What’s Wrong with Moral Foundations Theory, and How to get Moral Psychology Right

By Oliver Scott Curry

March 26, 2019

Original link:  http://behavioralscientist.org/whats-wrong-with-moral-foundations-theory-and-how-to-get-moral-psychology-right/?fbclid=IwAR2FMsH20-sGW1WIoirXrNG8nmuw1miG4_o7rtigArM_l7i4tSe6Uw-_25c

 

Image: Antonio Marín Segovia/Flickr

Once the exclusive preserve of philosophy and theology, the study of morality has now become a thriving interdisciplinary endeavor, encompassing research in evolutionary theory, genetics, biology, animal behavior, psychology, and anthropology. The emerging consensus is that there is nothing mysterious about morality; it is merely a collection of biological and cultural traits that promote cooperation.

Best known among these accounts is Jonathan Haidt’s Moral Foundations Theory (MFT). According to MFT: “Moral systems are interlocking sets of values, virtues, norms, practices, identities, institutions, technologies, and evolved psychological mechanisms that work together to suppress or regulate selfishness and make cooperative social life possible.” And MFT proceeds to argue that, because humans face multiple social problems, they have multiple moral values—they rely on multiple “foundations” when making moral decisions. These foundations include: Care, Fairness, Loyalty, Authority, and Purity.

• Care: “The suffering of others, including virtues of caring and compassion.”
• Fairness: “Unfair treatment, cheating, and more abstract notions of justice and rights.”
• Loyalty: The “obligations of group membership” including “self-sacrifice, and vigilance against betrayal.”
• Authority: “Social order and the obligations of hierarchical relationships, such as obedience, respect, and the fulfillment of role-based duties.”
• Purity: “Physical and spiritual contagion, including virtues of chastity, wholesomeness, and control of desires.”

These moral foundations have been operationalized, and measured, by the Moral Foundations Questionnaire (MFQ; you can complete it here).

MFT and the questionnaire have had an enormous impact on moral psychology. The central papers have been cited hundreds of times. And there is now a huge literature applying MFT to bioethics, charity, environmentalism, psychopathy, religion, and especially politics. However, MFT has some serious problems, both theoretical and empirical.

The main theoretical problem is that MFT’s list of foundations is not based on any particular theory of cooperation, or on any explicit theory at all. Indeed, Haidt, has explicitly argued against taking what he calls an “a priori or principled” approach to moral psychology, and instead has advocated taking an “ad hoc” approach. The shortcomings of this ad hoc approach, however, are all too plain to see.

First, MFT’s list of foundations has critical omissions. Despite claiming to be an evolutionary-cooperative account of morality, MFT fails to include the four most well-established types of evolved cooperation: kin altruism, reciprocal altruism, competitive altruism, and respect for prior possession.

• Kin altruism has no dedicated foundation in MFT. Although MFT argues that Care originally motivated investment in offspring, it is now applied to nonkin; and MFT treats “family” as just another type of “group.” The questionnaire (MFQ) does have two items pertaining to family, but they appear under Fairness and Loyalty, not Care.
• Reciprocal altruism has no dedicated foundation in MFT. Instead, MFT conflates reciprocity—a solution to iterated prisoners’ dilemmas—with fairness—a solution to bargaining problems. And the MFQ has no items pertaining to reciprocity.
• Competitive altruism—that is, costly signals of status, such as bravery or generosity—has no dedicated foundation in MFT, and no items in the MFQ.
• Respect for prior possession—that is, property rights and the prohibition of theft—has no dedicated foundation in MFT. The MFQ’s only mention of property occurs in an item about inheritance, under Fairness.

Second, in addition to these omissions, MFT includes two foundations that are not distinct types of evolved cooperation: Care and Purity.

• Care—like “altruism” or “benevolence”—is a generic category, not a specific type of cooperation. It doesn’t distinguish between the various distinct types of cooperation—kin altruism, mutualism, reciprocal altruism, competitive altruism and their corresponding psychological mechanisms—all of which involve caring for different people (including family, friends, strangers) for different reasons.
• Purity is supposed to stem from the need to avoid “people w/ diseases, parasites [&] waste products.” But “avoiding pathogens” is not itself a cooperative problem, any more than, say, “avoiding predators.” And, indeed, MFT offers no connection between purity and cooperation. On the contrary, Purity is described as an “odd corner” of morality because it is not “concerned with how we treat other people.” Hence, categorizing Purity as a moral foundation is anomalous.

Thus, MFT’s theory-free approach results in egregious errors of omission, conflation, and commission. It misses some candidate moral domains, combines others, and includes noncooperative domains. Most egregiously, the lack of theory means that MFT cannot rectify these errors; it cannot make principled predictions about what (other) foundations there might be, thus it cannot make progress toward a cumulative science of morality.

MFT also has empirical problems. The main problem is that MFT’s five-factor model of morality has not been well supported by studies using the MFQ. Some of the original studies, as well as replications in Italy, New Zealand, Korea, Sweden, and Turkey, and also a 27 country study using the short-form MFQ, have found that MFT’s five-factor model falls short of the conventionally acceptable degree of model fit (CFIs less than 0.90). These studies typically find that a two-factor model—“Care-Fairness” and “Loyalty-Authority-Purity”—is a better fit. And so despite MFT promising five moral domains, the MFQ typically delivers only two. The MFQ does not distinguish domains dedicated to Fairness, Loyalty, or Authority; nor does it establish that Care and Purity are distinct moral domains. Simply put, it does not establish that there are five moral foundations. Other research has taken issue with specific foundations, especially Purity and the link between disgust and morality; but that’s a story for another time.

To their credit, proponents of MFT acknowledge these problems. They accept that the original list of foundations was “arbitrary,” based on a limited review of only “five books and articles,” and never intended to be “exhaustive.” And they have positively encouraged research that could “demonstrate the existence of an additional foundation, or show that any of the current five foundations should be merged or eliminated.”

And so that is what my colleagues and I have done. But we have not done so by making yet more “ad hoc” suggestions. We have gone back to first principles, to the theory that can provide a rigorous, systematic foundation for a cooperative theory of morality—the mathematics of cooperation, the theory of non-zero-sum games. We call this approach Morality-as-Cooperation (MAC).

According to MAC, morality consists of a collection of biological and cultural solutions to the problems of cooperation recurrent in human social life. For 50 million years humans and their ancestors have lived in social groups. During this time, they faced a range of different problems of cooperation, and they evolved and invented a range of different solutions to them. Together, these biological and cultural mechanisms provide the motivation for cooperative behavior; and they provide the criteria by which we evaluate the behavior of others. And, according to MAC, it is precisely this collection of cooperative traits—these instincts, intuitions, and institutions—that constitute human morality.

Which problems of cooperation do humans face? And how are they solved? That’s where game theory comes in. Game theory makes a principled distinction between zero-sum and non-zero-sum games. Zero-sum games are competitive interactions that have a winner and a loser; one’s gain is another’s loss. Non-zero-sum games are cooperative interactions that can have two winners; they are win-win situations. Game theory also distinguishes between different types of non-zero-sum games and the strategies used to play them. Thus, it delineates mathematically distinct types of cooperation.

A review of this literature suggests that there are (at least) seven well established types of cooperation: (1) the allocation of resources to kin; (2) coordination to mutual advantage; (3) social exchange; and conflict resolution through contests featuring (4) hawkish displays of dominance and (5) dove-ish displays of submission; (6) division of disputed resources; and (7) recognition of prior possession.

In my research, I have shown how each of these types of cooperation can be used to identify and explain a distinct type of morality.

(1) Kin selection explains why we feel a special duty of care for our families, and why we abhor incest. (2) Mutualism explains why we form groups and coalitions (there is strength and safety in numbers), and hence why we value unity, solidarity, and loyalty. (3) Social exchange explains why we trust others, reciprocate favors, feel gratitude and guilt, make amends, and forgive. And conflict resolution explains why we (4) engage in costly displays of prowess such as bravery and generosity, why we (5) express humility and defer to our superiors, why we (6) divide disputed resources fairly and equitably, and why we (7) respect others’ property and refrain from stealing.

Our research has shown that examples of these seven types of cooperative behavior—help your family, help your group, return favors, be brave, defer to your superiors, be fair, and respect others’ property—are considered morally good all around the world and are probably cross-cultural moral universals.

And we have used MAC’s framework to develop a new measure of moral values that promises, and delivers, seven moral domains: (1) Family, (2) Group, (3) Reciprocity, (4) Heroism, (5) Deference, (6) Fairness, and (7) Property. This new Morality-as-Cooperation Questionnaire (MAC-Q) introduces the four moral domains that were missing from MFT: Family, Reciprocity, Heroism, Property. And unlike the MFQ, it distinguishes Family from Group (Loyalty), Group (Loyalty) from Deference (Authority), and Reciprocity from Fairness.

So this principled approach to morality, grounded firmly in the underlying logic of cooperation, outperforms an unprincipled approach. MAC explains more types of morality than MFT. It can generate novel principled predictions about morality’s content and structure—predictions that have thus far been supported by psychological and anthropological research. And it leads to a more comprehensive and reliable measure of moral values.

Equipped with this new map of the moral landscape, we can now examine familiar ground in greater detail and survey previously unexplored territory. We can take a fresh look at the genetic basis, and the psychological architecture, of morality. We can reassess the relationship between morals and politics. And we can investigate how and why moral values vary around the world. Above all, by using a theory to generate new testable predictions, we can pave the way for a genuine science of morality.

Oliver Scott Curry

Oliver Scott Curry is a senior researcher at the Institute of Cognitive and Evolutionary Anthropology, University of Oxford. His research investigates the nature, content, and structure of human morality, using a range of techniques from philosophy, experimental and social psychology, and comparative anthropology.

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Understanding gene interactions holds key to personalized medicine

by University of Toronto

March 25, 2019 

Original link: https://medicalxpress.com/news/2019-03-gene-interactions-key-personalized-medicine.html?fbclid=IwAR3MxlnKkFlr5XNwwR0QYkxqgSaz0kU2-k4__w-suZUSBH34Ivc9HJjbQFk

When the Human Genome Project was completed, in 2003, it opened the door to a radical new idea of health—that of personalized medicine, in which disease risk and appropriate treatment would be gleaned from one's genetic makeup. As more people had their genomes sequenced, disease-related genes would start coming into view— and while this is true in many ways, things also turned out to be much more complicated.

Sixteen years on, tens of thousands of people have had their genomes sequenced yet it remains a major challenge to infer future health from genome information. Part of the reason may be that genes interact with each other to modify trait inheritance in ways that aren't totally clear, write Donnelly Centre researchers in an invited perspective for the leading biomedical journal Cell.

"All the genome sequencing data is highlighting the complexity of inheritance for the human genetics community," says Brenda Andrews, University Professor and Director of U of T's Donnelly Centre for Cellular and Biomolecular Research and a senior co-author, whose lab studies interactions between genes. "The simple idea of a single gene leading to a single disease is more likely to be an exception than a rule," she says.

Andrews and Charles Boone, who is also a senior co-author, are professors in U of T's Donnelly Centre and the Department of Molecular Genetics, as well as Senior Fellows of the Genetic Networks program at the Canadian Institute for Advanced Research, which Boone co-directs.

Genome wide association studies, or GWAS, which scan the genomes of patient populations and compare them to healthy controls, have unearthed thousands of mutations, or genetic variants, that are more prevalent in disease. Most variants are found in common diseases that affect large swathes of the world's population but their effects can be small and hard to see. Instead of there being a single gene for heart disease or schizophrenia, for example, there may be many combinations of subtle genetic changes scattered across the genome that tune up or down a person's susceptibility to these diseases.

Vast genetic diversity in the human population further influences trait inheritance while environmental effects, such as diet and upbringing, further complicate matters.

In some cases, a single gene variant can be extremely potent and cause a disease, as seen in cystic fibrosis, heamophilia and other inherited disorders. But even two people with the same disease variant can experience a wildly different disease severity which, presently, cannot be gleaned from their genomes. Even more astonishing, sequencing studies have identified people who carry damaging mutations but remain perfectly healthy, presumably protected by other, as yet unknown gene variants within their genomes.

"It would be a simpler problem if one particular mutation resulted in Disease X all of the time, but that's often not the case," says Michael Costanzo, Senior Research Associate in Boone's lab and one of the authors on the paper. "To understand the effect of combinations of variants is really difficult. We suspect it's particular sets of mutations that really impact what the disease outcome is going to be in a personal genome" says Costanzo. "How genes interact with each other is important and, given our current understanding of gene-gene interactions, it's not a problem that's easily solved by reading individual genome sequences."

It's a numbers game as most genome analysis methods lack the statistical power to confidently uncover multiple genes behind a disease. An often-cited calculation, by researchers at the Broad Institute in Boston, states that to identify a single pair of genes underlying a disease, on the order of half a million patients would have to have their genomes sequenced, with another half a million of healthy people as controls. "If most genetic diseases involve gene combinations, collecting enough patient data to find these interactions is a huge challenge," says Costanzo.

Genetic interactions—what are they and how can they be identified?

"The concept of genetic interaction is simple, but the physiological repercussions can be profound," write the authors. Two genes are said to interact if a combined outcome of their defects is bigger or lesser than expected from their individual outcomes. For example, a person carrying a mutation in either gene A or in gene B can be healthy, but if both A and B don't work, disease occurs.

Research in simple model organisms—most notably yeast—has mapped genome-wide genetic interactions revealing how thousands of genes organize into functional groups within a network. From this, basic principles emerged, allowing researchers to predict a gene's function and its relative importance for the cell's health based on its position in the network. Studies also revealed the identity of so-called "modifier genes" which can suppress the effect of damaging mutations and how genetic background influences trait inheritance.

These types of studies rest on the researchers' ability to switch off genes in precise combinations to find the ones that work together. For human genes, however, such tools did not exist until very recently.

That's all changed now thanks to the gene editing tool CRISPR with which human genes can be turned off in any combination with ease. Although no genome-wide map is yet available, early work indicates that the same principles uncovered in model organisms also apply to human genes. This is already helping reveal function of the less studied human genes and how they relate to disease. And with new computational approaches, it is becoming possible to integrate findings from model organisms with incoming human data to achieve an emerging glimpse of more meaningful insights about health from genome information.

Genetic interactions and cancer therapy

Freed from normal checks and balances, cancer cells stockpile mutations in their genomes and this sets them apart from healthy cells in a way that can be exploited for therapy. Knowing how genes interact in cancer holds promise for the development of selective drugs that kill only sick cells and leave healthy ones unharmed.

"Cancer is a genetic disease and ultimately the genetic wiring of a cancer cell is a product of mutations that occur its genome and we want to understand that," says Jason Moffat, a co-author on the paper and a professor of molecular genetics in the Donnelly Centre whose lab uses CRISPR to map genetic interactions in cancer cells. "With CRISPR, we can start to systematically map how genes interact in cancer cell lines in a similar fashion to how geneticists have mapped genetic interactions in yeast," he says.

This work has the potential to reveal distinct drug targets for different forms of disease. The goal is to find a drug that synergizes with a mutation that's only found in a type of cancer. The drug would then kill sick cells more precisely and with fewer side effects than chemotherapy or radiotherapy.

The knowledge of genetic interactions will also help shed light on why so many approved cancer drugs only work in some patients and not others.

"We can't think about genes in isolation anymore," says Boone. "We have to start looking at variants of multiple genes as a major component of genetic disease, because those combinations are going to be different for different people and these specific combinations may not only profoundly affect disease susceptibility, but they will likely dictate new personalized therapies."

Causes of autism

From Wikipedia, the free encyclopedia

This diagram shows the brain sections and how autism relates to them.

 

Many causes of autism have been proposed, but understanding of the theory of causation of autism and the other autism spectrum disorders (ASD) is incomplete. Research indicates that genetic factors predominate. The heritability of autism, however, is complex, and it is typically unclear which genes are responsible. In rare cases, autism is strongly associated with agents that cause birth defects. Many other causes have been proposed, such as childhood immunizations, but numerous epidemiological studies have shown no scientific evidence supporting any link between vaccinations and autism.

Related disorders

Autism involves atypical brain development which often becomes apparent in behavior and social development before a child is three years old. It can be characterized by impairments in social interaction and communication, as well as restricted interests and stereotyped behavior, and the characterization is independent of any underlying neurological defects. Other characteristics include repetitive-like tasks seen in their behavior and sensory interests. This article uses the terms autism and ASD to denote classical autism and the wider dispersion of symptoms and manifestations of autism, respectively. 

Autism's theory of causation is incomplete. It has long been presumed that there is a common cause at the genetic, cognitive, and neural levels for autism's characteristic triad of symptoms. However, there is increasing suspicion among researchers that autism does not have a single cause, but is instead a complex disorder with a set of core aspects that have distinct causes. Different underlying brain dysfunctions have been hypothesized to result in the common symptoms of autism, just as completely different brain problems result in intellectual disability. The terms autism or ASDs capture the wide range of disease processes at work. Although these distinct causes have been hypothesized to often co-occur, it has also been suggested that the correlation between the causes has been exaggerated. The number of people known to have autism has increased dramatically since the 1980s, at least partly due to changes in diagnostic practice. It is unknown whether prevalence has increased as well.

The consensus among mainstream autism researchers is that genetic factors predominate. Environmental factors that have been claimed to contribute to autism or exacerbate its symptoms, or that may be important to consider in future research, include certain foods, infectious disease, heavy metals, solvents, diesel exhaust, PCBs, phthalates and phenols used in plastic products, pesticides, brominated flame retardants, alcohol, smoking, illicit drugs, and vaccines. Among these factors, vaccines have attracted much attention, as parents may first become aware of autistic symptoms in their child around the time of a routine vaccination, and parental concern about vaccines has led to a decreasing uptake of childhood immunizations and an increasing likelihood of measles outbreaks. However, there is overwhelming scientific evidence showing no causal association between the measles-mumps-rubella (MMR) vaccine and autism, and there is no scientific evidence that the vaccine preservative thiomersal causes autism.

Genetics

Genetic factors may be the most significant cause for autism spectrum disorders. Early studies of twins had estimated heritability to be over 90%, meaning that genetics explains over 90% of whether a child will develop autism. However, this may be an overestimation, as new twin studies estimate the heritability at between 60–90%. Many of the non-autistic co-twins had learning or social disabilities. For adult siblings the risk for having one or more features of the broader autism phenotype might be as high as 30%.

However, in spite of the strong heritability, most cases of ASD occur sporadically with no recent evidence of family history. It has been hypothesized that spontaneous de novo mutations in the father's sperm or mother's egg contribute to the likelihood of developing autism. There are two lines of evidence that support this hypothesis. First, individuals with autism have significantly reduced fecundity, they are 20 times less likely to have children than average, thus curtailing the persistence of mutations in ASD genes over multiple generations in a family. Second, the likelihood of having a child develop autism increases with advancing paternal age, and mutations in sperm gradually accumulate throughout a man's life.

The first genes to be definitively shown to contribute to risk for autism were found in the early 1990s by researchers looking at gender-specific forms of autism caused by mutations on the X chromosome. An expansion of the CGG trinucleotide repeat in the promoter of the gene FMR1 in boys causes fragile X syndrome, and at least 20% of boys with this mutation have behaviors consistent with autism spectrum disorder. Mutations that inactivate the gene MECP2 cause Rett syndrome, which is associated with autistic behaviors in girls, and in boys the mutation is embryonic lethal.

Besides these early examples, the role of de novo mutations in ASD first became evident when DNA microarray technologies reached sufficient resolution to allow the detection of copy number variation (CNV) in the human genome. CNVs are the most common type of structural variation in the genome, consisting of deletions and duplications of DNA that range in size from a kilobase to a few megabases. Microarray analysis has shown that de novo CNVs occur at a significantly higher rate in sporadic cases of autism as compared to the rate in their typically developing siblings and unrelated controls. A series of studies have shown that gene disrupting de novo CNVs occur approximately four times more frequently in ASD than in controls and contribute to approximately 5–10% of cases. Based on these studies, there are predicted to be 130–234 ASD-related CNV loci. The first whole genome sequencing study to comprehensively catalog de novo structural variation at a much higher resolution than DNA microarray studies has shown that the mutation rate is approximately 20% and not elevated in autism compared to sibling controls. However, structural variants in individuals with autism are much larger and four times more likely to disrupt genes, mirroring findings from CNV studies.

CNV studies were closely followed by exome sequencing studies, which sequence the 1–2% of the genome that codes for proteins (the "exome"). These studies found that de novo gene inactivating mutations were observed in approximately 20% of individuals with autism, compared to 10% of unaffected siblings, suggesting the etiology of ASD is driven by these mutations in around 10% of cases. There are predicted to be 350-450 genes that significantly increase susceptibility to ASDs when impacted by inactivating de novo mutations. A further 12% of cases are predicted to be caused by protein altering missense mutations that change an amino acid but do not inactivate a gene. Therefore approximately 30% of individuals with autism have a spontaneous de novo large CNV that deletes or duplicates genes, or mutation that changes the amino acid code of an individual gene. A further 5–10% of cases have inherited structural variation at loci known to be associated with autism, and these known structural variants may arise de novo in the parents of affected children.

Tens of genes and CNVs have been definitively identified based on the observation of recurrent mutations in different individuals, and suggestive evidence has been found for over 100 others. The Simons Foundation Autism Research Initiative (SFARI) details the evidence for each genetic locus associated with autism.

These early gene and CNV findings have shown that the cognitive and behavioral features associated with each of the underlying mutations is variable. Each mutation is itself associated with a variety of clinical diagnoses, and can also be found in a small percentage of individuals with no clinical diagnosis. Thus the genetic disorders that comprise autism are not autism-specific. The mutations themselves are characterized by considerable variability in clinical outcome and typically only a subset of mutation carriers meet criteria for autism. This variable expressivity results in different individuals with the same mutation varying considerably in the severity of their observed particular trait.

The conclusion of these recent studies of de novo mutation is that the spectrum of autism is breaking up into quanta of individual disorders defined by genetics.

One gene that has been linked to autism is SHANK2. Mutations in this gene act in a dominant fashion. Mutations in this gene appear to cause hyperconnectivity between the neurons.

Epigenetics

Epigenetic mechanisms may increase the risk of autism. Epigenetic changes occur as a result not of DNA sequence changes but of chromosomal histone modification or modification of the DNA bases. Such modifications are known to be affected by environmental factors, including nutrition, drugs, and mental stress. Interest has been expressed in imprinted regions on chromosomes 15q and 7q.

Prenatal environment

The risk of autism is associated with several prenatal risk factors, including advanced age in either parent, diabetes, bleeding, and use of psychiatric drugs in the mother during pregnancy. Autism has been linked to birth defect agents acting during the first eight weeks from conception, though these cases are rare.

Infectious processes

Prenatal viral infection has been called the principal non-genetic cause of autism. Prenatal exposure to rubella or cytomegalovirus activates the mother's immune response and may greatly increase the risk for autism in mice. Congenital rubella syndrome is the most convincing environmental cause of autism. Infection-associated immunological events in early pregnancy may affect neural development more than infections in late pregnancy, not only for autism, but also for psychiatric disorders of presumed neurodevelopmental origin, notably schizophrenia.

Environmental agents

Teratogens are environmental agents that cause birth defects. Some agents that are theorized to cause birth defects have also been suggested as potential autism risk factors, although there is little to no scientific evidence to back such claims. These include exposure of the embryo to valproic acid, paracetamol, thalidomide or misoprostol. These cases are rare. Questions have also been raised whether ethanol (grain alcohol) increases autism risk, as part of fetal alcohol syndrome or alcohol-related birth defects. All known teratogens appear to act during the first eight weeks from conception, and though this does not exclude the possibility that autism can be initiated or affected later, it is strong evidence that autism arises very early in development.

Autoimmune and inflammatory diseases

Maternal inflammatory and autoimmune diseases can damage embryonic and fetal tissues, aggravating a genetic problem or damaging the nervous system.

Other maternal conditions

Thyroid problems that lead to thyroxine deficiency in the mother in weeks 8–12 of pregnancy have been postulated to produce changes in the fetal brain leading to autism. Thyroxine deficiencies can be caused by inadequate iodine in the diet, and by environmental agents that interfere with iodine uptake or act against thyroid hormones. Possible environmental agents include flavonoids in food, tobacco smoke, and most herbicides. This hypothesis has not been tested.

Diabetes in the mother during pregnancy is a significant risk factor for autism; a 2009 meta-analysis found that gestational diabetes was associated with a twofold increased risk. A 2014 review also found that maternal diabetes was significantly associated with an increased risk of ASD. Although diabetes causes metabolic and hormonal abnormalities and oxidative stress, no biological mechanism is known for the association between gestational diabetes and autism risk.

Maternal obesity during pregnancy may also increase the risk of autism, although further study is needed.

Maternal malnutrition during preconception and pregnancy influences fetal neurodevelopment. Intrauterine growth restriction is associated with ASD, in both term and preterm infants.

Other in utero

It has been hypothesized that folic acid taken during pregnancy could play a role in reducing cases of autism by modulating gene expression through an epigenetic mechanism. This hypothesis is supported by multiple studies.

Prenatal stress, consisting of exposure to life events or environmental factors that distress an expectant mother, has been hypothesized to contribute to autism, possibly as part of a gene-environment interaction. Autism has been reported to be associated with prenatal stress both with retrospective studies that examined stressors such as job loss and family discord, and with natural experiments involving prenatal exposure to storms; animal studies have reported that prenatal stress can disrupt brain development and produce behaviors resembling symptoms of autism. However, other studies have cast doubts on this association, notably population based studies in England and Sweden finding no link between stressful life events and ASD.

The fetal testosterone theory hypothesizes that higher levels of testosterone in the amniotic fluid of mothers pushes brain development towards improved ability to see patterns and analyze complex systems while diminishing communication and empathy, emphasizing "male" traits over "female", or in E-S theory terminology, emphasizing "systemizing" over "empathizing". One project has published several reports suggesting that high levels of fetal testosterone could produce behaviors relevant to those seen in autism.

Based in part on animal studies, diagnostic ultrasounds administered during pregnancy have been hypothesized to increase the child's risk of autism. This hypothesis is not supported by independently published research, and examination of children whose mothers received an ultrasound has failed to find evidence of harmful effects.

Some research suggests that maternal exposure to selective serotonin reuptake inhibitors during pregnancy is associated with an increased risk of autism, but it remains unclear whether there is a causal link between the two. There is evidence, for example, that this association may be an artifact of confounding by maternal mental illness.

Perinatal environment

Autism is associated with some perinatal and obstetric conditions. A 2007 review of risk factors found associated obstetric conditions that included low birth weight and gestation duration, and hypoxia during childbirth. This association does not demonstrate a causal relationship. As a result, an underlying cause could explain both autism and these associated conditions. There is growing evidence that perinatal exposure to air pollution may be a risk factor for autism, although this evidence suffers from methodological limitations, including a small number of studies and failure to control for potential confounding factors.

Postnatal environment

A wide variety of postnatal contributors to autism have been proposed, including gastrointestinal or immune system abnormalities, allergies, and exposure of children to drugs, vaccines, infection, certain foods, or heavy metals. The evidence for these risk factors is anecdotal and has not been confirmed by reliable studies.

Amygdala neurons

This theory hypothesizes that an early developmental failure involving the amygdala cascades on the development of cortical areas that mediate social perception in the visual domain. The fusiform face area of the ventral stream is implicated. The idea is that it is involved in social knowledge and social cognition, and that the deficits in this network are instrumental in causing autism.

Autoimmune disease

This theory hypothesizes that autoantibodies that target the brain or elements of brain metabolism may cause or exacerbate autism. It is related to the maternal infection theory, except that it postulates that the effect is caused by the individual's own antibodies, possibly due to an environmental trigger after birth. It is also related to several other hypothesized causes; for example, viral infection has been hypothesized to cause autism via an autoimmune mechanism.

Interactions between the immune system and the nervous system begin early during embryogenesis, and successful neurodevelopment depends on a balanced immune response. It is possible that aberrant immune activity during critical periods of neurodevelopment is part of the mechanism of some forms of ASD. A small percentage of autism cases are associated with infection, usually before birth. Results from immune studies have been contradictory. Some abnormalities have been found in specific subgroups, and some of these have been replicated. It is not known whether these abnormalities are relevant to the pathology of autism, for example, by infection or autoimmunity, or whether they are secondary to the disease processes. As autoantibodies are found in diseases other than ASD, and are not always present in ASD, the relationship between immune disturbances and autism remains unclear and controversial. A 2015 systematic review and meta-analysis found that children with a family history of autoimmune diseases were at a greater risk of autism compared to children without such a history.

When an underlying maternal autoimmune disease is present, antibodies circulating to the fetus could contribute to the development of autism spectrum disorders.

Gastrointestinal connection

Gastrointestinal problems are one of the most commonly associated medical disorders in people with autism. These are linked to greater social impairment, irritability, behavior and sleep problems, language impairments and mood changes, so the theory that they are an overlap syndrome has been postulated. Studies indicate that gastrointestinal inflammation, immunoglobulin E-mediated or cell-mediated food allergies, gluten-related disorders (celiac disease, wheat allergy, non-celiac gluten sensitivity), visceral hypersensitivity, dysautonomia and gastroesophageal reflux are the mechanisms that possibly link both.

A 2016 review concludes that enteric nervous system abnormalities might play a role in several neurological disorders, including autism. Neural connections and the immune system are a pathway that may allow diseases originated in the intestine to spread to the brain. A 2018 review suggests that the frequent association of gastrointestinal disorders and autism is due to abnormalities of the gut–brain axis.

The "leaky gut" hypothesis is popular among parents of children with autism. It is based on the idea that defects in the intestinal barrier produce an excessive increase of the intestinal permeability, allowing substances present in the intestine, including bacteria, environmental toxins and food antigens, to pass into the blood. The data supporting this theory are limited and contradictory, since both increased intestinal permeability and normal permeability have been documented in people with autism. Studies with mice provide some support to this theory and suggest the importance of intestinal flora, demonstrating that the normalization of the intestinal barrier was associated with an improvement in some of the ASD-like behaviours. Studies on subgroups of people with ASD showed the presence of high plasma levels of zonulin, a protein that regulates permeability opening the "pores" of the intestinal wall, as well as intestinal dysbiosis (reduced levels of Bifidobacteria and increased abundance of Akkermansia muciniphila, Escherichia coli, Clostridia and Candida fungi) that promotes the production of proinflammatory cytokines, all of which produces excessive intestinal permeability. This allows passage of bacterial endotoxins from the gut into the bloodstream, stimulating liver cells to secrete tumor necrosis factor alpha (TNFα), which modulates blood–brain barrier permeability. Studies on ASD people showed that TNFα cascades produce proinflammatory cytokines, leading to peripheral inflammation and activation of microglia in the brain, which indicates neuroinflammation. In addition, neuroactive opioid peptides from digested foods have been shown to leak into the bloodstream and permeate the blood–brain barrier, influencing neural cells and causing autistic symptoms.

After a preliminary 1998 study of three children with ASD treated with secretin infusion reported improved GI function and dramatic improvement in behavior, many parents sought secretin treatment and a black market for the hormone developed quickly. Later studies found secretin clearly ineffective in treating autism.

Endogenous opiate precursor theory

In 1979, Jaak Panksepp proposed a connection between autism and opiates, noting that injections of minute quantities of opiates in young laboratory animals induce symptoms similar to those observed among autistic children. The possibility of a relationship between autism and the consumption of gluten and casein was first articulated by Kalle Reichelt in 1991.

Opiate theory hypothesizes that autism is the result of a metabolic disorder in which opioid peptides gliadorphin (aka gluteomorphin) and casomorphin, produced through metabolism of gluten (present in wheat and related cereals) and casein (present in dairy products), pass through an abnormally permeable intestinal wall and then proceed to exert an effect on neurotransmission through binding with opioid receptors. It has been postulated that the resulting excess of opioids affects brain maturation, and causes autistic symptoms, including behavioural difficulties, attention problems, and alterations in communicative capacity and social and cognitive functioning.

Although high levels of these opioids are eliminated in the urine, it has been suggested that a small part of them cross into the brain causing interference of signal transmission and disruption of normal activity. Three studies have reported that urine samples of people with autism show an increased 24-hour peptide excretion. A study with a control group found no appreciable differences in opioid levels in urine samples of people with autism compared to controls. Two studies showed an increased opioid levels in cerebrospinal fluid of people with autism.

The theory further states that removing opiate precursors from a child's diet may allow time for these behaviors to cease, and neurological development in very young children to resume normally. As of 2014 there is no good evidence that a gluten-free diet is of benefit as a standard treatment for autism. Problems observed in studies carried out include the suspicion that there were transgressions of the diet because the participants asked for food containing gluten or casein to siblings and peers; and the lack of a washout period, that could diminish the effectiveness of the treatment if gluten or casein peptides have a long term residual effect, which is especially relevant in studies of short duration. In the subset of people who have gluten sensitivity there is limited evidence that suggests that a gluten-free diet may improve some autistic behaviors.

Lack of vitamin D

The hypothesis that vitamin D deficiency has a role in autism is biologically plausible, but not researched.

Lead

Lead poisoning has been suggested as a possible risk factor for autism, as the lead blood levels of autistic children has been reported to be significantly higher than typical. The atypical eating behaviors of autistic children, along with habitual mouthing and pica, make it hard to determine whether increased lead levels are a cause or a consequence of autism.

Locus coeruleus–noradrenergic system

This theory hypothesizes that autistic behaviors depend at least in part on a developmental dysregulation that results in impaired function of the locus coeruleus–noradrenergic (LC-NA) system. The LC-NA system is heavily involved in arousal and attention; for example, it is related to the brain's acquisition and use of environmental cues.

Mercury

This theory hypothesizes that autism is associated with mercury poisoning, based on perceived similarity of symptoms and reports of mercury or its biomarkers in some autistic children. This view has gained little traction in the scientific community as the typical symptoms of mercury toxicity are significantly different from symptoms seen in autism. The principal source of human exposure to organic mercury is via fish consumption and for inorganic mercury is dental amalgams. The evidence so far is indirect for the association between autism and mercury exposure after birth, as no direct test has been reported, and there is no evidence of an association between autism and postnatal exposure to any neurotoxicant. A meta-analysis published in 2007 concluded that there was no link between mercury and autism.

Oxidative stress

This theory hypothesizes that toxicity and oxidative stress may cause autism in some cases. Evidence includes genetic effects on metabolic pathways, reduced antioxidant capacity, enzyme changes, and enhanced biomarkers for oxidative stress; however, the overall evidence is weaker than it is for involvement oxidative stress with disorders such as schizophrenia. One theory is that stress damages Purkinje cells in the cerebellum after birth, and it is possible that glutathione is involved. Autistic children have lower levels of total glutathione, and higher levels of oxidized glutathione. Based on this theory, antioxidants may be a useful treatment for autism.

Viral infection

Many studies have presented evidence for and against association of autism with viral infection after birth. Laboratory rats infected with Borna disease virus show some symptoms similar to those of autism but blood studies of autistic children show no evidence of infection by this virus. Members of the herpes virus family may have a role in autism, but the evidence so far is anecdotal. Viruses have long been suspected as triggers for immune-mediated diseases such as multiple sclerosis but showing a direct role for viral causation is difficult in those diseases, and mechanisms whereby viral infections could lead to autism are speculative.

Social construct

The social construct theory says that the boundary between normal and abnormal is subjective and arbitrary, so autism does not exist as an objective entity, but only as a social construct. It further argues that autistic individuals themselves have a way of being that is partly socially constructed.

Asperger syndrome and high-functioning autism are particular targets of the theory that social factors determine what it means to be autistic. The theory hypothesizes that individuals with these diagnoses inhabit the identities that have been ascribed to them, and promote their sense of well-being by resisting or appropriating autistic ascriptions.

Discredited theories

Vaccines

Scientific studies have refuted a causal relationship between vaccinations and autism. Despite this, some parents believe that vaccinations cause autism and therefore delay or avoid immunizing their children, for example under the "vaccine overload" hypothesis that giving many vaccines at once may overwhelm a child's immune system and lead to autism, even though this hypothesis has no scientific evidence and is biologically implausible. Because diseases such as measles can cause severe disabilities and death, the risk of death or disability for an unvaccinated child is higher than the risk for a child who has been vaccinated. Despite all this, antivaccine activism continues. A developing tactic appears to be the "promotion of irrelevant research [as] an active aggregation of several questionable or peripherally related research studies in an attempt to justify the science underlying a questionable claim."

Refrigerator mother

Bruno Bettelheim believed that autism was linked to early childhood trauma, and his work was highly influential for decades both in the medical and popular spheres. 

Parents, especially mothers, of individuals with autism were blamed for having caused their child's condition through the withholding of affection. Leo Kanner, who first described autism, suggested that parental coldness might contribute to autism. Although Kanner eventually renounced the theory, Bettelheim put an almost exclusive emphasis on it in both his medical and his popular books. Treatments based on these theories failed to help children with autism, and after Bettelheim's death, it came out that his reported rates of cure (around 85%) were found to be fraudulent.

MMR vaccine

The MMR vaccine as a cause of autism is one of the most extensively debated hypotheses regarding the origins of autism. Andrew Wakefield et al. reported a study of 12 children who had autism and bowel symptoms, in some cases reportedly with onset after MMR. Although the paper, which was later retracted by the journal, concluded "We did not prove an association between measles, mumps, and rubella vaccine and the syndrome described," Wakefield nevertheless suggested during a 1998 press conference that giving children the vaccines in three separate doses would be safer than a single dose. 

In 2004, the interpretation of a causal link between MMR vaccine and autism was formally retracted by ten of Wakefield's twelve co-authors. The retraction followed an investigation by The Sunday Times, which stated that Wakefield "acted dishonestly and irresponsibly". The Centers for Disease Control and Prevention, the Institute of Medicine of the National Academy of Sciences, and the U.K. National Health Service have all concluded that there is no evidence of a link between the MMR vaccine and autism. 

In February 2010, The Lancet, which published Wakefield's study, fully retracted it after an independent auditor found the study to be flawed. In January 2011, an investigation published in the journal BMJ described the Wakefield study as the result of deliberate fraud and manipulation of data.

Thiomersal (thimerosal)

Perhaps the best-known hypothesis involving mercury and autism involves the use of the mercury-based compound thiomersal, a preservative that has been phased out from most childhood vaccinations in developed countries including US and the EU. Parents may first become aware of autistic symptoms in their child around the time of a routine vaccination. There is no scientific evidence for a causal connection between thiomersal and autism, but parental concern about the thiomersal controversy has led to decreasing rates of childhood immunizations and increasing likelihood of disease outbreaks. In 1999, due to concern about the dose of mercury infants were being exposed to, the U.S. Public Health Service recommended that thiomersal be removed from childhood vaccines, and by 2002 the flu vaccine was the only childhood vaccine containing more than trace amounts of thimerosal. Despite this, autism rates did not decrease after the removal of thimerosal, in the US or other countries that also removed thimerosal from their childhood vaccines.

A causal link between thimerosal and autism has been rejected by international scientific and medical professional bodies including the American Medical Association, the American Academy of Pediatrics, the American College of Medical Toxicology, the Canadian Paediatric Society, the U.S. National Academy of Sciences, the Food and Drug Administration, Centers for Disease Control and Prevention, the World Health Organization, the Public Health Agency of Canada, and the European Medicines Agency.

Lancet MMR autism fraud

From Wikipedia, the free encyclopedia

Lancet MMR autism fraud

Claims	A link between the measles, mumps and rubella vaccination and regressive autistic spectrum disorder
Year proposed	1998
Original proponents	Andrew Wakefield

The Lancet MMR autism fraud centred on the publication in 1998 of a research paper titled Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children in The Lancet. The paper, authored by Andrew Wakefield, claimed to link the MMR vaccine to colitis and autism spectrum disorders. Events surrounding the research study and the publication of its findings led to Wakefield being struck off the medical register. The paper was retracted in 2010.

Characterised as "perhaps the most damaging medical hoax of the 20th Century", it led to a sharp drop in vaccination rates in the UK and Ireland. Promotion of the claimed link, which continues in anti-vaccination propaganda despite being refuted, led to an increase in the incidence of measles and mumps, resulting in deaths and serious permanent injuries. Following the initial claims in 1998, multiple large epidemiological studies were undertaken. Reviews of the evidence by the Centers for Disease Control and Prevention, the American Academy of Pediatrics, the Institute of Medicine of the US National Academy of Sciences, the UK National Health Service, and the Cochrane Library all found no link between the MMR vaccine and autism.  Physicians, medical journals, and editors have described Wakefield's actions as fraudulent and tied them to epidemics and deaths.

An investigation by journalist Brian Deer found that Wakefield had multiple undeclared conflicts of interest, had manipulated evidence, and had broken other ethical codes. The Lancet paper was partially retracted in 2004 and fully retracted in 2010, when Lancet's editor-in-chief Richard Horton described it as "utterly false" and said that the journal had been deceived. Wakefield was found guilty by the General Medical Council of serious professional misconduct in May 2010 and was struck off the Medical Register, meaning he could no longer practise as a doctor in the UK. In 2011, Deer provided further information on Wakefield's improper research practices to the British Medical Journal, which in a signed editorial described the original paper as fraudulent. The scientific consensus is that there is no link between the MMR vaccine and autism and that the vaccine's benefits greatly outweigh its risks.

1998 The Lancet paper

In February 1998, a group led by Andrew Wakefield published a fraudulent paper in the respected British medical journal The Lancet, supported by a press conference at the Royal Free Hospital in London. This paper reported on twelve children with developmental disorders referred to the Royal Free Hospital. The parents or physicians of eight of these children were said to have linked the start of behavioral symptoms to MMR vaccination. The paper described a collection of bowel symptoms, endoscopy findings and biopsy findings that were said to be evidence of a possible novel syndrome that Wakefield would later call autistic enterocolitis, and recommended further study into the possible link between the condition and the MMR vaccine. The paper suggested that the connection between autism and the gastrointestinal pathologies was real, but said it did not prove an association between the MMR vaccine and autism.

At the press conference before the paper's publication, later criticized as "science by press conference", Wakefield said that he thought it prudent to use single vaccines instead of the MMR triple vaccine until this could be ruled out as an environmental trigger; parents of eight of the twelve children studied were said to have blamed the MMR vaccine, saying that symptoms of autism had set in within days of vaccination at approximately 14 months. Wakefield said, "I can't support the continued use of these three vaccines given in combination until this issue has been resolved." In a video news release issued by the hospital to broadcasters in advance of the press conference, he called for MMR to be "suspended in favour of the single vaccines". In a BBC interview Wakefield's mentor Roy Pounder, who was not a coauthor, "admitted the study was controversial". He added: "In hindsight it may be a better solution to give the vaccinations separately,... When the vaccinations were given individually there was no problem." These suggestions were not supported by Wakefield's coauthors nor by any scientific evidence.

The initial press coverage of the story was limited. The Guardian and the Independent reported it on their front pages, while the Daily Mail only gave the story a minor mention in the middle of the paper, and the Sun did not cover it.

Public controversy

The controversy began to gain momentum in 2001 and 2002, after Wakefield published papers suggesting that the immunisation programme was not safe. These were a review paper with no new evidence, published in a minor journal, and two papers on laboratory work that he said showed that measles virus had been found in tissue samples taken from children who had autism and bowel problems. There was wide media coverage including distressing anecdotal evidence from parents, and political coverage attacking the health service and government peaked with unmet demands that Prime minister Tony Blair reveal whether his infant son, Leo, had been given the vaccine. It was the biggest science story of 2002, with 1257 articles mostly written by non-expert commentators. In the period January to September 2002, 32% of the stories written about MMR mentioned Leo Blair, as opposed to only 25% that mentioned Wakefield. Less than a third of the stories mentioned the overwhelming evidence that MMR is safe. The paper, press conference and video sparked a major health scare in the United Kingdom. As a result of the scare, full confidence in MMR fell from 59% to 41% after publication of the Wakefield research. In 2001, 26% of family doctors felt the government had failed to prove there was no link between MMR and autism and bowel disease. In his book Bad Science, Ben Goldacre describes the MMR vaccine scare as one of the "three all-time classic bogus science stories" by the British newspapers (the other two are the Arpad Pusztai affair about genetically modified crops, and Chris Malyszewicz and the MRSA hoax).

Confidence in the MMR vaccine increased as it became clearer that Wakefield's claims were unsupported by scientific evidence. A 2003 survey of 366 family doctors in the UK reported that 77% of them would advise giving the MMR vaccine to a child with a close family history of autism, and that 3% of them thought that autism could sometimes be caused by the MMR vaccine. A similar survey in 2004 found that these percentages changed to 82% and at most 2%, respectively, and that confidence in MMR had been increasing over the previous two years.

A factor in the controversy is that only the combined vaccine is available through the UK National Health Service. As of 2010 there are no single vaccines for measles, mumps and rubella licensed for use in the UK. Prime minister Tony Blair gave support to the programme, arguing that the vaccine was safe enough for his own son, Leo, but refusing on privacy grounds to state whether Leo had received the vaccine; in contrast, the subsequent Prime Minister, Gordon Brown, explicitly confirmed that his son has been immunised. Cherie Blair confirmed that Leo had been given the MMR vaccination when promoting her autobiography.

Administration of the combined vaccine instead of separate vaccines decreases the risk of children catching the disease while waiting for full immunisation coverage. The combined vaccine's two injections results in less pain and distress to the child than the six injections required by separate vaccines, and the extra clinic visits required by separate vaccinations increases the likelihood of some being delayed or missed altogether; vaccination uptake significantly increased in the UK when MMR was introduced in 1988. Health professionals have heavily criticized media coverage of the controversy for triggering a decline in vaccination rates. There is no scientific basis for preferring separate vaccines, or for using any particular interval between separate vaccines.

John Walker-Smith, a coauthor of Wakefield's report and a supporter of the MMR vaccine, wrote in 2002 that epidemiology has shown that MMR is safe in most children, but observed that epidemiology is a blunt tool and studies can miss at-risk groups that have a real link between MMR and autism. However, if a rare subtype of autism were reliably identified by clinical or pathological characteristics, epidemiological research could address the question whether MMR causes that autism subtype. There is no scientific evidence that MMR causes damage to the infant immune system, and there is much evidence to the contrary.

In 2001, Berelowitz, one of the co-authors of the paper, said "I am certainly not aware of any convincing evidence for the hypothesis of a link between MMR and autism". The Canadian Paediatric Society, the Centers for Disease Control and Prevention, the Institute of Medicine of the National Academy of Sciences, and the UK National Health Service have all concluded that there is no evidence of a link between the MMR vaccine and autism, and a 2011 journal article described the vaccine–autism connection as "the most damaging medical hoax of the last 100 years".

Developing scandal

Conflict of interest

In February 2004, after a four-month investigation, reporter Brian Deer wrote in The Sunday Times of London that, prior to submitting his paper to The Lancet, Wakefield had received £55,000 from Legal Aid Board solicitors seeking evidence to use against vaccine manufacturers, that several of the parents quoted as saying that MMR had damaged their children were also litigants, and that Wakefield did not inform colleagues or medical authorities of the conflict of interest. When the editors of The Lancet learned about this, they said that based on Deer's evidence, Wakefield's paper should have never been published because its findings were "entirely flawed". Although Wakefield maintained that the legal aid funding was for a separate, unpublished study (a position later rejected by a panel of the UK General Medical Council), the editors of The Lancet judged that the funding source should have been disclosed to them. Richard Horton, the editor-in-chief, wrote, "It seems obvious now that had we appreciated the full context in which the work reported in the 1998 Lancet paper by Wakefield and colleagues was done, publication would not have taken place in the way that it did." Several of Wakefield's co-researchers also strongly criticized the lack of disclosure.

Deer continued his reporting in a Channel 4 Dispatches television documentary, MMR: What They Didn't Tell You, broadcast on 18 November 2004. This documentary alleged that Wakefield had applied for patents on a vaccine that was a rival of the MMR vaccine, and that he knew of test results from his own laboratory at the Royal Free Hospital that contradicted his own claims. Wakefield's patent application was also noted in Paul Offit's 2008 book, Autism's False Prophets. 

In January 2005, Wakefield sued Channel 4, 20/20 Productions, and the investigative reporter Brian Deer, who presented the Dispatches programme. However, after two years of litigation, and the revelation of more than £400,000 in undisclosed payments by lawyers to Wakefield, he discontinued his action and paid all the defendants' costs. 

In 2006, Deer reported in The Sunday Times that Wakefield had been paid £435,643, plus expenses, by British trial lawyers attempting to prove that the vaccine was dangerous, with the undisclosed payments beginning two years before the Lancet paper's publication. This funding came from the UK legal aid fund, a fund intended to provide legal services to the poor.

Retraction of an interpretation

The Lancet and many other medical journals require papers to include the authors' conclusions about their research, known as the "interpretation". The summary of the 1998 Lancet paper ended as follows:

Interpretation We identified associated gastrointestinal disease and developmental regression in a group of previously normal children, which was generally associated in time with possible environmental triggers.

In March 2004, immediately following the news of the conflict of interest allegations, ten of Wakefield's 12 coauthors retracted this interpretation, while insisting that the possibility of a distinctive gastrointestinal condition in children with autism merited further investigation. However, a separate study of children with gastrointestinal disturbances found no difference between those with autism spectrum disorders and those without, with respect to the presence of measles virus RNA in the bowel; it also found that gastrointestinal symptoms and the onset of autism were unrelated in time to the administration of MMR vaccine.

Manipulation of data

On 8 February 2009, Brian Deer reported in The Sunday Times that Wakefield had "fixed" results and "manipulated" patient data in his 1998 paper, creating the appearance of a link with autism. Wakefield denied these allegations, and even filed a complaint with the Press Complaints Commission (PCC) over this article on 13 March 2009. The complaint was expanded by a 20 March 2009 addendum by Wakefield's publicist. In July 2009, the PCC stated that it was staying any investigation regarding the Times article, pending the conclusion of the GMC investigation. In the event, Wakefield did not pursue his complaint, which Deer published with a statement that he and The Sunday Times rejected it as "false and disingenuous in all material respects", and that the action had been suspended by the PCC in February 2010.

General Medical Council investigation

The General Medical Council (GMC), which is responsible for licensing doctors and supervising medical ethics in the UK, investigated the affair. The GMC brought the case itself, not citing any specific complaints, claiming that an investigation was in the public interest. The then-secretary of state for health, John Reid, called for a GMC investigation, which Wakefield himself welcomed. During a debate in the House of Commons, on 15 Mar 2004, Dr. Evan Harris, a Liberal Democrat MP, called for a judicial inquiry into the ethical aspects of the case, even suggesting it might be conducted by the CPS. In June 2006 the GMC confirmed that they would hold a disciplinary hearing of Wakefield. 

The GMC's Fitness to Practise Panel first met on 16 July 2007 to consider the cases of Dr. Wakefield, Professor John Angus Walker-Smith, and Professor Simon Harry Murch. All faced charges of serious professional misconduct. The GMC examined, among other ethical points, whether Wakefield and his colleagues obtained the required approvals for the tests they performed on the children; the data-manipulation charges reported in the Times, which surfaced after the case was prepared, were not at question in the hearings. The GMC stressed that it would not be assessing the validity of competing scientific theories on MMR and autism. The General Medical Council alleged that the trio acted unethically and dishonestly in preparing the research into the MMR vaccine. They denied the allegations. The case proceeded in front of a GMC Fitness to Practise panel of three medical and two lay members.

On 28 January 2010, the GMC panel delivered its decision on the facts of the case: Wakefield was found to have acted "dishonestly and irresponsibly" and to have acted with "callous disregard" for the children involved in his study, conducting unnecessary and invasive tests. The panel found that the trial was improperly conducted without the approval of an independent ethics committee, and that Wakefield had multiple undeclared conflicts of interest.

Full retraction and fraud allegations

In response to the GMC investigation and findings, the editors of The Lancet announced on 2 February 2010 that they "fully retract this paper from the published record".

The Hansard text for 16 March 2010 reported Lord McColl asking the Government whether it had plans to recover legal aid money paid to the experts in connection with the measles, mumps and rubella/measles and rubella vaccine litigation. Lord Bach, Ministry of Justice dismissed this possibility. 

In an April 2010 report in The BMJ, Deer expanded on the laboratory aspects of his findings recounting how normal clinical histopathology results generated by the Royal Free Hospital were later changed in the medical school to abnormal results, published in The Lancet. Deer wrote an article in The BMJ casting doubt on the "autistic enterocolitis" that Wakefield claimed to have discovered. In the same edition, Deirdre Kelly, President of the European Society of Pediatric Gastroenterology and Nutrition and the Editor of the Journal of Pediatric Gastroenterology and Nutrition expressed some concern about The BMJ publishing this article while the GMC proceedings were underway.

On 24 May 2010, the GMC panel found Wakefield guilty of serious professional misconduct on four counts of dishonesty and 12 involving the abuse of developmentally challenged children, and ordered that he be struck off the medical register. John Walker-Smith was also found guilty of serious professional misconduct and struck off the medical register, but that decision was reversed on appeal to the High Court in 2012, because the GMC panel had failed to decide whether Walker-Smith actually thought he was doing research in the guise of clinical investigation and treatment. The High Court criticised "a number of" wrong conclusions by the disciplinary panel and its "inadequate and superficial reasoning". Simon Murch was found not guilty.

On 5 January 2011, The BMJ published the first of a series of articles by Brian Deer, detailing how Wakefield and his colleagues had faked some of the data behind the 1998 Lancet article. By looking at the records and interviewing the parents, Deer found that for all 12 children in the Wakefield study, diagnoses had been tweaked or dates changed to fit the article's conclusion. Continuing BMJ series on 11 January 2011, Deer said that based upon documents he obtained under freedom of information legislation, Wakefield—in partnership with the father of one of the boys in the study—had planned to launch a venture on the back of an MMR vaccination scare that would profit from new medical tests and "litigation driven testing". The Washington Post reported that Deer said that Wakefield predicted he "could make more than $43 million a year from diagnostic kits" for the new condition, autistic enterocolitis. WebMD reported on Deer's BMJ report, saying that the $43 million predicted yearly profits would come from marketing kits for "diagnosing patients with autism" and "the initial market for the diagnostic will be litigation-driven testing of patients with AE [autistic enterocolitis, an unproven condition concocted by Wakefield] from both the UK and the USA". According to WebMD, the BMJ article also claimed that the venture would succeed in marketing products and developing a replacement vaccine if "public confidence in the MMR vaccine was damaged".