Letter from La Donna Ford, MD to the NIH Interagency Autism Coordinating Committee

As evidence mounts for a causal role in the autism epidemic, letter urges NIH committee to prioritize research on heritable (germline) impacts of modern general anesthetic gases.

The following letter was submitted to the NIH Interagency Autism Coordinating Committee, a federal advisory committee that coordinates federal efforts and provides advice to the Secretary of Health and Human Services on issues related to autism. 

July 1, 2021

To the Members of the IACC:

I am writing to urge that your committee recommend federal funding to investigate a question of urgent importance in autism etiology: the genetic and epigenetic impacts of halogenated anesthetic gases on the germ cells (egg, sperm, and lineage of precursors) of the parent generation, and the ensuing impacts on offspring neurodevelopment, in particular the early transcriptional dysregulation of brain-related genes.

Last year I co-authored a commentary on this topic, "General anesthesia, germ cells and the missing heritability of autism: an urgent need for research," in the respected peer-reviewed scientific journal Environmental Epigenetics, with Jill Escher, a well-known autism research philanthropist who has been raising questions about this and related matters for many years (Escher and Ford 2020).  

I am a retired anesthesiologist and mother of a young man, Connor, who has a severe form of idiopathic autism. Based on my experience as a physician with extensive experience in clinical practice and my keen interest in autism causation research, I can say with confidence that this hypothesis, which has gained enthusiastic attention from molecular biologists, germ cell toxicologists, and reproductive biologists, is likely the most important one yet raised in the history of autism. Allow me to explain as best I can, briefly, and in layperson's terms.

Every year more than 50 million inpatient surgeries are performed in the United States, including procedures on pregnant women, neonates, young children, older children, adolescents and pre-conception adults. Since the 1960s, my field has adopted waves of new agents to induce the state of anesthesia, including but not limited to intravenous agents like propofol and halogenated anesthetic gases such as halothane, enflurane, isoflurane, desflurane and sevoflurane (which I will call "GA"). These drugs are nearly miraculous in their ability to induce global suppression of the nervous system in the patient so as to enable the myriad procedures of modern surgery (anything from neonatal hernia repair, to plastic surgery, to heart surgery, to orthopedic surgery, to appendectomies, among countless others).

That's the good news. The bad news is that these agents are highly toxic. In their ordinary doses they are of course lethal, with patients kept alive only via intubation and careful monitoring. They are neurotoxic-- in fact, the FDA has issued a warning regarding neurotoxicity in patients under the age of three. They are genotoxic — seen to induce DNA damage at the site of contact and peripheral blood. They are reproductive toxicants -- which can damage sperm and egg. More importantly for our purposes, a rash of new studies in mammal models show they can induce epigenetic changes in germ cells that can result in abnormal neurodevelopment in the offspring. These papers are cited in our Environmental Epigenetics paper, and I will not repeat them now, except to add that a remarkable newly published study in Biology of Reproduction has shown how fetal exposure to sevoflurane can induce abnormal binding of transcription factors in sperm DNA, resulting in dysregulated transcription of autism-related genes in offspring -- and abnormal brain and autism-related behavioral phenotypes (Wang et al. 2021). In other words, it appears, based on animal studies, that germ cell exposure to GA agents can exert an adverse intergenerational impact.

In hindsight, this hypothesis strikes most people as rather obvious. And indeed researchers first noticed these heritable effects via mouse experiments in the early 1980s. But regrettably, no heritable-effect studies were performed again until a few years ago (Escher and Ford 2020), and the FDA does not test for germline impacts of GA. As a practitioner neither I nor my colleagues gave any consideration to our patients' germ cells. This facet of GA toxicology has languished in a blind spot for nearly 4 decades.

While I believe that surgeries under GA are likely benign to germline in most cases, I am deeply concerned about certain exposures, for example, exposures to GA in infancy and childhood, as well as repeated or prolonged exposures, including in adulthood. And while GA likely poses little absolute risk to a patient's germ cells, the population level risk may be substantial. If just 1% of U.S. patient exposures result in an adverse heritable effect, that could result in 500,000 cases of some level of abnormal neurodevelopment per year.

Through the years I have watched many hypotheses of autism causation come and go. The current trend is to presume autism's strong heritability "genetic" -- an idea that seems sensible on its face but is lacking in actual molecular evidence except with regards to rare de novo germline mutations which can only explain a fraction of the cases. And while I have no way of knowing what subsection of autism cases may be explained by heritable impacts of parental exposures to GA, I must point out the unprecedented power of this hypothesis to explain a great number of unsolved mysteries of autism, including the following:

--The tremendous increase in prevalence in recent decades, particularly in industrialized countries
--Autism's strong heritability (via broad impacts across parental germ cells)
--Strong sibling recurrence
--The genesis of autism in early abnormalities of transcription of brain-related genes, impacting neurogenesis, neural migration, and synaptic function
--The heterogeneity of autism spectrum disorders
--The skewed male-to-female ratio (males are markedly more affected in the mammalian experiments)
--Regional and demographic variations in prevalence
--The "broader autism phenotype" seen in parents and siblings

The IACC was created to push federal agencies to finally answer questions about autism, and I can think of no other question in autism research that deserves more attention than this. And this attention is 40 years overdue. If the committee wishes to learn more about this important emerging hypothesis, please do not hesitate to contact me or my co-author. Thank you for your attention.

Respectfully,

La Donna Ford, MD
Foster City, California
[email protected]

References:

Escher J, Ford LD. General anesthesia, germ cells and the missing heritability of autism: an urgent need for research, Environmental Epigenetics 2020;6(1), dvaa007, https://doi.org/10.1093/eep/dvaa007
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Wang HL, Forestier S, Corces VG. Exposure to sevoflurane results in changes of transcription factor occupancy in sperm and inheritance of autism. Biology of Reproduction 2021;ioab097, https://doi.org/10.1093/biolre/ioab097