The NEW TREND: genome-wide association studies (GWAS) with cohorts >1 million (or many millions of) individuals

On 25 Feb 2019, these GEITP pages described “an unprecedented cohort size of more than 1 million”, in which a genome-wide association study (GWAS) was carried out to search for genes (genotype; or genetic architecture) statistically significantly (P <5.0 x 10–8) associated with a phenotype (trait). In that Feb 25th publication, the complex trait being studied was insomnia; and these GEITP pages had predicted that — given the exploding numbers of humans whose DNA and personal history are being collected in repositories (not 'suppositories') — we will see this "trend of more-than-1-million individuals" in GWAS. Well, it has happened far sooner than expected. J Attached are THREE reports (all from the Feb 2019 issue of Nature Genetics) of GWAS — each one of which comprises a cohort exceeding 1 million individuals. The first [attached] study (in 'sample sizes up to 1.2 million subjects'), authors discovered 566 genetic variants in 406 genetic loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness), as well as alcohol use, with 150 loci exhibiting evidence of pleiotropic association (i.e. a single gene that contributes to more than one trait). The second [attached] study (in a 'combined sample of over 1 million individuals'), authors studied several complex phenotypes ("general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains") [!!]. Across all GWAS, authors identified hundreds of associated genetic loci — including 99 loci associated with general risk tolerance, shared genetic influences across risk tolerance and the risky behaviors — with bioinformatics analyses implying a role for glutamatergic and GABA-ergic neurotransmission (intriguingly, authors found no evidence of enrichment for genes previously hypothesized to be related to risk tolerance!!). In the third [attached] study, authors analyzed a large health insurance dataset to assess genetic and environmental contributions of 560 disease-related phenotypes in 56,396 twin-pairs and 724,513 sibling-pairs — out of 44,859,462 individuals living in the US. Authors estimated the contribution of environmental risk factors (socio-economic status, air pollution and climate) to each disease-related trait. They found significant heritability and shared environment for a substantial number of co-morbidities (i.e. the simultaneous presence of two or more chronic diseases or conditions in the same patient) and average monthly healthcare cost. Comprehending all the information in these GWAS, these days, is about the same as trying to drink water from a fire hose. 🙂 DwN Nat Genet Feb 2o19; 51: 237-244 & 245-257 & 327-334

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“Origins of Life” have been created by a NASA experiment ???

As these GEITP pages have considered from time to time, how “life” began on Earth is relevant to gene-environment (GxE) interactions — in some ways similar to the relevance of GxE to evolution of life over the past 4+ billion years. In assessing the role of specific geochemical environments and mineral phases when life first emerged, the synthesis of biomolecules (e.g. amino acids, and their condensation into peptides), from geochemical carbon and nitrogen sources, is an important consideration. One type of mineral that would have been abundant — in the mildly acidic, iron-rich oceans of the early Earth — is the iron oxyhydroxides, which can precipitate in a variety of stable or metastable redox states.

Iron oxides/oxyhydroxides are versatile reactive minerals that can drive redox reactions and concentrate phosphorus-containing molecules, trace metals, organic molecules, and other anions. On the early Earth, iron oxyhydroxides and/or “green rust” would likely have been present in oceans — as well as seafloor sediments — playing a fundamental role in elemental cycling and redox chemistry. Iron oxyhydroxides would also have been a primary component in alkaline hydrothermal vents, which have been proposed as the likely environment for emergence of metabolism due to their ambient pH (i.e. acid-base properties), Eh (activity/energy of electrons), ion/chemical, and temperature gradients. In the anoxic (oxygen-starved) iron (Fe2+)-rich early oceans, these minerals would have been only partially oxidized and, thus, redox-active (i.e. perhaps able to promote prebiotic chemical reactions).

Authors [see attached article] show that pyruvate, a simple organic molecule that can form in hydrothermal systems, can undergo reductive amination (conversion of a carbonyl group to an amine, via the intermediate imine) in the presence of mixed-valence iron oxyhydroxides to form the amino acid alanine, as well as the reduced product lactate. Maximal yield of alanine was observed when the iron oxyhydroxide mineral contained 1:1 ratio of Fe(II):Fe(III), under alkaline conditions, and at moderately warm temperatures (these represent conditions that may be found, e.g. in iron-containing sediments near an alkaline hydrothermal vent system). The partially oxidized state of the precipitate was significant in promoting amino acid formation: pure ferrous hydroxides did not drive reductive amination — but instead promoted pyruvate conversion to lactate; moreover, ferric hydroxides did not result in any reaction. Thus, prebiotic chemistry — driven by redox-active iron hydroxide minerals on the early Earth — would have been strongly affected by geochemical gradients of Eh, pH, and temperature. Subsequently, liquid-phase products would be able to diffuse to other conditions within the sediment column to participate in further reactions, leading to the “beginnings of life”. J

DwN

Proc Natl Acad Sci USA 2o19; vol. 116: https://doi.org/10.1073/pnas.1812098116

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Separating host and microbiome contributions to drug pharmacokinetics and drug toxicity

These GEITP pages have discussed, on several occasions, the importance of the “brain-gut-microbiome” (i.e. interaction of each patient’s gut bacteria/virus/fungus with intestine AND brain of the same patient). Of all the many ways the ecosystem of microbes (comprising 92% of YOUR total DNA) in a person’s gut and other tissues might affect health — its potential influences on brain may be the most far-reaching. Now, a study of two larger groups of Europeans [see attached article] has identified several species of gut bacteria that are largely missing in people who exhibit major depressive disorder (MDD). Researchers cannot say whether the absence (of these specific bacterial species) is the cause, or an effect, of the illness — but they have shown that many gut bacteria could produce, or degrade, substances that affect nerve cell function, and perhaps also mood.

Several studies in mice had indicated that gut microbes can affect behavior, and studies of small cohorts of humans had suggested this microbial repertoire is altered during depression. To test such an association in a larger group, authors [see attached] examined 1,054 Belgians they had recruited to assess a “normal” microbiome. Some in the group (N of 173) had been diagnosed with MDD — or had performed poorly on a quality-of-life survey — and the team compared their microbiomes with those of “non-depressed” participants. Two kinds of bacteria, Coprococcus and Dialister, were missing from microbiomes of the depressed subjects, but were not absent from those describing on the questionnaire “a high quality of life”. The finding (reported last week in Nat Microbiol) continued to be significant, when researchers had allowed for factors such as age, sex, or antidepressant use (all of which influence the microbiome). When the team looked at a 2nd group (1,054 Dutch people whose microbiomes had also been sampled) — they found the same two bacterial species were missing in depressed people; they were also missing in seven subjects suffering from MDD (the data “do not prove causality”, but they are “an independent observation backed by two groups of people”).

Searching for something that could correlate microbes to mood — authors compiled a list of 56 substances important for proper nervous system function that gut microbes either produce or break down; they found that Coprococcus produces a metabolite of dopamine (a brain signal involved in depression), although it’s not clear whether the bacteria degrade the neurotransmitter or whether the metabolite has its own function. The same microbe produces an anti-inflammatory substance called butyrate; it is known that increased inflammation may play a role in depression. Subjects with MDD also had an increase in bacteria implicated in Crohn disease, an inflammatory disorder. How do these bacterial metabolites get into the central nervous system? Authors suggest that one possible channel is the vagus nerve, which links brain to the gut.

Authors of the 1-MB article [attached] describes attempts to study interpersonal variation in drug efficacy and drug toxicity; however, quantifying microbial contributions to drug metabolism is challenging — particularly in cases where host and microbiome perform the same metabolic transformation. Authors combined gut commensal (living in a relationship in which one organism derives food or other benefits from another organism, without hurting or helping it) genetics with gnotobiotics [denoting an environment for rearing organisms in which all microorganisms are either known or excluded (e.g. ‘germ-free mouse colony’)] to measure brivudine drug metabolism (analog of thymidine, which gets incorporated into viral DNA — blocking the action of DNA polymerases, thus inhibiting viral replication) across tissues in mice that vary in a single microbiome-encoded enzyme. Informed by information from these measurements, authors built a pharmacokinetic model that quantitatively predicts microbiome contributions to systemic drug and metabolite exposure — (as a function of bioavailability, host and microbial drug-metabolizing activity, drug and metabolite absorption, and intestinal transit kinetics). Studies of clonazepam (used to treat seizures and panic attacks) illustrated how this approach dissociates microbiome contributions to metabolism of drugs, subject to multiple metabolic routes and transformations.

Together, these two studies provide experimental and computational strategies to untangle host and microbial contributions to drug metabolism and effects on brain. Quantitative understanding of the interplay between host and microbiome-encoded metabolic activities will clarify how nutritional, environmental, genetic, and galenic (principles of preparing and compounding medicines in order to optimize their absorption) factors affect drug metabolism and could enable tailored intervention strategies to improve drug responses. This approach could also be adapted to other foreign chemicals, food components, and endogenous metabolites. 🙂

DwN

Science 8 Feb 2o19; 363: 600 + 6 pp & p. 569 [editorial]­­

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Climate Change Reconsidered — Fossil Fuels II

These GEITP pages have covered not only gene-environment interactions but also fraud and corruption involving gene-environment interactions. One such example, often discussed herein, has been the governmental policy to support the Linear No-Threshold (LNT) Model — although experimental evidence is lacking (and has been insufficient since the 1920s). The result has been billions and billions of dollars spent, and so much wasted time and effort in carcinogen- and toxicant-testing based on the LNT since the 1960s.

A second example is the supposed “anthropogenic global warming” (AGW), first declared in the 1980s; AGW advocates decided to change the name of this political/environmental movement in 2009 to “climate change”, because no substantial further global warming has been observed since 1997. The Intergovernmental Panel on Climate Change (IPCC) was established in 1988 by the United Nations (UN) as a group of scientists, chosen by governments and other large groups around the world, to study “the chance that humans might be causing the Earth to heat up unnaturally.” [Note that their directive is NOT to study the natural causes of climate change — which has been occurring every century on Earth since it first formed, 4.54 billion years ago.] As further proof of the political nature of the IPCC, this organization shared the 2007 Nobel Peace Prize with former Vice President Al Gore, who has no training in any discipline related to climate science. The result has been trillions of dollars spent since the 1980s in the US, the EU and Australia, and so much wasted time and effort on a hypothesis that has yet to provide any scientific evidence.

In contrast, the Nongovernmental International Panel on Climate Change (NIPCC) is an international panel of nongovernment scientists and scholars who have come together to understand all causes and consequences of climate change. Because they are not “predisposed to believe” climate change is caused by human greenhouse gas emissions, they are able to look at evidence that the IPCC has chosen to ignore. Because the NIPCC is not funded by any government, they are not biased toward the assumption that “greater government activity is necessary to stop climate change.” In other words, the NIPCC represents science whereas the IPCC represents a political agenda.

NIPCC originated during a 2003 meeting in Milan, organized by the Science and Environmental Policy Project (SEPP), a nonprofit research and education organization based in Arlington, Virginia. SEPP was founded in 1990 by Dr. S. Fred Singer, an atmospheric physicist from the University of Virginia; following Dr. Singer’s retirement in 1992, SEPP became incorporated. NIPCC is currently a joint project of SEPP, The Heartland Institute, and the Center for the Study of Carbon Dioxide and Global Change.

NIPCC has produced 13 reports to date (these can all be downloaded from the internet):

**Nature, Not Human Activity, Rules the Climate

**Climate Change Reconsidered: The 2009 Report of the Nongovernmental International Panel on Climate Change (NIPCC)

**Climate Change Reconsidered: 2011 Interim Report

**Climate Change Reconsidered II: Physical Science

**Climate Change Reconsidered II: Biological Impacts

**Scientific Critique of IPCC’s 2013 ‘Summary for Policymakers’

**Commentary and Analysis on the Whitehead & Associates 2014 NSW Sea-Level Report

**Why Scientists Disagree About Global Warming

**Written Evidence Submitted to the Commons Select Committee of the United Kingdom Parliament

**NIPCC vs IPCC

**Chinese Translation of Climate Change Reconsidered

**Global Warming Surprises: Temperature data in dispute can reverse conclusions about human influence on climate

**Data versus Hype: How Ten Cities Show
**Sea-level Rise Is a False Crisis

Climate Change Reconsidered II Fossil Fuels is therefore the latest book, published in January 2019 — written by SEPP and the Center for the Study of Carbon Dioxide and Global Change — representing the 5th edition in the CCR series. The following citation should be used for this report:

Bezdek, R., Idso, C.D, Legates, D., and Singer, S.F. (Eds.) 2019. Climate Change Reconsidered II: Fossil Fuels. Nongovernmental International Panel on Climate Change (NIPCC). Arlington Heights, IL: The Heartland Institute

The print version is black and white. You can download this color version (for free) online at:

http://climatechangereconsidered.org/wp-content/uploads/2019/01/Climate-Change-Reconsidered-II-Fossil-Fuels-FULL-Volume-with-covers.pdf

DwN

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Dating of hominins living in Denisova Cave (southeastern Siberia)

These GEITP pages have often discussed evolution and dispersal (migration) of hominins (i.e. any species of early human that is more closely related to humans than chimpanzees — including modern human) during the past 6 million years. The time period — during which the Neanderthals and the Denisovans lived, and where they were geographically distributed — is still being studied. Denisovan remains are known only from the locality of Denisova Cave, located in the foothills of the Altai Mountains in southeastern Siberia [the 4th attachment (editorial) shows a nice photo of the front of that cave]. Neanderthal remains have also been recovered from “deposits” (fecal material) of this cave. The cave consists chiefly of three large chambers (Main Chamber, East Chamber and South Chamber), each containing deposits several meters deep.

Excavations have yielded Middle Paleolithic (~300,000 to 30,000 years ago) stone artefacts and a variety of Upper (Late) Paleolithic (~50,000 to 10,000 years ago) artefacts — as well as remains of (non-human) animals and plants. The fragmentary remains of four Denisovans, two Neanderthals, and a daughter of Neanderthal and Denisovan parents (providing evidence for admixture between these two populations) — have also been recovered; their genomes have been sequenced, as has DNA extracted from the Pleistocene (i.e. geological epoch which lasted from ~2,588,000 to 11,700 years ago, spanning Earth’s most recent period of repeated glaciations) sediments.

Denisova Cave is a key site for understanding the complex relationships between hominin groups that inhabited Eurasia in the Middle and Late Pleistocene epoch. Authors [see attached Douka et al. article] reported three direct dates for hominin fragments and obtained a mitochondrial DNA (mtDNA) sequence from one of them. Authors [by a Bayesian age-modeling approach that combines chronometric (radiocarbon, uranium series and optical ages), stratigraphic and genetic data to calculate probabilistically the age of the human fossils at the site] estimate the age of the oldest Denisovan fossil at the site as early as 195,000 years ago. All Neanderthal fossils — as well as Denisova fossil, and daughter fossil of the Neanderthal x Denisovan parents — were dated to between 80,000 and 140,000 years ago. The youngest Denisovan dates to 76,000–52,000 years ago.

Authors [see attached Jacobs et al. article] performed similar studies on this same Denisovan cave material independently — and reconstructed the environmental context of hominin occupation of the site from ~300,000 to 20,000 years ago. The first article is far more detailed than the second article. 🙂

DwN

Nature 31 Jan 2o19; 565: 594–599 & 640–644 [two articles] & Nature pp 571-572 [editorial] & Science 1 Feb 2o19; 363: p 438 {editorial]

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NASA scientists offer new clues to how life started on Earth after reproducing the origins of life on the ocean floor in a lab

NASA scientists offer new clues to how life started on Earth after reproducing the origins of life on the ocean floor in a lab
Nebert, Daniel (nebertdw)
Tue 2/26, 1:37 PM

I <> that this is “the first time that a lab has reated” organic molecules such as amino acids and alpha-hydroxy-lactic acid……

But I could be wrong.

NASA is able to recreate the ‘origins of life’

By Chris Ciaccia

A new NASA study has recreated the origins of life, building the ocean’s floors from 4 billion years ago as humanity attempts to understand how life started on Earth and where else it might be found.

The study, conducted by astrobiologists at NASA’s Jet Propulsion Laboratory (JPL) and published in Proceedings of the National Academy of Sciences, looks at how life began near hydrothermal vents on the ocean floor.

“Understanding how far you can go with just organics and minerals before you have an actual cell is really important for understanding what types of environments life could emerge from,” said Laurie Barge, the lead investigator, in a statement. “Also, investigating how things like the atmosphere, the ocean and the minerals in the vents all impact this can help you understand how likely this is to have occurred on another planet.”

Barge and her team were able to recreate the seafloor by filling beakers with mixtures that were similar to the primordial ocean, including water, minerals and ammonia and pyruvate that are generally located near hydrothermal vents. The mixture was heated to 158 degrees Fahrenheit, the oxygen was removed, and they added iron hydroxide, or “green rust,” which was abundant in the early days of the planet.

The green rust reacted with the traces of oxygen that were left, which produced the amino acid alanine and the alpha hydroxy acid lactate. Some researchers believe these could combine (like Legos) and create further complex molecules which could then be a precursor to life.

“We’ve shown that in geological conditions similar to early Earth, and maybe to other planets, we can form amino acids and alpha hydroxy acids from a simple reaction under mild conditions that would have existed on the seafloor,” Barge added in the statement.

While it’s important to note NASA has not created life itself in the experiment, it does raise the possibility that the hydrothermal vents could appear elsewhere in the universe and be a building block for life.

“If we have these hydrothermal vents here on Earth, possibly similar reactions could occur on other planets,” said JPL’s Erika Flores, co-author of the new study. We don’t have concrete evidence of life elsewhere yet,” said Barge. “But understanding the conditions that are required for life’s origin can help narrow down the places that we think life could exist.”

The implications of the research are vast, especially as new celestial bodies are discovered, with some having the components to host life. In 2018, researchers discovered that Saturn’s moon, Enceladus, has the “building blocks for life,” after complex organic molecules were found on the natural satellite.

A recently discovered exoplanet that orbits Barnard’s Star – known as Barnard b – could have the potential for extraterrestrial life if water exists somewhere on the planet. That’s due to the possibility of geothermal heating, which could create an ocean for primitive life.

Follow Chris Ciaccia on Twitter @Chris_Ciaccia

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Genome-wide analysis of INSOMNIA in more than 1 million individuals !!!

These GEITP pages have often discussed genome-wide association studies (GWAS). GWAS are studies in which some phenotype (trait) is selected to be studied, and then thousands of individuals’ genomes are screened for statistically significant genetic loci associated with that selected trait. Benefits of GWAS findings are not as useful for “risk assessment” or “prediction of risk” — as much as they are for “identifying genetic pathways” that may lead to drug development to treat the phenotype being studied. Two articles [attached] just came out today and will appear in the March 2019 issue of Nature Genetics. The trait selected is INSOMNIA; this depends on self-reported problems recorded in questionnaires. GEITP would regard this phenotype as “soft” (i.e. not every individual is as reliable as other individuals).

Insomnia is the second most prevalent mental disorder (after depression). One-third of the general population reports insomnia complaints. Diagnostic criteria for insomnia disorder (i.e. difficulties with initiating or maintaining sleep, with accompanying daytime complaints, at least three times a week for at least three months, which cannot be attributed to inadequate circumstances for sleep) are met by 10% of individuals, and as much as one-third of older age individuals. Insomnia contributes significantly to risk and severity of cardiovascular, metabolic, mood, and neurodegenerative disorders. Insomnia also increases risk of developing anxiety disorders, alcohol abuse, and major depression. Common drug treatments target synaptic neurotransmission (via GABA-ergic pathways), hypothalamic neuropeptides (via hypocretin/orexin), cortical arousal (via histamine receptors), or the melatonin system, but these drugs have had variable effectiveness, can be habit-forming, and have side-effects.

Despite evidence of a considerable genetic component (heritability 38–59%), only a small number of genetic loci moderating the risk of insomnia have been identified until now. Authors [see Jansen et al., the 4-MB pdf attachment] decided to increase substantially the sample size, to allow detection of additional genetic risk variants for insomnia complaints, which may aid in understanding its neurobiological mechanisms. By combining data collected in the UK Biobank (UKB) version 29 (n = 386,533) and in 23andMe [a privately held personal genomics and biotechnology company (n = 944,477)] — authors obtained an unprecedented sample size of 1,331,010 individuals (this is the largest cohort yet for any GWAS). Insomnia complaints were measured using questionnaire data; an independent sample (the Netherlands Sleep Register), which gives access to similar question data, as well as clinical interviews assessing insomnia disorder, was used to validate the specific questions so that they were good proxies of insomnia disorder. Meta-analysis explained 2.6% of the variance.

Authors [see Lane et al., the 2-MB pdf attachment] studied UK Biobank participants of European ancestry (n = 453,379). In this sample, 29% of individuals self-reported frequent insomnia symptoms (“usually”), and the prevalence was relatively higher in women (32% versus 24% in men) and in older participants, shift workers, and individuals with shorter self-reported sleep duration. Authors adjusted for age, sex, ten principal components of ancestry, and genotyping array using 14,661,600 genotyped — and imputed genetic variants across the autosomes (i.e. all chromosomes except the sex chromosomes) and genotyped variants on the X chromosome. They identified 57 association signals explaining 1% of the variance; of these, 20 loci were identified in both analyses, 28 loci were identified in analysis of frequent insomnia symptoms only, and 9 were identified in analysis of any insomnia symptoms only.

Both studies identified considerable genetic correlations with psychiatric traits and sleep duration, and modest correlations with other sleep-related traits. Mendelian randomization recognized causal effects of insomnia on depression, diabetes, and cardiovascular disease, and “protective effects” of educational attainment and intracranial volume [???] Evidence of shared genetic factors was found between insomnia — and restless legs syndrome, aging, and cardiometabolic, behavioral, psychiatric, and reproductive traits. Evidence was also found for a possible causal link between insomnia and coronary artery disease, depressive symptoms, and subjective well-being. These mind-boggling studies represent harbingers of “things to come” with GWAS: bigger cohorts, more small-effect genes and genetic loci discovered, and more possibilities for uncovering novel genetic pathways for which drug therapy might be developed in the future. 🙂

DwN

Nat Genet March 2019; vol 51: pages to be determined soon !!

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How a scientist’s disputed views about pollution may change EPA

By popular demand from more than several GEITP’ers, I am sharing the Tues Feb 19th front-page article in the Los Angeles Times.

Often we at GEITP have chatted about Ed Calabrese and his uncovering of the fraud surrounding the Biological Effects of Ionizing Radiation (BEIR) committee’s recommendations for the Linear No-Threshold Model — based on (1946) Nobel Laureate Hermann J Muller’s questionable studies and conclusions (on radiation effects causing mutations) in the 1920s and 1930s.

DwN
How a scientist’s disputed views about pollution may change EPA

Ed Calabrese’s theory that low doses of toxic chemicals are good for people could soon become U.S. policy.

By Susanne Rust

In early 2018, a deputy assistant administrator in the EPA, Clint Woods, reached out to a Massachusetts toxicologist best known for pushing a public health standard [i.e. rejection of the Linear No-Threshold (LNT) Model], suggesting that low levels of toxic chemicals and radiation might be good for people.

“I wanted to check to see if you might have some time in the next couple of days for a quick call to discuss a couple items,” Woods wrote to Ed Calabrese. Less than two weeks later, Calabrese’s suggestions on how the Environmental Protection Agency should assess toxic chemicals and radiation were introduced, nearly word for word, into the U.S. government’s official journal, the Federal Register.

“This is a major big time victory,” Calabrese wrote in an email to Steve Milloy, a former coal and tobacco lobbyist who runs a website, junkscience.com — one of whose goals is to discredit mainstream climate science. “Yes. It is YUGE!” wrote Milloy, in response.

It was a glorious moment for Calabrese, who had been snubbed for decades by mainstream public health scientists because of his controversial research and theories. It also signified the major shift that the EPA has taken under the Trump administration. More than any before it, this White House has actively sought out advice from industry lobbyists and the scientists they commission in setting pollution rules. Denouncing the Obama-era EPA as an agency beholden to environmental extremists, the administration has not only dismissed mainstream science but embraced widely discredited alternatives that critics say are not consistent with the agency’s focus on improving public and environmental health.

Calabrese’s role illustrates a different side of this shift: the potential removal of long-standing public health practices and the incorporation of industry-backed and disputed science into federal environmental policy. Calabrese spent decades advancing his ideas, facing skepticism and criticism from peers in the toxicology community while winning funding from companies whose bottom lines conformed to his views.

He says most of the pushback he receives comes from left-of-center toxicologists who see him as “the devil incarnate” for accepting industry funding and challenging their ideology. He maintains his science is solid and will be vindicated in time. “These environmental regulatory people are very closed-minded,” he said. They won’t reconsider their standards, and see that some of the agents they call harmful “actually can induce adaptive responses,” Calabrese said.

This view — that pollution and radiation can be beneficial — has many experts worried. The fact that such a position might become EPA policy, they say, portends a future in which corporate desires outweigh public and environmental health.

“Industry has been pushing for this for a long time,” said David Michaels, former assistant secretary of labor for the Occupational Safety and Health Administration who’s a professor of environmental and occupational health at George Washington University. “Not just the chemical industry, but the radiation and tobacco industries too.”

If the EPA ultimately adopts Calabrese’s proposed new regulations, researchers say it could change decades of standards and guidelines on clean air, water and toxic waste. It could also fundamentally alter the way the government assesses new chemicals and pesticides entering the marketplace. “This is industry’s holy grail,” Michaels said.

Can pollution be healthy?

For decades, federal agencies charged with investigating and regulating carcinogens, toxic chemicals and radiation have been guided by the assumption that if a substance is dangerous at some level, it is harmful at any level. The higher the exposure, the more harm done. The lower the dose, the less. But the risk doesn’t entirely disappear, until the substance is entirely removed.

This is known as the linear no-threshold model, and industry dislikes it because it generally assumes that there is no level, or threshold, of exposure that can be considered totally safe.

But research done on low exposures to toxins has been less than definitive. Experiments designed to test carcinogens and radiation at low levels often produce conflicting results — with, for example, some studies of a chemical showing harm, other studies showing no effect, and a few suggesting a net benefit. In other cases, there is no information at all to guide regulators. In the face of such uncertainty, the EPA and other agencies have taken a cautious approach by relying on the linear no-threshold model. Where data are absent or uncertain, they assume some level of risk.

It is an imperfect but protective approach, many public health specialists say. They argue that in a human population that varies widely in age, health, genetic susceptibility, and levels of chemical exposures, it is imperative that the agency cast a wide, conservative and protective net. For decades, national and international scientific bodies have upheld this approach. It has been reviewed and re-reviewed dozens of times, including most recently by the congressionally chartered National Council on Radiation Protection and Measurements, the National Academy of Sciences, Engineering and Medicine and the EPA.

At the same time, industry has funded scientists to conduct and promote research designed to poke holes in the linear no-threshold model. And that is where Calabrese comes in. He has long argued that regulators “erred on the side of being protective” at the cost of billions of dollars a year to industry.

Calabrese is a proselytizer of hormesis, the idea that dangerous chemicals and radiation are beneficial at low doses. He says they have a stimulating effect. Polluting industries have promoted hormesis as an alternative to linear no-threshold for decades, but they had gotten little traction until the EPA embraced it in April.

“It’s clearly not mainstream,” said Thomas Burke, professor and director of the Risk Sciences and Public Policy Institute at Johns Hopkins’ Bloomberg School of Public Health. Burke and other experts say there are clearly scenarios in which toxic chemicals can have beneficial effects in clinical and pharmacological settings, such as in the case of tamoxifen, which at low doses is effective at preventing and treating breast cancer but at higher doses can lead to blood clots, stroke and uterine cancer.

But, they say, what happens in a clinical setting can’t and shouldn’t be immediately applied to a regulatory, public health setting. In the clinical case, “you have a doctor controlling and administering the medication to an individual,” said David Jacobs, a professor of public health at the University of Minnesota, who has published studies showing hormetic effects in some industrial pollutants. “The doctor can pull the medication at any time.

“There is no way to control the dose a person gets from an industrial or agricultural chemical,” he said. “It’s not being doled out in pills and monitored by a physician who can lower it if the patient isn’t responding well.” Therefore, Jacobs said, it would be dangerous to use hormesis as a framework for protecting public and environmental health.

“It really doesn’t pass the sniff test” when applying it to public health, Burke said, while allowing for its place in the forum of ideas. “I always teach my classes that there are other theories. It’s like any part of science, there are different points of view. Whether it’s about climate change or low doses.” But he also teaches that one needs to know who has skin in the game. And in the case of hormesis, he said, that’s industry.

Big bucks from Big Tobacco

In the early 1980s, Calabrese was a tenured professor at the University of Massachusetts, stringing together public agency and industry-funded grants to study chemicals in drinking water and the effects of ozone on mice. His funders included the EPA, the state of Massachusetts, the Hoffmann-La Roche pharmaceutical company, and semiconductor giant Digital Corp.

Then in 1985, he reached out to the Council for Tobacco Research, the research arm of the tobacco industry, seeking a grant to examine “a possible inherited and metabolic susceptibility to lung cancer in smokers.” His proposal was declined. Sheldon Sommers, a physician at New York’s Lenox Hill Hospital and scientific director of the council, wrote in response to the grant application that Calabrese’s proposal “is a mad hatter’s tea party sort of epidemiologic approach, and a total $2.1 million-plus would likely be frittered away, in my opinion,” according to documents from the UC San Francisco Truth Tobacco Industry Documents archive.

But by the 1990s, Calabrese had solidly established himself as a trusted scientist with the tobacco industry. He found it was interested in research that questioned the methods that regulatory agencies use to assess risk. In a 1994 proposal to R.J. Reynolds, Calabrese offered to investigate a new kind of smokeless cigarette for the company, but also incorporate into his research “the loss of current benefits associated with smoking, such as protection from certain types of cancers and other illnesses.”

It was when he began his work on hormesis that Calabrese got attention from a broader range of industries. With seed money from R.J. Reynolds, Dow Chemical, Procter & Gamble and others, as well as the EPA — Calabrese established a hormesis working group at the University of Massachusetts, which he called the Biological Effects of Low Level Exposures, or BELLE. Minutes from a 1990 advisory board meeting show the group chose not to use the word “hormesis” in its official name. According to documents, Calabrese and his funders also held off on pushing a hormesis regulatory agenda until they’d built a sizable base of published scientific research.

Between 1990 and 2013, Calabrese received more than $8 million from companies and institutions, including R.J. Reynolds, Exxon Mobil, Dow Chemical, General Electric, the Department of Energy and the U.S. Air Force, to conduct research on hormesis. Spokesmen from Exxon Mobil and the Air Force say they no longer fund Calabrese’s work.

Calabrese established his own scientific society, the International Dose Response Society, and the hormesis journal — now called Dose Response — where he served as editor-in-chief. He wrote hundreds of articles, in his journal and in others (including “Should hormesis be the default model in risk assessment?” and “The importance of hormesis to public health”), organized dozens of conferences, and delivered scores of talks.

His publication portfolio is vast and broad. It includes not just studies of hormesis, but research on soil ingestion, opinion pieces on law and regulatory policy, historical treatise on science,scathing — and a few posthumous rebukes of revered scientists, such as Hermann Muller, a Nobel Prize winner and founder of the linear no-threshold model.

Calabrese insists his funding does not influence his work. “My job involves finding financial support to do studies in my field,” Calabrese said. “I seek support from the private and public sectors. The university independently evaluates each of these for compliance with the rules.”

Not all of his money comes from industry or government agencies with extensive toxic waste sites. Between 2000 and 2013, Calabrese received $50,000 from the EPA to hold a conference on soil ingestion, and $50,000 from the California Environmental Protection Agency for a reference database he built on cancer publications. He also received a $750,000 joint grant from the EPA and the American Chemistry Council, the chemical industry’s trade group, to study soil ingestion by construction workers.

Yet, despite his prolific career, he has instigated criticism and rebuke from many of his peers for his push for public and environmental health policy. He has been described as a “prominent industry consultant,” having “outlying views” whose science is “way out there.” For years he failed to get regulatory agencies to take him seriously. Then Donald Trump was elected president.

Active pursuit by the White House

On Sept. 5, 2017, nearly nine months after Trump was sworn in as president and seven months after Scott Pruitt was confirmed as administrator of the EPA, Calabrese wrote an email to Milloy, the former coal lobbyist. The Times obtained the emails through a public records request to the University of Massachusetts. “I wanted to connect with you on whether and how it may be possible to get the EPA to consider changing the LNT [linear no-threshold model] to something far better,” Calabrese wrote. Milloy had served on Trump’s EPA transition team and was still in touch with high-ranking officials in then-Secretary Pruitt’s agency.

A few months later, Calabrese wrote to Milloy again, letting him know that he’d corresponded with Ryan Jackson, Pruitt’s chief of staff, and sensed interest in a move against linear no-threshold. Not long after Woods, the EPA’s deputy assistant of the Office of Air and Radiation, emailed Calabrese asking if he wanted to talk about “default linear assumptions” and other items.

The two arranged a call, and on April 19, 2018, Woods sent Calabrese draft language for a small section in the EPA’s proposed new ruling on transparency, called “Strengthening Transparency in Regulatory Science.” “It is good what you have, but you need a little more,” wrote Calabrese, who then suggested a line, which he altered twice, in email exchanges with Woods, before settling on this: “EPA shall also incorporate the concept of model uncertainty when needed as a default to optimize low dose risk estimation based on the major competing models (LNT, Threshold, and Hormesis).”

In other words, if the EPA is uncertain about a particular chemical’s impact at low doses, it would abandon linear no-threshold as a default, and try other models instead, including hormesis. On April 25, Milloy sent Calabrese the final wording for the draft proposal, which included Calabrese’s line nearly word-for-word. “I am almost passing out with surprise and euphoria,” Calabrese wrote Milloy after seeing the document.

The rule was posted for comment in the Federal Register on April 30, although a final ruling has not been announced. John Konkus, an EPA spokesman, said the input and perspective from “the editor-in-chief of the journal Dose Response” was welcomed and reflected the perspective of “a wide variety of scientific experts” the agency reached out to when drafting the proposal.

Public health specialists outside the agency say that if the final language is adopted, it is likely to tie the EPA in knots as it tries, and then debates, all the alternative models. It could also have profound effects on current and future standards for drinking water, air, and toxic waste sites. “EPA tries to be conservative in its setting of risks,” said Jan Beyea, a retired radiation physicist who has worked with the National Academies of Science. “Calabrese and collaborators think that most pollutants are good for you at low doses, so no need to be conservative.” EPA spokeswoman Molly Block declined to speculate on whether the rule would be passed and how it would affect environmental rules that were set based on the linear no-threshold model.

Industry groups have praised the proposed change. “We support moving away from over-reliance on the linear no-threshold default,” wrote a spokesman for the American Chemistry Council, the trade group for the chemical industry. LNT is a method, he says, that “frequently results in inflated health risk estimates and unwarranted, costly risk management decisions.” Milloy also seemed pleased with the proposed ruling. “The EPA should be open and transparent about how and what they are basing their decisions on,” he said, “and they should be using the best science available.” In any case, he said, “we’re winning.”

Susanne Rust

Susanne Rust is an investigative reporter specializing in environmental issues. Before coming to the Los Angeles Times, she was the editor of Columbia University’s Energy & Environmental Reporting Project, where she oversaw several reporting projects, including a series that examined ExxonMobil’s understanding of climate science in the 1980s, 1990s and early 2000s. Rust started her career in 2003 as a science reporter at the Milwaukee Journal Sentinel. She is the recipient of numerous journalism awards, and was a John S. Knight fellow at Stanford University in 2009, and the Center for Investigative Reporting’s environment reporter between 2010 and 2014.

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Plant defense: A phytolexin (kiwellin-1) blocks metabolic activity of fungal virulence factor

This topic is an excellent gene-environment interactions example. Attack of a fungus (environmental signal) on the host (a corn plant) results in genes (responding to the environmental signal) that mobilize a chemical (kiwellin-1) to defend itself against the invading fungus. Organisms, such as fungi, that cause disease in plants, often secrete proteins that aid the fungus’s growth and reproduction in the host. These are termed effector proteins, and some like to manipulate key metabolic pathways in the plant. Authors [see attached article] identified a protein in maize (corn) that blocks the enzymatic activity of a fungal effector enzyme — thereby preventing the effector’s ability to influence maize metabolism in a way that limits the plant’s defense response.

Authors studied infection of maize by the fungus Ustilago maydis, which can cause corn smut disease and results in substantial crop loss worldwide. The enzyme chorismate mutase (Cmu1), which converts chorismate to prephenate, is a known effector protein of this fungus.

Authors engineered a tagged version of Cmu1 to search for any plant proteins that might interact with Cmu1 in maize leaves infected specifically with U. maydis. Authors found a maize protein (which they call ZmKWL1) that binds to Cmu1. They then determined that ZmKWL1 is a member of a family of 20 proteins (in maize) called the kiwellins, and only ZmKWL1 was highly expressed in response to the U. maydis infection. Furthermore, ZmKWL1 exclusively bound and inhibited purified U. maydis Cmu1 in cell culture, whereas maize versions of chorismate mutase were not affected by ZmKWL1 (the specificity of this interaction is remarkable, given the structural similarity between the fungal and maize enzymes).

Phylogenetic analysis suggests that plant kiwellins have a versatile scaffold that can specifically counteract pathogen effectors such as

Cmu1. During colonization, the fungal enzyme Cmu1 is translocated to the cytosol of plant cells, where its chorismate mutase activity seems to channel chorismate into the phenylpropanoid pathway — thereby preventing biosynthesis of salicylic acid, a central signal for plant innate immune responses against biotrophic pathogens. Interfering with salicylic acid biosynthesis pathways is a well-known general strategy of plant-pathogenic fungi, oomycetes (fungus-like filamentous, microscopic, absorptive organisms that reproduce both sexually and asexually) and nematodes (roundworms). Salicylic acid is used by secreted chorismate mutase and isochorismatase enzymes.

DwN

Nature 31 Jan 2o19; 565: 650–653 [article] & pp 575-577 [News’N’Views editorial]

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How can we optimally integrate Behavioral Medicine into Clinical Genetics and Genomics??

As a human geneticist, I have always been interested ethical behavior, i.e. in how each individual patient might agree to undergoing a particular “genetic test” versus refusing to have such a test — based on many factors (age, gender, trait being examined for, education, ethnicity, etc.). The attached article (coauthored by eight behavioral scientists from various universities around the U.S.) summarizes what they believe we should consider as ethical challenges (barriers) and potential actions to take, in order to hasten integration of clinical genetics and genomics with behavioral medicine.

Authors believe that behavioral medicine and related work in the communication, behavioral, and social sciences — is well equipped to help address these challenges. Decision science, for example, has produced abundant evidence that human decision-making is not as unpredictable as it might appear, but rather is driven by several core principles (e.g. the desire to pursue the minimum satisfactory condition or outcome, when faced with complex choices). It is certainly true that patients bring many different emotions and motivations to settings where they are making sense of, or making decisions regarding, health information.

In one genomic-sequencing cohort study cited by the authors, participants who had been expected to become distraught in response to unwelcome genetic feedback were, in turn, less likely to seek those results; however, this pattern did not occur among individuals who tended to focus on personal values and strengths in the context of threat. Findings such as these only scratch the surface of understanding the panoply of psychological constructs driving a person’s engagement with genetic information.

One central question is the extent to which access to genetic information might influence behavior — particularly behaviors (e.g. consenting to screening, making lifestyle changes, and adhering to treatments) that reduce the effects of genetic risk. So far, evidence of such an effect across a range of behaviors has been mixed; one meta-analysis suggested little to no effect, whereas another provided more promising evidence. In general, this literature is only in its infancy and is based largely on communication of single-gene results in mostly homogeneous populations.

Whether genetic risk information influences behavior and decision-making is also only part of the story — behavioral medicine can help us understand how, when, and why it might have such an effect. Moving from the individual to the population, the promises of precision medicine and population health — rely squarely on the ability to enable broad and sustainable access within complex health systems to genomics informed innovation. Implementation science frameworks offer a roadmap for interdisciplinary considerations of the important technical and contextual factors required to shape dissemination accordingly. Various data from previous genetics and genomics research are perfect examples of medical advancements ripe for the application of research on human behavior.

DwN

Am J Hum Genet Feb 2019; 104: 193–196

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