Paul Patterson is an iconic figure in the field of autism.When mentioned in the context of autism his name is synonymous to the possible role of immunological mechanisms. Contrary to other researchers within the field, Paul is what is considered a scientist of “hard data” and a bench top researcher. If you are going to start an argument with him, you better come prepared. He knows both the literature as well as the methodology.
Paul graduated from the Johns Hopkins University in 1970 and went from there to build his academic career at Caltech. In 2005 he was made the Anne and Benjamin Biaginni Professor of Biological Sciences for Caltech. As of this year he is a Professor Emeritus for that academic institution. Paul is now suffering from ill-health and we are all praying for him.
A couple of years ago I approached Paul to see if he could provide some comments to a chapter from a book that I was editing (Imaging the Brain in Autism). He readily agreed and was the first author to provide a contribution to the book. I am copying a few of the paragraphs that he contributed as an opinion piece.
I am looking forwards to many scientific dialogues with my good friend Paul Patterson. We (the autism research community) are all wishing him a speedy recovery.
By Paul H. Patterson, Ph.D.
Talks and papers by geneticists working on autism frequently begin with a variant of the phrase, “autism is a genetic disease”. My understanding of the term “genetic disease” is that it applies to disorders in which a mutation invariably leads to the disease, such as in Huntington’s. Some disorders, such as Fragile X, are monogenic and include features of autism, but the overall phenotype is clearly distinct from idiopathic or sporadic autism. There are also some very rare mutations and copy number variants that cause autism, but these account for only a small fraction of the disorder. This situation has been termed, “The mystery of the missing genes”, or “Where did all the heritability go?”
The assertion that autism is a genetic disease is often justified by a statement that the concordance between monozygotic twins is 90% when one twin is diagnosed with the broader phenotype of autism spectrum disorder (ASD), while the concordance between dizygotic twins is near zero. These numbers are based primarily on older twin studies. However, a new, very large twin study used contemporary standards of diagnosis (ADOS and ADI-R) and came up with rather different numbers. For strict autism, probandwise concordance for monozygotic male twins was 58%, and 21% for dizygotic pairs. For female twins, the concordance was 60%, and 27% for dizygotic pairs. For ASD, the probandwise concordance for male twins was 77%, and 31% for dizygotic pairs. For female twins, the concordance was 50%, and 36% for dizygotic pairs (Konigsmark and Murphy 1972). Not only are the figures for monozygotic pairs considerably lower than older studies, but the concordance for dizygotic pairs is much higher than for siblings (sibling concordance values have ranged from 5% to 18%). These values agree with findings from another very large twin study (Hallmayer et al. 2011), which reported a dizygotic twin concordance of 31% for ASD. The significant discrepancy between ASD risk for siblings versus dizygotic twins leads to the hypothesis that the intrauterine environment plays a key role in the risk for autism. Indeed, recent evidence reveals an association between ASD in the offspring and the presence of inflammatory markers in maternal serum or amniotic fluid (Rosenberg et al. 2009). Moreover, maternal infection during the first trimester increases the risk for ASD in the offspring (Goines et al. 2011).
Another mental disorder that is often cited as being highly heritable is schizophrenia, and here also there is the mystery of the missing genes. Moreover, there are well-documented associations between maternal infection and schizophrenia in the offspring, as well as associations between anti-flu antibodies or cytokines in maternal serum and increased risk for schizophrenia in the offspring (Atladóttir et al. 2010). In fact, extensive epidemiologic work has shown that the effect sizes of various maternal infections are considerably larger than the most studied candidate genes for schizophrenia (Table 1-1). In fact, summing the risks for these various infections suggests that >30% of schizophrenia cases could be prevented if maternal infections were eliminated (attributable proportion calculation) (Brown and Derkits 2009). In further support of the influence of the maternal-fetal environment, indirect evidence indicates that the concordance rate for SZ appears to be much higher for monochorionic twins, which share a placenta, than for dichorionic twins, which do not share a placenta (Brown and Derkits 2009).
Table 1-1 Comparison of the effect sizes for schizophrenia for various maternal infections and candidate genes. Data courtesy of Alan Brown
Maternal infection Odds Genes Odds
Influenza—1st half of pregnancy 3.0 NRG1 1.1–1.2
Toxoplasmosis 2.6 DISC1 1.1–1.2
Genital/Reproductive—periconception 5.3 DTNBP1 0.9–2.7
Respiratory—2nd trimester 2.1 COMT 1.1
MHC class I sequences— SNPs 1.1–1.3
It is important to take these epidemiological findings into account in order to more accurately balance the relative importance of genes and environment in autism. For instance, overstating the importance of genetics has implications for understanding the developmental origins of this disorder. A great deal has been made of findings that many of the genes suggested to be involved in autism code for proteins that function at synapses, and that the excitatory-inhibitory balance is important. How could synapses not be relevant for mental illness? Emphasizing genetics relative to environmental influences has also influenced research funding. Enormous expenditures have been (and are still being) made in the search for the ever-elusive candidate genes, while far less is being spent on the epidemiology of a variety of environmental risk factors and the pathophysiologies underlying them using animal models.
Is it not simply a truism that genes and environment (both surrounding the fetus and encountered later by the offspring) must interact to yield the autism phenotype(s)? This should be reflected in correcting the balance of funding as well as the mislabeling of autism as a “genetic disorder”. Heritability estimates based on out-of-date twin studies should also be revised.
Note: I think that most scientists within the field readily agree with Paul about the overstated importance that genetics has had in autism research. We hope that sometime in the future NIH and other funding organizations realize that their current path of funding is not yielding the desired results.
Addendum: Unfortunately I just found out that Paul passed away at the end of June this year (bit.ly/1qHeyEQ). Truly a remarkable person and a dear friend. He will be missed. I am extremely sad. –I feel incredibly honored that one of the last things he penned in academics, even when sick, was the opinion piece published in this blog.