometre area centred on West Hollywood are four times more likely to be diagnosed with autism than are those living elsewhere in the state12. Some residents worried that something in the water was triggering autism — perhaps the legacy of a 1959 nuclear accident at the Santa Susana Field Laboratory in nearby Simi Valley — but Hollywood shares its water supply with Los Angeles, where autism rates are not uniformly high. Moreover, rates are high whether families have lived in Hollywood for years or have just moved there, Bearman says.

He suspects that the real reason for the cluster has to do with neighbourliness: a parent explains to a neighbour over the back fence where to find help and how to navigate the medical and educational systems. Once a cluster of informed, involved parents builds up, specialists are more likely to settle in that area, diagnosing and treating even more kids, Bearman says.

Another 10% of the increase may be explained by a social change with biological implications: people having children when they are older. Some research has found that children born to parents older than 35 have a higher risk of being diagnosed with autism. Studies are divided about whether the mother’s age or the father’s has the strongest influence, but Bearman’s work on parents older than 40 suggests that the mother’s age matters more13.

The fact that he still cannot explain 46% of the increase in autism doesn’t mean that this ‘extra’ must be caused by new environmental pollutants, Bearman says. He just hasn’t come up with a solid explanation yet. “There are lots of things that could be driving that in addition to the things we’ve identified,” he says.

But many researchers now say that at least part of the rise in autism is real and caused by something in the environment. Rather than quibbling over recounts they are focusing on finding the causes.

Since autism was first identified, ideas about its cause have swung to and fro between nature and nurture. The early focus on ‘refrigerator’ mothers resulted in a backlash and a stronger focus on genetics. The pendulum now seems to have settled somewhere in the middle, which is where many think it should be. “The bulk of the autism research that’s occurred has only looked at genetics,” says Lisa Croen, director of the autism research programme at the health-insurance provider Kaiser Permanente, in Oakland, California. “We’ve learned a lot but we haven’t found the magic bullet. I think that’s because part of the picture has been missing.”

Several major federally funded trials, together with other smaller ones, are now under way in the United States and elsewhere to try to fish out what makes a child autistic. They are hoping to uncover unknown risk factors and markers for autism by monitoring environmental exposures and taking regular biological samples from children and their parents.

In 2007, for example, the Study to Explore Early Development (SEED), under the auspices of the CDC, began recruiting about 2,700 children aged two to five. The study includes developmental evaluations, questionnaires, a review of medical records and analysis of blood, cheek-cell and hair samples to examine genetic make-up and exposures to environmental chemicals. The Early Autism Risk Longitudinal Investigation (EARLI), funded by the National Institutes of Health, is enrolling up to 1,200 families that have a child with autism and are preparing to have another baby. The study intends to look for any interplay between environmental factors and genetic susceptibility that might contribute to autism risk in their next child.



“These studies are really going to fundamentally change the landscape,” says Croen, who is a lead investigator on SEED. She and others expect a dramatic improvement in the understanding of autism and its prevalence over the next five to ten years.

Craig Newschaffer, an epidemiologist at Drexel University in Philadelphia, Pennsylvania and an investigator with EARLI, says that a focus on the rise in diagnoses may be less important than figuring out what is causing autism in the first place. “If it is an environmental cause that’s contributing to an increase,” he says, “we certainly want to find it.” It may be time to move on from the question of whether or not autism is truly rising, “I think it’s probably a nearly intractable question to answer.” 

Karen Weintraub is a freelance writer in Cambridge, Massachusetts.

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    10. Kadesjö, B., Gillberg, C. & Hagberg, B. J. Autism Dev. Disord. 29, 327-331 (1999). | Article | PubMed |
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    12. King, M. D. & Bearman, P. S. Am. Sociol. Rev. 76, 320-346 (2011). | Article | PubMed |
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Autism’s fight for facts: A voice for science ""


The e-mail that ended one career for Alison Singer, but started another, arrived as she was cooking dinner for her daughters one evening in January 2009. Singer was preoccupied. At a committee meeting she was due to attend in Washington DC the next day, she and others were set to vote on a plan that would direct much of the United States’ spending on autism research for the next year.

Singer, who had her laptop perched on the kitchen counter, immediately noticed the e-mail from another committee member — a mother who was convinced that vaccines had caused her son’s autism. The message proposed last-minute language for inclusion in the plan, endorsing more research into whether vaccines can trigger the disorder of communication and movement. Singer knew immediately that this would cause her serious difficulties. Having read the literature and talked to numerous scientists, she was convinced that no studies supported a link between autism and vaccines. But she was also the top communications executive at Autism Speaks in New York, autism’s most prominent research and advocacy group. The organization supports vaccine-related research, and Singer knew that her bosses would expect her to vote for more studies of vaccines as a possible cause of the condition.

At 11:10 p.m., Singer hit ‘send’ on an e-mail of her own, to Bob and Suzanne Wright, the co-founders of Autism Speaks. “I’ve concluded that as a matter of personal conscience, I cannot vote in favor of dedicating more funds to vaccine research that has already been undertaken and which I and many others find conclusive,” her message read. “I feel compelled to offer my resignation.”

With that, Singer became a solo operator in the world of autism-research funders. Within months, she would launch the Autism Science Foundation (ASF), a tiny New York-based charity with a relentless focus on rigorous science, a niche supporting the youngest researchers and a guiding principle that “vaccines save lives; they do not cause autism”.

The ASF is scarcely a blip on the big screen of autism-research spending: in this, its second full year of operations, it is awarding US$220,000 in grants to young researchers; last year, it spent $180,000. The two major non-governmental players in US autism research, the Simons Foundation in New York and Autism Speaks, last year spent $54 million and $21 million, respectively (see ‘All change for autism’).

But Singer’s charity is drawing notice as much for the aims and quality of its work as for its magnitude. In August, GuideStar, a major charity-rating group based in Washington DC, singled out the ASF as a “promising start-up”, calling it “a shining star to those interested in real science and evidence based interventions”.

The fledgling foundation has also won endorsements from leaders at the American Academy of Pediatrics in Elk Grove Village, Illinois; the National Institutes of Health (NIH) in Bethesda, Maryland; and the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia. “The Autism Science Foundation is an important voice for scientific direction in the autism community,” says Coleen Boyle, the director of the National Center on Birth Defects and Developmental Disabilities at the CDC.

The jury is still out on whether Singer and her tiny organization can do much to combat the perception of a link between autism and vaccines that has become cemented in many minds. But if anyone is going to do it, Singer is a strong candidate. She “is a force of nature”, says Thomas Insel, director of the National Institute of Mental Health in Bethesda, which spends more than $80 million on autism each year — more than half of the NIH’s autism budget. “I have enormous respect for her abilities.”

“She is one of the most strong-willed people that I have ever met,” adds Christie Buchovecky, an ASF-funded graduate student at Baylor College of Medicine in Houston, Texas, who has a 12-year-old cousin with autism. “And she somehow manages to do that while still being extremely caring and supportive. She knows where the parents are coming from.”

All in the family

On Saturdays 40 years ago, when Singer (then Alison Tepper) was 5 years old and wanted to be in ballet class, she and her parents would set out on a very different errand: visiting her autistic 7-year-old brother, Steven, at the Willowbrook State School, an institution on Staten Island, New York, that housed more than 5,000 people diagnosed with mental retardation and developmental disabilities. Singer’s parents had placed Steven in Willowbrook out of fear for their children’s safety. Steven could be self-injurious and a danger to others; once, he had brought a whole wall unit, including a television, crashing to the floor.

Willowbrook was a Dickensian institution that would eventually come to symbolize everything that was wrong with the way America cared for its mentally ill. In 1965, New York Senator Robert Kennedy alluded to the facility as “a snake pit”. In 1972, an undercover exposé by local television channel WABC-TV showed residents sitting and staring vacantly; rocking, often naked, in overcrowded, barren rooms; or abandoned on bathroom floors. When Singer and her family visited Steven, they would see him only in the visitors’ room. Still, the stench of urine bothered Singer. So did the noise. “There was a lot of screaming,” she recalls. “I didn’t like it.”

In 1971, shortly before the documentary aired, the Tepper family moved from the New York borough of Queens to the suburbs, and transferred Steven to a nearby facility called Letchworth Village. In time, the family — Singer also has a younger brother — began visiting Steven less often. Singer’s mother, who had been told she was to blame for Steven’s condition, instructed her daughter to tell people that she had just one, younger, brother. “People didn’t talk about it then. No one talked about it,” Singer says. “There was a tremendous stigma associated with autism.”

Singer carried her secret out of childhood as she set out to become a journalist. In 1993, having graduated with a degree in economics from Yale University in New Haven, Connecticut, and a master’s from Harvard Business School in Boston, Massachusetts, she was hired as vice-president of programming for the cable division of television network NBC. Singer was charged with bringing news content to desktop computers through the new phenomenon called the Internet. She married in 1994; in 1997, her first daughter, Jodie, was born. Singer thought something was wrong, she says, “from the day she was born”. Jodie cried constantly. She didn’t want to eat. She wouldn’t sleep. One diagnosis followed another: failure to thrive; early colic; late colic. “I just thought I didn’t have the mommy gene,” Singer recalls.

She started questioning her mother over and over. “‘Did Steven ever do this? Did Steven ever behave like this?’ My mom would say: ‘No, Steven never did that’.” Singer also took heart from a conversation with an obstetrician who assured her that autism is “not genetic”. Still, as Jodie became a toddler, Singer remained deeply troubled by her inability to communicate. “She used to recite the Madeline book from beginning to end perfectly,” says Singer. “But if I said, ‘Do you want juice?’ she couldn’t answer yes or no.”

Singer called the state department of health several times to schedule an assessment for Jodie. Each time, in a rush of ambivalence, she would call back and cancel. Finally, she made a firm appointment. When a psychologist and a case worker visited her at home, Jodie was two years, eight months old. (Singer had just given birth to Jodie’s healthy younger sister, Lauren.) Singer expected them to say that nothing was wrong. Instead, they diagnosed Jodie as severely autistic, telling Singer gravely, “Don’t worry, we’re going to get her help.” When they were gone, says Singer, “I just bawled”.

Then, she says, “I pulled myself together”.

Driving on

‘Together’ seems an apt word for Singer. She comes across as organized, articulate and, above all, driven — although not without a sense of humour. On a September day, Singer showed this reporter around what she jokingly referred to as “the worldwide headquarters” of the ASF: a cubicle on the fourth floor of a lower Manhattan office building. There, Singer’s one paid member of staff — Jonathan Carter, a recent college graduate with an autistic brother — was labouring over the just-relaunched ASF website. Singer herself does not draw a salary.

“People didn’t talk about it then. There was a tremendous stigma associated with autism.”

It’s a long way from the high-flying position she held at Autism Speaks, where in her last year she made $187,000. Bob and Suzanne Wright had made Singer their first employee when they launched the group in 2005, shortly after their grandson was diagnosed with autism. They were well placed to make things happen: Bob Wright was chief executive of media conglomerate NBC Universal and vice-chairman of General Electric, NBC’s parent company. During the group’s first months, when Singer served as interim chief executive, she, Suzanne Wright and an assistant constituted the entire staff. Working with a shared passion and purpose, from an office on the 51st floor of NBC Universal’s headquarters, Singer and Suzanne Wright became fast friends. “Suzanne doesn’t take no for an answer and neither do I. So we got a lot done,” Singer recalls.

Their completed to-do list included landing coverage for Autism Speaks on television programmes Oprah and Larry King Live, and in the pages of The Wall Street Journal. Singer turned the organization’s website into the most highly trafficked in the autism world. The group, she later wrote in her resignation e-mail, “elevated ‘autism’ to the global vocabulary”. In 2008, Singer’s final year with Autism Speaks, the charity raised more than $70 million.

But there was friction, too. The Wright’s daughter, Katie, fervently believed that vaccines were the cause of her son’s autism, and was pushing her parents to fund more vaccine research. This didn’t sit well with Singer. Although she had been open to such research when Jodie was first diagnosed, Singer had followed the growing number of studies that debunked any link between autism and the once-suspect measles, mumps and rubella vaccine, or between autism and thimerosal, a mercury-containing preservative that was used in some early-childhood vaccines until 2001. For the past several years, she says, the data have been very clear. “There were no studies indicating a link between autism and vaccines.” As time went on, Singer became increasingly uncomfortable with her organization’s continued funding of vaccine-related research. She was even more disturbed by its failure to state, publicly and unequivocally, that all the data show that vaccines do not cause autism.

The committee meeting in January 2009 brought matters to a head. The Interagency Autism Coordinating Committee, a group of federal-agency and public representatives, was charged with developing an annual strategic plan for autism research, which would be used to guide work done by federal agencies, both internally and in collaboration with private foundations. Singer refused to support a plan that would broadly sanction vaccine studies. “She knew that her resignation would be seen as a desertion,” says Paul Offit, chief of infectious diseases at the Children’s Hospital of Philadelphia in Pennsylvania, and now a close colleague of Singer’s and a member of the ASF’s board of directors. “It was a very, very hard thing for her to do.”

The day after she resigned, Singer spoke at the committee meeting, letting members know how she was going to vote, and why. There were two votes related to vaccine research at the meeting. The first, on whether to add the language that had circulated the previous evening, failed. The committee also voted on whether to cut two existing vaccine-research objectives from the plan. All the other members representing advocacy groups or affected families opposed removing the objectives; Singer and the federal-agency scientists did not, and the objectives remained. Autism Speaks immediately put out a press release distancing itself from Singer and withdrawing its support for federal autism-research plan.

Suzanne Wright has not contacted Singer, or replied to e-mails from her, since Singer resigned. But Singer did receive many supportive messages. “I understand your reasons completely and agree with you wholeheartedly,” wrote one supporter, Mark Krinsky, whose son, now 25, has autism. “What are your plans? Any group would be lucky to get you but maybe you should start a new one. I will volunteer.”

It was letters and phone calls such as these, says Singer, “that got me thinking about starting a new advocacy group”. She launched the ASF in March 2009.

Personal challenge

Singer, who drives a blue Honda minivan decorated with bumper stickers reading “Autism Science Foundation” and “Vaccinate your baby”, spends two days a week working from her home in Scarsdale, an upmarket northern suburb of New York. This allows her to juggle a mother’s duties with her work. One Monday afternoon, she arrives home from the office to find Lauren, now 11, downstairs finishing her homework, and Jodie, 14, upstairs with Keith Amerson, one of her therapists. Amerson, who is an expert in a leading autism therapy called applied behaviour analysis (ABA), has been working with Jodie since she was diagnosed.

Today, Jodie is sitting beside Amerson at a table, in front of two plastic plates. The yellow one has one piece of toy food on it; the green one has several. “Jodie, which one has more?” asks Amerson. Jodie points to the yellow plate.

When her mother comes in, Jodie lights up. The two bounce on the bed in Jodie’s bedroom and sing a song, that, Singer says, they have sung “a thousand times”. Jodie: “Say: ‘I love my Jodie.'” Singer: “I love my Jodie.”

But Jodie is challenging. She sleeps for as little as four hours a night. Every door and window in the house has had an alarm ever since, in the wee hours one winter morning, shoeless and clad in pyjamas, she set off down the driveway in search of an egg roll at a Chinese restaurant. Luckily, Singer was awake and stopped her.

When Amerson pushes Jodie to find the prices beside pictures of root beer and cake on a sheet of paper, and enter them in a calculator, Jodie cries “Oh no!” and runs her flapping, nervous hands through her brown pony tail. “Do you need some help?” asks Amerson. “Keith!” replies Jodie. “Say: ‘I need some help,'” counters Amerson. “I need some help,” Jodie says.

The goal of ABA therapy, says Amerson, “is to make her as independent as possible and to improve the quality of her life”. A task as quotidian as writing ‘$1.74’ legibly, with the decimal point in the right place, is a large challenge, its achievement a victory. “It’s very tough work,” he says.

Young brains

Alison Singer (right) in 1968. Her brother Steven (left) has autism, as does her daughter Jodie.Alison Singer (right) in 1968. Her brother Steven (left) has autism, as does her daughter Jodie.A. SINGER

On 8 February 2010, almost a year after it launched, the ASF awarded its first grants, splitting $180,000 between six PhD students. Singer has chosen to focus on the youngest scientists because, she says, “it fuels the pipeline for the future. You are encouraging that person to pursue autism research as opposed to research in some other disease.” The foundation boosted its funding by more than 20% this year, handing out a further six awards to graduate students and postdoctoral researchers.

Chosen by a ten-member scientific advisory board, the awards run the gamut from basic science to diagnosis and treatment. One 2011 recipient, Jill Locke at the University of Pennsylvania and the Children’s Hospital of Philadelphia, is working to translate behavioural techniques proven in the research setting to Philadelphia’s public schools. She is training school personnel to improve the social interactions between children with autism and their playground peers. Another recipient is Haley Speed, a postdoctoral fellow at the University of Texas Southwestern Medical Center in Dallas, who is building on work that she recently co-authored in Cell, describing a mouse with a mutation in the Shank3 gene, which is linked to autism in humans (M. A. Bangash et al. Cell 145, 758–772; 2011). In the past, Speed had failed to win NIH postdoctoral awards, and she believes that the riskiness of her current research — in which she hopes to find compounds that could correct the animals’ abnormal neuron-to-neuron communication and restore normal behaviour — would not help her case with conservative study sections at the biomedical agency. “The ASF had faith in us, whereas the NIH did not,” she says.

Speed adds that it inspires her to know that $10 and $20 donations from affected families are paying for her work. “On a bad day, if your equipment breaks or your experiment fails — which they all do — it gives you an extra boost as you to go pick yourself up and do it all again.”

Indeed, many donations to the ASF come in small cheques from affected families and their friends, or larger ones from the proceeds of football goal-a-thons and charity motorbike rides. (A significant amount has also come from large donors, including Offit, who has donated all the royalties from the sales of his books challenging the anti-vaccine movement to ASF — an amount he estimates in tens of thousands of dollars.) Singer does not think that her opposition to vaccine research limits the group’s ability to raise funds — far from it. She says the organization has mobilized the thousands of families who were sick of the autism story being hijacked by the vaccine hypothesis. “ASF is their voice.”

The ASF is still dwarfed by the size and reach of other organizations supporting autism research. The Simons Foundation does not fund vaccine research, but Autism Speaks spends about 2% of its budget — nearly twice as much as the ASF spent on all research this year — on studies that are relevant to vaccines, says Geri Dawson, chief science officer for Autism Speaks and a professor of psychiatry at the University of North Carolina at Chapel Hill. “We are not funding any studies that directly address whether vaccines cause autism,” says Dawson. “The evidence strongly suggests that there is not a link between autism and vaccines. What we are trying to understand through our research funding is the role of the immune system in autism, which certainly could be relevant to the question of vaccines.”

For instance, Dawson says, Autism Speaks is funding studies investigating the idea that disorders in the cellular powerhouses, mitochondria, might influence responses to immune challenges such as infection and immunization. “We are willing to leave the door open for the possibility of rare cases in which an immunization may have triggered the onset of autism symptoms due to an underlying medical or genetic condition.”

Singer calls Dawson’s words “a carefully crafted ‘big tent’ political statement designed to appeal to both sides of the issue” and an attempt “not to offend any potential donors on either side”. Her concern, she says, is that statements suggesting that the jury is still out on autism and vaccines put children “at risk for vaccine-preventable disease”.

In an e-mail, Katie Wright wrote that she “totally respects” Singer’s beliefs about Jodie. “However, Alison doesn’t live my life, doesn’t know what caused my son’s autism and wasn’t with me the night he had a febrile seizure or the day he stopped talking. It is important not to tell other parents you know better than they do about their child’s autism. We all love our kids very much, Alison and I certainly agree on that.”

The long haul

Although the world of autism research is expanding, horizons for many of those with the condition have scarcely changed. Singer’s brother, Steven, lives in a group home in Rockland County, not far from Scarsdale. Now 47, he attends a day programme and helps to deliver Meals on Wheels three mornings a week. Still, he has never spoken, and needs round-the-clock supervision. “If he had had early intervention when he was two, when his brain was more malleable, then who knows where he would be today,” says Singer, who visits him several times a year. “But I’m a big believer that you never stop trying.”

Singer is not deterred by the sometimes agonizingly slow pace of science, or by the stark fact that the genetics and aetiology research that her foundation is funding is unlikely to ever directly benefit Steven or Jodie. Singer now believes that her daughter’s autism was largely caused by genes, but genetic testing when she was first diagnosed revealed no known pathogenic deletions or duplications in her genome. Singer had Jodie retested earlier this year, after a glut of studies identified mutations implicated in autism. The tests still came up empty.



Nonetheless, Singer believes that the ASF’s research into treatment will improve the lives of people who have autism today — including Jodie. She also focuses on her other daughter, Lauren, who has already asked whether she, too, will have a child with autism.

Says Singer: “I would like to be able to answer her with: ‘If you do, we will know how to help.'” 

See Editorial page 5

Meredith Wadman is a reporter for Nature in Washington DC.



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Special issue on neuroscience: The autism enigma ""

Everything about autism spectrum disorder conspires to make it hard to understand. It takes diverse forms, from profound communication and behavioural problems to social difficulties coupled with normal language and even precocious talents. (Here, Nature will refer to them all as autism.) The prevalence of autism is rising — by some counts, steeply — but the reasons for that are unclear. Causes of the condition include a complicated mixture of genetic and environmental factors, most unknown (see page 5). Its roots lie in the development of the human brain, a process that, despite huge leaps in neuroscience, remains mysterious. So as awareness rises and parents clamour for answers, scientists can offer few certainties. Hearsay and unsubstantiated theories sometimes fill the void.

This week, Nature searches for some truths about autism. Some researchers have evidence to combat the notion that the rise in prevalence can all be explained by changes in how the condition is diagnosed (see page 22). Others are debating the idea that some scientists and engineers are themselves ‘on the spectrum’, and are at high risk of having a child with autism (see page 25). At the same time, researchers are learning that although autism is a clearly disability, certain characteristics of it could be an advantage in science (see page 33). A debunked link between vaccines and autism still clouds the public discussion, but some advocates have taken a firm stand in favour of rigorous science, and the answers it will eventually provide (see page 28). Much more content can be found at

Even before fundamental problems are solved, research is revealing better ways to support people with autism. If the condition is diagnosed early, a growing repertoire of evidence-based therapies can be applied to give children the best possible chance of living full lives. Meanwhile, the spotlight on autism is helping to reduce stigma.

The complexities that make autism hard to understand are a magnet for researchers — and this should lead to a future with less fiction and more much-needed fact. 



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Scientists and autism: When geeks meet ""


In the opening scene of The Social Network, Jesse Eisenberg portrays a cold Mark Zuckerberg getting dumped by his girlfriend, who is exasperated by the future Facebook founder’s socially oblivious and obsessive personality. Eisenberg’s Zuckerberg is the stereotypical Silicon Valley geek — brilliant with technology, pathologically bereft of social graces. Or, in the parlance of the Valley: ‘on the spectrum’.

Few scientists think that the leaders of the tech world actually have an autism spectrum disorder (ASD), which can range from the profound social, language and behavioural problems that are characteristic of autistic disorder, to the milder Asperger’s syndrome. But according to an idea that is creeping into the popular psyche, they and many others in professions such as science and engineering may display some of the characteristics of autism, and have an increased risk of having children with the full-blown disorder.

The roots of this idea can largely be traced to psychologist Simon Baron-Cohen at the University of Cambridge, UK. According to a theory he has been building over the past 15 years, the parents of autistic children, and the children themselves, have an aptitude for understanding and analysing predictable, rule-based systems — think machines, mathematics or computer programs. And the genes that endow parents with minds suited to technical tasks, he hypothesizes, could lead to autism when passed on to their children, especially when combined with a dose of similar genes from a like-minded mate1.

The notion has an intuitive plausibility. In the public mind, it meshes with the stereotype of the scientist or computer geek as smart but socially awkward. (Baron-Cohen has speculated that luminaries such as Albert Einstein and Isaac Newton had Asperger’s syndrome.) And in scientific circles, many accept that certain autistic traits — social difficulties, narrow interests, problems with communication — form a continuum across the general population, with autism at one extreme. As most experts believe that genes have an important role in autism, it’s also plausible that two parents with milder, ‘autistic-like’ traits could be more likely to have a child with autism.

It also fits at least some clinicians’ experiences. “I see deep geeks of all sorts,” says Bryna Siegel, a clinical psychologist who runs the autism clinic at the University of California, San Francisco, referring to the parents of children with autism. “They don’t make great eye contact, all their clothing is from the Intel shop, they don’t have a lot of social understanding. I do think that when these geeks marry each other, that’s bad news for the offspring.” But critics of Baron-Cohen’s theories aren’t hard to find. Autism researchers say that his work has focused primarily on a subset of people with ‘high-functioning’ autism — such as Asperger’s syndrome — who have good language capabilities and at-least average intelligence. They say that the data are insufficient to support his theories and that many experiments cry out for independent replication.

“They’re some really good hypotheses to think about, but they need to be tested,” says John Constantino, a psychiatrist at Washington University in St Louis. “There’s not a lot of data.” Some critics are also rankled by Baron-Cohen’s history of headline-grabbing theories — particularly one that autism is an ‘extreme male’ brain state. They worry that his theory about technically minded parents may be giving the public wrong ideas, including the impression that autism is linked to being a ‘geek’.

Baron-Cohen acknowledges that “there is a problem that there are too few attempts at replication” of his studies, and says that he remains “open minded about these hypotheses until there are sufficient data to evaluate them”. But he says he doesn’t see a problem with introducing theories before definitive evidence has been collected. “I would see it as a positive contribution rather than a concern that scientists move from preliminary evidence to formulate the more general theory, especially when the theory is highly testable, since this is how science advances,” he says.

Bucking the system

In the 1990s, while most research on autism focused on problems with social interaction, Baron-Cohen became fascinated by the obsessive, narrow interests and repetitive behaviours that also characterize the condition. He noticed that children with autism were drawn to things such as machines, numbers, calendars and spinning objects2. One child might memorize the technical specifications of gadgets; another would flip light switches on and off incessantly.

“The old view was that [such behaviours] were lacking in purpose, they just did it,” says Baron-Cohen. But he started seeing these eccentricities from a new perspective. “They’re figuring out how the family DVD player works, or understanding the electrical circuitry of the house. The child is doing it to understand the system.” In autism, he theorizes, the brain has an average or superior ability to understand predictable systems, or ‘hypersystemize’, coupled with an inability to empathize, or understand other people’s intentions and feelings.

Simon Baron-Cohen noticed that children with autism are drawn to 'systems' such as machines and numbers.Simon Baron-Cohen noticed that children with autism are drawn to ‘systems’ such as machines and numbers.BLAZE ALBEMARLE/EYEVINE

Baron-Cohen cites several lines of evidence in support of his theory. In a 2003 study3, for example, he found that people with autism scored highly on the ‘systemizing quotient’, a questionnaire he designed. In a survey of undergraduates at the University of Cambridge, he found that those studying mathematics were more likely to have been diagnosed with autism than were students majoring in medicine, law or social science4. And, using another questionnaire called the autism quotient, he found that students in science and maths had higher scores on measures of autistic traits than did students in the humanities and social sciences5. Baron-Cohen says that although these surveys do not measure systemizing ability directly, they demonstrate that systemizing is a trait of autism, and also part of the ‘broader autistic phenotype’ that includes some of the wider population.

Baron-Cohen’s critics, however, are sceptical of these surveys, in which subjects answer questions about themselves such as: ‘I notice patterns in things all the time’ and ‘I would rather go to a library than to a party’. “Whether those self-perceptions, as with any of our self-perceptions, are accurate is questionable,” says Francesca Happé, a cognitive neuroscientist at King’s College London.

It would be more objective, say Happé and others, to test children with and without autism on their abilities to understand systems, and then compare the scores. “Rigorous studies are still missing,” says Uta Frith, a developmental psychologist at University College London. “At the moment, he has people saying, ‘yes, I’m a person interested in details’, as opposed to actually observing them on tasks.”

Baron-Cohen says that his lab is doing such follow-up work. He says that questionnaires can be advantageous because data can be collected quickly, and that even though biases can creep in, “you do find consistent patterns”. He also points to a 2001 study6 in which he showed that children with Asperger’s syndrome can outperform typical children at figuring out how simple mechanical systems work. But critics counter that the children with Asperger’s were selected on the basis of having average or above average IQs, whereas the typical children were selected at random. Similarly, critics point out that the Cambridge students with autism are highly unusual because they function well enough to attend one of the top universities in the world.

This is a common complaint about Baron-Cohen’s work. “He’s tended to focus on very bright individuals with ASD,” says Catherine Lord, a clinical psychologist and autism researcher at Weill Cornell Medical College in New York. “A lot of the things he might say in describing those individuals are pretty irrelevant for most people with ASD.”

“I do think that when these geeks marry each other, that’s bad news for the offspring.”

Baron-Cohen acknowledges that “some of the psychological research is focused on high-functioning children with autism”, because, he says, they have the language capabilities to perform the tests. “But my thought is that it could apply across the system,” he says of the systemizing theory, to all children who have some form of the disorder.

Earlier this year, Liz Pellicano, a developmental psychologist at the Institute of Education in London, tested how a group of children with a wider range of ASD compare with a control group in figuring out a system. Her team designed a small room in which the floor was arrayed with 16 identical green lights. The children were asked to find the one light that, when pressed, would turn from green to red. The target light was on the same side of the room 80% of the time. Children with autism, including Asperger’s syndrome, were much worse at figuring out this system than the children in the control group7. “They weren’t systematic,” says Pellicano. “When they were searching, they were unbelievably haphazard.” In her view, she says, studies such as this show that Baron-Cohen’s theory “isn’t standing up to empirical tests”.

Baron-Cohen says he is not sure that Pellicano’s paradigm was testing the same sort of systemizing he describes. But, he says, he’s “glad that at least people are starting to look at systemizing”. So far, most work on the subject has come out of his lab. “I think our published studies are rigorous, but there are still too few studies into systemizing,” he says. “It is still way too early to be able to look across dozens or hundreds of studies to evaluate that theory.”

Like father, like son?

Baron-Cohen proposes that systemizing ability can be inherited — and that in information-technology (IT) enclaves such as Silicon Valley, where hypersystemizers are more likely to meet, pair off and have children, the result is a higher incidence of autism.

Back in 1997, for example, he concluded that fathers of children with autism were more than twice as likely to be engineers as were fathers of non-autistic children8. But autism researchers Christopher Jarrold and David Routh at the University of Bristol, UK, pointed out that Baron-Cohen reported the analysis of data only for engineers, not for the other occupations surveyed. After analysing the same data9, they found that fathers of children with autism were more likely to work in medicine, science and accountancy, as well as engineering, and less likely to have manual occupations. They suggested that these fathers were simply more likely to have reached a higher level of education.

Baron-Cohen says that when he reanalysed the data and controlled for education level, he found that fathers of children with autism were still more likely to be engineers, although the difference was smaller.

One of Baron-Cohen’s most recent studies comes from the town of Eindhoven, a technology hub in the Netherlands. By examining school records, he found that children living in the town were 2–4 times more likely to be diagnosed with autism than were children living in two other Dutch towns of similar size10 — evidence that he takes as support for the idea that parents who are strong systemizers could be more likely to have a child with autism. But, he says, he chose to study Eindhoven after parents contacted him about an autism epidemic there, rather than, as some researchers may prefer, comparing the prevalence of autism in randomly selected IT regions with that of non-IT regions with similar demographics. And the Eindhoven school records did not disclose parental age or level of education — both of which are positively correlated with autism diagnoses — or whether the parents worked in the IT industry.

Indeed, researchers say that several other factors could explain the seeming correlation between autism and science or engineering. A 2010 analysis of autism diagnoses in California11 did not find that autism clustered preferentially around areas rich in IT industry. Instead, it found that clusters tended to occur in areas where parents were older and educated to a higher level than were parents in surrounding areas. “Virtually all of these clusters were also clusters of higher education,” says lead author Irva Hertz-Picciotto, an epidemiologist at the University of California, Davis.

People who have progressed further in education tend to have children later in life, and at least some evidence suggests that older parents are at higher risk of having children with autism. Parents who are more educated are also more likely to be aware of the symptoms of autism and to seek a diagnosis, which can open the door to support and education services. One Silicon Valley school for children with learning disabilities costs US$30,000 per student per year, but if a child has been diagnosed with autism, the school district may pick up the tab.

In response to criticisms of his Eindhoven study, Baron-Cohen says he plans to follow up by looking at the age, occupation and other details of the parents, and that he’d also like to examine autism rates in other IT centres, such as Silicon Valley. He’s putting together a large online survey ( to gather detailed information about the general population — including age, education, occupation and hobbies — to explore whether these factors correlate with having a child with autism. He says that Hertz-Picciotto’s study didn’t support his hypothesis because it “was not designed to look at autism in IT-rich regions. What I’m doing is coming at it in a different way,” he says.

Despite the criticisms of Baron-Cohen’s experiments, most of his colleagues commend him for putting his theories forward, and many are open to the possibility that parts of them could prove correct. “He does try to address big questions that many of us would be too wimpy to take on,” says Lord.

Constantino is testing related ideas. He has developed the ‘social responsiveness scale’ — a questionnaire to measure autistic-like traits in the general population. He found hints that parents with more autistic-like traits tend to partner with each other, and that when they do, their children have even more of those traits than their parents12. Those children, however, are not more likely to be diagnosed with autism13. What is needed now, Constantino says, is a large study that determines whether having two parents with autistic-like traits is more common among people with autism than in the general population. “Those are the kind of data one needs,” he says, “rather than to infer, from an epidemiological cluster in a place where people tend to be a little nerdier, that that’s why you’ve got more autism there.”



For now, the idea that technical brilliance requires a dash of autism seems to have taken root, at least in some tech and science hubs. It’s a trend that, for Happé, provokes mixed feelings. “On the one hand, I’m glad that ‘geek chic’ has some kudos in our current society, because a lot of people with AS or ASD have a jolly tough and unpleasant life, and if people can recognize their talents a little more, I’m glad for that.”

On the other hand, she says, “a large number of children with autism have significant intellectual disabilities and no speech. For their parents to be surrounded by people spotting all these famous people and saying they have autism, it must be absolutely infuriating.” 

Lizzie Buchen is a freelance writer based in San Francisco.

  • References

    1. Baron-Cohen, S. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 30, 865-872 (2006). | Article | ISI |
    2. Baron-Cohen, S. & Wheelwright, S. Br. J. Psychiatry 175, 484-490 (1999). | Article | PubMed | ISI | ChemPort |
    3. Baron-Cohen, S., Richler, J., Bisarya, D., Gurunathan, N. & Wheelwright, S. Phil. Trans. R. Soc. Lond. B 358, 361-374 (2003). | Article | ISI |
    4. Baron-Cohen, S., Wheelwright, S., Burtenshaw, A. & Hobson, E. Hum. Nature 18, 125-131 (2007). | Article |
    5. Baron-Cohen, S., Wheelwright, S., Skinner, R., Martin, J. & Clubley, E. J. Autism Dev. Disord. 31, 5-17 (2001). | Article | PubMed | ChemPort |
    6. Baron-Cohen, S., Wheelwright, S., Spong, A., Scahill, V. & Lawson, J. J. Dev. Learn. Disord. 5, 47-78 (2001).
    7. Pellicano, E. et al. Proc. Natl Acad. Sci. USA 108, 421-426 (2011). | Article | PubMed |
    8. Baron-Cohen, S., Wheelwright, S., Stott, C., Bolton, P. & Goodyer, I. Autism 1, 153-163 (1997). | Article |
    9. Jarrold, C. & Routh, D. A. Autism 2, 281-289 (1998). | Article |
    10. Roelfsema, M. T. et al. J. Autism Dev. Disord. (2011).
    11. Van Meter, K. C. et al. Autism Res. 3, 19-29 (2010). | PubMed | ISI |
    12. Constantino, J. N. & Todd, R. D. Biol. Psychiatry 57, 655-660 (2005). | Article | PubMed | ISI |
    13. Virkud, Y. V., Todd, R. D., Abbacchi, A. M., Zhang, Y. & Constantino, J. N. Am. J. Med. Genet. B 150B, 328-334 (2009).



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Mental-health guide accused of overreach ""

  1. Corrected:

Psychologist David Elkins had modest ambitions for his petition. He and his colleagues were worried that proposed changes to an influential handbook of mental disorders could classify normal behaviours as psychological conditions, potentially leading to inappropriate treatments. So they laid out their concerns in an open letter, co-sponsored by five divisions of the American Psychological Association in Washington DC. “I thought, ‘Well, maybe we’ll get a couple or maybe 30 signatures’,” says Elkins, an emeritus professor at Pepperdine University in Malibu, California.

But the letter, posted online on 22 October (, touched a nerve. Within 10 days more than 2,800 people had signed it, many identifying themselves as mental-health professionals.

The petition targets proposed revisions to the Diagnostic and Statistical Manual of Mental Disorders (DSM), a tome used by psychiatrists, psychologists, counsellors and others worldwide to diagnose mental maladies and set research agendas. The American Psychiatric Association, based in Arlington, Virginia, plans to publish a new edition of the manual, DSM-5, in 2013. The association has declined to comment on Elkins’s petition.

Psychiatrist Allen Frances, who was the chief architect of DSM-IV and is an outspoken critic of its successor, has dubbed the open letter a “buyer’s revolt”. “I think the petition is the last best hope to influence the DSM-5 from the outside,” says Frances, an emeritus professor at Duke University School of Medicine in Durham, North Carolina.

Elkins’s petition is not the first to raise concerns that the DSM-5 proposals could overreach. In June, the British Psychological Society, based in Leicester, issued a critique that highlighted, for example, the proposed addition of ‘attenuated psychosis syndrome’. The society argued that this could be used “to stigmatize eccentric people”.

“There should be a black box warning about how child bipolar disorder is being overdiagnosed.”

Elkins and his colleagues have complained about other proposals, such as the elimination of a ‘bereavement exclusion’ in the diagnosis of major depression. The previous edition of the manual recommended that the condition not be diagnosed in people grieving the death of a loved one within the previous two months. The revisions shorten this to two weeks, a change that troubles psychiatrist Ramin Mojtabai of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. Categorizing these patients as having depression could boost the use of medications when psycho­therapy may be the better treatment, he says.

Efforts to tighten loose definitions of attention deficit and hyperactivity disorder (ADHD) and bipolar disorder in children have also proved controversial. In response to worries that inexact criteria may have contributed to a surge in diagnoses of these conditions since the 1990s, the DSM-5 task force has proposed a syndrome called ‘disruptive mood dysregulation disorder’, which would provide an alternative to labelling a child as bipolar or having ADHD. But Frances says that is not enough. “There should be a black box warning about how child bipolar disorder is being overdiagnosed,” he says. “Instead, they’ve created a new disorder.”



Field trials of the proposed DSM-5 criteria have been completed and investigators plan to publish the results. Helena Kraemer, a statistician and emeritus professor at Stanford University School of Medicine in Palo Alto, California, who is on the DSM-5 committee, says that results from trials of some criteria will indicate whether they generate more frequent diagnoses.

But Mojtabai cautions that trial results may not reflect what will happen when DSM-5 is published. “Any trial is artificial,” he says. “The clinicians in these trials have intensive training, but people who will use this manual in clinical practice will not receive that level of instruction.” 


This story originally stated that the DSM-5 petition was co-sponsored by the American Psychological Association. In fact, it was co-sponsored by five divisions of the association, not the association as a whole. The text has been changed to reflect this.



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