Involvement of mitochondrial DNA in the initiation of autoimmune disease ???

COMMENT:
Dear anonymous 6th-grade teacher,

This sounds like a very astute student; I wonder if one or both of her parents might have careers in some aspect of biological science or medicine? The original report of using mitochondrial DNA to trace human ancestry back to the original “African Eve”, published in Science or Nature back in the 1980s, was subsequently found to be naïve. I’ve searched for, but cannot find, that original paper (author was an evolutionary geneticist from California, as I recall). I did find two relevant follow-up papers (1989 & 1996), which answer part of your question (summaries pasted below). Remember, the first human genome was not fully sequenced until well after 1996, so these papers precede that accomplishment by several years. In recent years, far more has been learned from fossil DNA — about the Great Human Diaspora.

As with everything in science — what starts out as “appearing simple” — winds up being far more complex, by many orders of magnitude. The myth that “all mtDNA always comes from the mother” is no longer true; there are a few published cases where they found the mtDNA derived 100% from the father, and other cases where some percentage of mtDNA is paternally-derived. So, to start with, the mother’s mitochondria are NOT ALWAYS the only ones that get passed on to her children…

Then, our (nuclear) genomic DNA (gDNA) — as well as our mtDNA today — represents what has been passed down from an unknown small number of original Homo sapiens when they first appeared ~300,000 years ago. But, of course, with mutations and chromosomal rearrangements (that have occurred over about 15,000 generations of modern humans) — things DO change A LOT over that amount of time. And, quite remarkably, DNA from fossil bones has shown us that there are five fundamental “isolated geographic groups” in the world: African, Asian, Caucasian, Oceanian and Amerindian — from which all ethnic groups on Earth originate.

From complicated mathematical extrapolations, researchers have even estimated the approximate number of men and number of women that “appear to have participated” in the “original genetic bottleneck” of a tribe migrating out of Africa toward southeast Asia, or through the Caucasus Mountains into (present-day) Europe, or across the Siberia Strait into the Americas, etc. But, even this today, is far too simplistic, due to back-migrations and cross-group admixtures (among modern humans, Denisovans and Neanderthals).

To re-summarize this study and editorial [see attached] — when mitochondria become “stressed” by one or another environmental adversity, some of the (circular) mtDNA — breaks up into small fragments, and the study found that VDAC oligomerization in the mitochondrial outer membrane, causes leaks when mitochondria are stressed — resulting in these mtDNA fragments leaking out into the cytosol, where “self-antibodies” to one’s own mtDNA are then formed, perhaps playing a role in initiation of one or another autoimmune disease. Authors thus suggest VDAC as a potential drug target to prevent this pathology from occurring. 😊

Am J Hum Genet. 1989 Jan;44(1):73-85.

Origin and differentiation of human mitochondrial DNA.

Excoffier L1, Langaney A.

Author information

Abstract

A recent study of mitochondrial DNA (mtDNA) polymorphism has generated much debate about modern human origins by proposing the existence of an “African Eve” living 200,000 years ago somewhere in Africa. In an attempt to synthesize information concerning human mtDNA genetic polymorphism, all available data on mtDNA RFLPs have been gathered. A phylogeny of the mtDNA types found in 10 populations reveals that all types could have issued from a single common ancestral type. The distribution of shared types between continental groups indicates that caucasoid populations could be the closest to an ancestral population from which all other continental groups would have diverged (This is now all proven to be wrong) A partial phylogeny of the types found in five other populations also demonstrates that the myth of an African Eden was based on an incorrect “genealogical tree” of mtDNA types. Two measures of molecular diversity have been computed on all samples on the basis of mtDNA type frequencies, on one hand, and on the basis of the number of polymorphic sites in the samples, on the other. A large discrepancy is found between the two measures except in African populations; this suggests the existence of some differential selective mechanisms. The lapse of time necessary for creating the observed molecular diversity from an ancestral monomorphic population has been calculated and is found generally greater in Oriental and caucasoid populations. Implications concerning human mtDNA evolution are discussed. PMID: 2562823 PMCID: PMC1715476

Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13859-63.

Misconceptions about mitochondria and mammalian fertilization: implications for theories on human evolution.

Ankel-Simons F1, Cummins JM.

Author information

Abstract

In vertebrates, inheritance of mitochondria is thought to be predominantly maternal, and mitochondrial DNA analysis has become a standard taxonomic tool. In accordance with the prevailing view of strict maternal inheritance, many sources assert that during fertilization, the sperm tail, with its mitochondria, gets excluded from the embryo. This is incorrect. In the majority of mammals—including humans—the midpiece mitochondria can be identified in the embryo even though their ultimate fate is unknown. The “missing mitochondria” story seems to have survived–and proliferated-unchallenged in a time of contention between hypotheses of human origins, because it supports the “African Eve” model of recent radiation of Homo sapiens out of Africa. We will discuss the infiltration of this mistake into concepts of mitochondrial inheritance and human evolution. PMID: 8943026 PMCID: PMC19448

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Many clinical trials are not getting posted publicly, as required by law

This topic more or less falls within the theme of these GEITP pages — having to do with fraud and corruption in science; however, this editorial [see attached] is more specifically about laziness, or “lack of respecting federal existing requirements.” For 20 years, the U.S. government has urged companies, universities, and other institutions that conduct CLINICAL TRIALS to record their results in a federal database, so that physicians and patients can see whether new treatments are safe and effective. Even after a 2007 law mandated that “it is required that clinical trials registered in the federal database be made public” (in a timely manner), few trial sponsors have consistently done so. ☹

In 2017, the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) tried again — enacting a long-awaited “Final Rule” to clarify the law’s expectations and penalties for failing to disclose trial results. The rule took full effect two years ago (on 18 Jan 2018), giving trial sponsors ample time to comply. But a recent investigation shows that many still ignore this requirement, while federal officials do little or nothing to enforce the law. Science journal examined more than 4,700 trials whose results should have been posted on the NIH website ClinicalTrials.gov, under the 2017 rule. Reporting rates by most large pharmaceutical companies and some universities have improved sharply, but performance by many other trial sponsors — including (ironically) NIH itself — has been lackadaisical. Those sponsors, typically either the institution conducting a trial or its funder, must deposit results and other data within 1 year of completing a trial [see attached editorial].

However — of 184 sponsor organizations having at least five trials due (as of 25 Sept 2019), 30 companies, universities, or medical centers never met a single deadline (see https://scim.ag/ctgov). As of that date, these habitual violators had failed to report any results for 67% of their trials, and they averaged 268 days late for those and all trials that missed their deadlines. They included such eminent institutions as Harvard University–affiliated Boston Children’s Hospital, University of Minnesota, and Baylor College of Medicine — all three among the top 50 recipients of NIH grants in 2019. The violations cover trials in virtually all fields of medicine, and the missing or late results offer potentially vital information for the most desperate patients. [For example, in one long-overdue trial, researchers compared the efficacy of different chemotherapy regimens in 200 patients with advanced lymphoma; another — nearly two years late — tested immunotherapy against conventional chemotherapy in about 600 people with late-stage lung cancer.]

On a somewhat related topic, a personal irritation that some colleagues know I’ve been upset about — is when any scientific grant is finished, and the researcher (postdoc, grad student or other) has all the data, but “never gets around to writing up the manuscript.” The grant, given to the Principal Investigator, is a gift, it is a privilege, paid for with taxpayers’ money, and everyone should feel responsible to the taxpayers for completing the task of writing up the project which was funded, whether or not the data are exciting, or boring, or completely negative and disappointing. ☹

comment: Todd, this is an excellent idea. They’ve had the Journal of Irreproducible Results (JIR) — since 1955. For anyone not aware of this journal, it is a spoof (science satire). Sort of like Mad Magazine. 😊 [JIR was founded in Israel in 1955 by virologist Alexander Kohn and physicist Harry J. Lipkin, who wanted a humor magazine about science — for scientists.]

DwN

Science 17 Jan 2020; 367: 240-243

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A “sensory appendage protein” protects malaria vectors from pyrethroids ??

The wide distribution of insecticide-treated mosquito nets — over the past two decades, across malaria-endemic regions — has markely decreased the incidence of malaria, saving probably millions of lives. Recently, however, malaria-carrying mosquitoes have now been found to have developed strong resistance to the pyrethroid chemicals used in these insecticidal nets. An understanding of the mechanisms underlying this recently developed “resistance” — would benefit society by making mosquitoes once again more susceptible. This topic is a classic “gene-environment interactions” and “evolution by adaptation” story 😊 : the environmental “signal” is the insecticide-treated net, which is causing difficulty for these mosquitoes to survive; hence, genes in their genome have been modified so as to “overcome” this adversity and once again allow the poor mosquito to survive. ☹

Authors [see attached article and editorial] discovered a surprising means by which mosquitoes in Africa neutralize pyrethroids: the insects use a class of small proteins normally involved in chemical communication, to improve the mosquito’s chances of survival. This intense selection pressure — exerted by pyrethroid-impregnated bed nets — has triggered widespread and escalating resistance to pyrethroids in Anopheles populations; and this adaptation (by the mosquito’s genome) to this environmental adversity now threatens to reverse the gains that been made by malaria control. Authors show that expression of sensory appendage protein-2 (SAP2), enriched in mosquito’s legs, is involved in pyrethroid resistance in Anopheles gambiae. SAP2-gene expression was found to be increased in insecticide-resistant populations and to become further induced — if the insect comes into contact with pyrethroids. SAP2-gene silencing fully restored pyrethroid sensitivity (and mortality of the mosquitoes) — whereas SAP2-gene over-expression resulted in increased resistance — probably owing to high-affinity binding of SAP2 to pyrethroid insecticides.

Anopheles mosquitoes are the only genus capable of transmitting human malaria. Contact with pyrethroid insecticide also decreases the likelihood that mosquitoes will survive long enough to develop and transmit the Plasmodium parasite (which causes malaria in warm-blooded hosts). Pyrethroid nets contain the synergist piperonyl butoxide (PBO), a potent inhibitor of metabolic resistance mediated by cytochromes P450s — one of the most widespread, and hitherto most potent, resistance mechanisms. Blocking this resistance mechanism allows these PBO–pyrethroid nets to produce insecticide susceptibility, leading to a reduction in malaria cases in areas in which metabolic resistance had prevailed.

Data-mining of the mosquito genome reveals a “selective sweep” near the SAP2 locus in mosquito populations of three West African countries (Cameroon, Guinea and Burkina Faso), concomitant with the reported increased frequency in haplotype-associated single-nucleotide variants (SNVs) — this finding is consistent with previous reports of increasing resistance of mosquitoes in Burkina Faso (recall that ‘haplotype’ represents a group of genes inherited together on one chromosome of the chromosome pair, i.e. originating from one of the two parents). This study therefore identifies a previously undescribed mechanism of insecticide resistance that is likely to be highly relevant to future malaria-control efforts.

DwN

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Mullti-omics profiling of mouse gastrulation at single-cell resolution

From time-to-time, these GEITP pages have discussed topics of developmental biology (such as this paper) — because there are many similarities to evolution (and both involve gene-environment interactions). Early mammalian developmental stages include: [a] Zygotic stage (zygote is formed when sperm and egg fuse); [b] Blastocyst stage (single-celled zygote begins to divide into a solid cluster of cells, which then becomes a hollow ball called a blastocyst (which attaches to endometrium of the mother’s uterus); [c] Gastrulation stage (single-cell-layered blastula is re-organized into a multi-layered structure called the gastrula, which includes the inner cell mass). Formation of the three primary germ cell layers (endoderm, mesoderm, exoderm) during gastrulation is an essential step in establishing the vertebrate body plan; this process is known to be associated with major transcriptional changes (DNA being transcribed into RNA).

Global epigenetic reprogramming accompanies these changes [which were studied in the attached paper]. Authors describe a “single-cell multi-omics map” of chromatin accessibility, DNA methylation, and RNA expression during the onset of gastrulation in mouse embryos. The initial exit from pluripotency (ability of a cell to develop into any of the three primary germ cell layers) coincides with the establishment of a global repressive epigenetic landscape — followed by emergence of lineage-specific epigenetic patterns during gastrulation. Cells — committed to mesoderm and endoderm — undergo widespread coordinated epigenetic rearrangements at enhancer marks, driven by ten-eleven translocation (TET)-mediated demethylation and concomitant increase in chromatin accessibility. In contrast, the methylation and chromatin accessibility landscape of ectodermal cells is already established in the early epiblast (the outermost layer of the gastrula — before it differentiates into ectoderm and mesoderm).

Hence, regulatory elements associated with each germ layer are either epigenetically primed, or remodeled — before cell-fate decisions — which provides the molecular framework for a hierarchical emergence of the primary germ layers. Recent technological advances have enabled the profiling of multiple molecular layers at single-cell resolution, providing novel opportunities to study the relationship between the transcriptome (DNA —> mRNA) and epigenome (genes involved in DNA methylation, RNA interference, histone modifications, chromatin remodeling) during cell-fate decisions. Authors [see attached article] studied single-cell nucleosome-, methylome- and transcriptome-sequencing (scNMT-seq) to profile 1,105 single cells isolated from mouse embryos at four developmental stages [embryonic day (E)4.5, E5.5, E6.5 and E7.5] representing the exit from pluripotency and primary germ-layer specification. Cells were assigned to a specific lineage by mapping their RNA-expression profiles to a comprehensive single-cell atlas for each developmental stage. Using dimensionality reduction, authors show that all three molecular layers contain sufficient information to separate cells by stage and by lineage identity.

To relate epigenetic changes to the transcriptional dynamics across stages, authors calculated — for each gene and across all embryonic cells — correlations between RNA expression and corresponding DNA methylation, or chromatin accessibility, at the gene’s promoter region. Out of 5,000 genes tested, authors identified 125 genes, the expression of which showed significant correlation with promoter DNA methylation, and 52 genes with expression significantly correlated with chromatin accessibility. These loci largely comprise markers of early pluripotency and germ cells (e.g. Dppa4, Zfp42, Tex19.1 and Pou3f1), which are repressed, coinciding with the global increase in methylation, and decrease in chromatin accessibility. In addition, authors identified Trap1a and Zfp981 genes, which so far have unknown roles in development. In summary, this mind-boggling study (mind-boggling because it boggles our minds what can now be done at the single-cell level) shows that regulatory elements (associated with each germ layer) are either epigenetically primed, or remodeled — before cell-fate decisions occur, providing a molecular framework for a hierarchical emergence of the three primary germ cell layers. 😊

DwN

Nature 19/26 Dec 2019; 576: 487-491

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HAPPY NEW YEAR OF THE RODENT

25 January 2020: HAPPY NEW YEAR OF THE RAT (or mouse, … or rodent)

— These GEITP pages think that the MOUSE is much cuter than the RAT. 😊

Kingdom Animalia Phylum Chordata Class Mammalia Order Rodentia Family Muridae Genus Rattus Species rattus

Genus Mus Species musculus

DwN

nb..mm takes no responsibility for using a stock photo… however it is well water-marked

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Scientists discover ‘why stress turns hair white’

This news article — published this week in BBC.com — is an example of the gene-environment interactions theme of these GEITP pages. In this case, the environmental signal is “stress”, and the genes that respond to this signal include a pathway that increases risk of turning one’s hair white. The scientific paper can be found in Nature online.

The protein that is released during stress was identified as cyclin-dependent kinase (CDK). Although authors propose that “perhaps targeting the CDK gene might prevent stress-induced grey hair, it must be kept in mind that “CDK” is not a single gene but rather represents at least five genes. Moreover, this complex is involved in dozens of other critical-life pathways. So, to block this drug (trying to prevent grey hair) — might be more than a little bit naïve. ☹
DWN

Scientists discover ‘why stress turns hair white’

· 22 January 2020

· https://www.bbc.com/news/health-51208972

Scientists say they may have discovered why stress makes hair turn white, and a potential way of stopping it frim happening — without reaching for the dye.

In experiments on mice, stem cells that control skin and hair color became damaged after intense stress.

In a chance finding, dark-furred mice turned completely white within weeks.

The US and Brazilian researchers said this avenue was worth exploring further — perhaps to develop a drug that might prevent hair color loss during our normal aging process. Men and women can go grey any time from their mid-30s, with the timing of parental hair color change giving most of the clues on when.

Although it’s mostly down to the natural aging process and genes, stress can also play a role. But scientists were not clear exactly how stress affects the hairs on our heads.

Researchers behind the study, published in Nature, from the Universities of Sao Paulo and Harvard, believed the effects were linked to melanocyte stem cells, which produce melanin and are responsible for hair and skin color. And while carrying out experiments on mice, they stumbled across evidence this was the case. “We now know for sure that stress is responsible for this specific change to your skin and hair, and how it works,” says Prof Ya-Cieh Hsu, research author from Harvard University.
‘Damage is permanent’

Pain in mice triggered the release of adrenaline and cortisol, making their hearts beat faster and causing their blood pressure to rise, which affects the nervous system and causes acute stress. This process then increased the rate of depletion of stem cells that produce melanin in hair follicles.

“I had expected stress was bad for the body,” said Prof Hsu. “But the detrimental impact of stress that we discovered was beyond what I imagined. After just a few days, all the pigment-regenerating stem cells were lost. And, once they’re gone, you can’t regenerate pigment any more — the damage is permanent.”

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Corrupting Medical Education

In keeping with these GEITP pages sometimes discussing fraud and corruption in science — the attached article by Jane M. Orient, MD (who practices internal medicine in Tucson AZ, and serves as executive director of Assn Am Physicians & Surgeons and managing editor of the J.A.P.S.), is especially remarkable in that she brings together medical care and fundamental climatology, combined with how these fields intersect with public policy and (unfortunately) politics. Because this topic dovetails into GEITP discussions from last Sept (“Corrupting Medical Education”), we have included those articles and comments below.

A “climate emergency” has recently been declared by one segment of the population, and there are pressure groups — throughout the Western World [but, interestingly, not Asia, Africa or South America) — that are demanding radical change in all areas of life, including medical ethics. And there seems to be “no time” for reflection or the gathering or discussion of scientific evidence. Just this morning on The Weather Channel, there was an advertisement about “The Rush to Save the Planet.” Can this become even more hysterical and nonsensical than it is today?

According to the first of the A.A.P.S. Principles of Medical Ethics, “The physician’s first professional obligation is to his patient, then to his profession. His ethical obligation to his community is the same as that of any other citizen.” The AAPS motto “omnia pro aegroto” means “everything for the patient.” In recent decades, organized medicine — notably the Am Med Assn (AMA) and the Am Coll of Physicians (APS) — has introduced a fundamental transformation: Individual patient welfare has now become subordinate to a perceived collective benefit. The AMA states “there are multiple stakeholders, whose interests must be balanced.” Various groups seek to divert physicians’ energy and capitalize on their trusted status to promote a political agenda.

In the current widely promoted extreme view, “our ailing planet” is supposed to be our first priority. In a Nov 2019 N Engl J Med article, authors write: “We believe that the current imperative for climate action requires physicians to mobilize politically as they have before, again becoming fierce advocates for major social and economic change. A truly ethical relationship with the planet that we inhabit so precariously, and with the generations who will follow, demands nothing less.” Another article [see attached] wrote in the 1990 Ann Int Med: “global environmental change including, potentially, global warming, which is produced by the growing numbers and activities of human beings, threatens the habitability of the planet and the health of its inhabitants. Thus, it is socially responsible for physicians to use “their expertise about the environment” to try to prevent such change.”

In this 5-page Guest Editorial, Dr. Orient carefully lays out the problems with this naïve view: [a] If one studies and understands the actual atmospheric scientific data that exist, there is no climate crisis; [b] the UN International Panel on Climate Change (IPCC) even admits that proposed “actions to curb global warming” will have no measurable impact on climate; [c] It is impossible to replace the >80% of the world’s energy now generated by coal, oil, and natural gas — with wind or solar energy, given the requirements for land, metals, concrete, and energy-intensive manufacture (also, these ‘renewal energies’ actually cost more and create a larger ‘carbon footprint’ than fossil fuels); [d] Rising atmospheric CO2 levels claimed to be correlated with rising global temperatures actually show that warming ocean temperatures precedes the rise in CO2 levels, not the other way around; [e] Life on Earth is based on carbon, and CO2 is beneficial to plants (thus, to consider lowering CO2 is complete nonsense); [f] Ice-core data show ~115,000-year Glacial-Interglacial cycles — since coming out of our last serious Glacial Cycle ~11,500 years ago, it only makes sense that Earth must be warming, before it again cools; [g] The (‘consensus’) assertion that “97% of climate scientists agree with the apocalyptic climate scenarios” is completely bogus (the actual value is well under 20%, simply because most scientists are as illiterate as journalists sand politicians about climatology); and [h] Fossil fuel energy is correlated with better health — therefore, eliminating fossil fuels will negatively affect human health, and especially for those in poverty.

Those GEITPers who have an open scientific mind are urged to read carefully the attached article. 😊 Those GEITPers who cannot separate political agenda from science will probably delete this GEITP email without looking at the attached article. ☹

DwN

From: Nebert, Daniel (nebertdw)
Sent: Monday, September 23, 2019 3:48 PM
Subject: Corrupting Medical Education

We have one final episode on this topic. Among a number of comments to Professor Boat’s email, I have chosen three and we will keep them “anonymous.”

—DwN

From: Anonymous PhD professor
Sent: Thursday, September 19, 2019 10:03 AM

May I offer a different approach to this problem? If med schools need to be 5 or 6 years long – in order to cover all important material to teaching med students everything, well then that should happen. The amount of (increasing, exploding) information that is now relevant to health and well-being of our species (our planet) can probably never be covered in the short 4 years allotted now, nor in the ensuing years of internship and residence. If overall information has increased, and the educational needs are increased, then why not increase the length of time spent in medical school…?

From: Anonymous MD faculty
Sent: Thursday, September 19, 2019 4:21 PM

We “should be teaching gun control, social justice, racial inclusivity, health disparities, cultural diversity, and global warming in medical school?” Come on. Give me a break. Recently our own medical school curriculum decided to drop biochemistry, as a “course no longer needed for physicians.” What’s next – should we drop pathology? physiology? parasitology? microbiology?

Any reasonably intelligent child – who ultimately might attend medical school – should be able to learn all he needs to know about “social justice, racial inclusivity, health disparities and cultural diversity” during his childhood years within his own family, combined with his early school years, and church. I am reminded of Robert Fulghum’s book, decades ago: “All I Really Need to Know I Learned in Kindergarten.” If a child by age 12 does not “know” about these issues, what further can be learned by a college or medical school course in such topics?

“Gun control” and “global warming,” on the other hand, are absolutely 100% political issues, and certainly not related to any “medical education.” The extremely complex field of “climate change” (which has been occurring since Earth first formed) can be taught in middle school – if teachers are willing to teach the actual principles of atmospheric sciences.

From: Anonymous retired Jesuit Priest
Sent: Friday, September 20, 2019 4:12 PM

Rigorous scientific medical training should be the overwhelming goal of medical schools. All this “social reality promotion” is taken care of by other institutions (prior to medical school) in our general society; in fact, this is why new “social scientists” within the medical profession have become aware, in the first place, of these purported social problems. However, I do not want to go to a physician to hear him preach to me about social ills!

From: Nebert, Daniel (nebertdw)
Sent: Thursday, September 19, 2019 9:04 AM

Thank you for your email, Tom. This topic can easily “tip over into” polarizing politics of the “extreme left” versus the “extreme right.” In presenting this [see everything below], I’ve tried hard to stay in the “strait-and-narrow” — between medical education and politics. There were hundreds of online “comments” to those newspaper articles — which I chose not to share with GEITP, because many were inappropriate for these GEITP pages.

DwN

From: Boat, Thomas
Sent: Thursday, September 19, 2019 6:39 AM
To: Nebert, Daniel (nebertdw)
Subject: RE: Corrupting Medical Education

Dan— I am usually in agreement with your assessments. On this one, I cannot be more concerned about your position. If medicine does not engage health promotion and prevention and get more involved with mitigating social determinants of health as well as promoting behavioral as well as physical health, our nation will continue to be in a position of rescuing more and more adults whose health could have been improved through early life (0-5) attention to all dimensions of health promotion as a part of well child care. This effort must include attention to family well-being, but also school, community, state and national support and policies for improving environments in which children are raised. Medicine can be a direct participant and an advocate for these efforts.

See the recently released report from the National Academies of Sciences, Engineering and Medicine titled Fostering Healthy Mental, Emotional and Behavioral Development for Children and Youth. The social and economic welfare of our country is at stake — as increasing numbers of our children are hitting adulthood with behavioral disorders, chronic diseases, and inability to contribute to society by productively joining the workforce. If medicine does not do its part, shame on us. One further point, if these considerations are not a part of training, medicine is unlikely to contribute. This is not left wing thinking. Please do not make an important determinant of our economic future a polarizing issue. You can share this point of view with others if you wish.

Tom

[Emeritus; formerly Dean of the University of Cincinnati College of Medicine; formerly Director of Cincinnati Children’s Hospital]

From: Nebert, Daniel (nebertdw)
Sent: Wednesday, September 18, 2019 4:53 PM
Subject: Corrupting Medical Education

In the Sept 17 article “Corrupting Medical Education” [see far below], some of you told me that they cannot download the original Sept 12 article by Dr. Goldfarb — without a subscription to Wall Street Journal. Consequently, I am now pasting it below, for everyone’s reading pleasure. This article was in WSJ online evening of Sept 12, out in print morning of Sept 13. For your bedtime reading pleasure. One of the ongoing themes of these GEITP pages is to discuss fraud and corruption in science and medicine.

DwN

Take Two Aspirin and Call Me by My Pronouns
At ‘woke’ medical schools, curricula are increasingly focused on social justice rather than treating illness.

By Stanley Goldfarb

Sept. 12, 2019 5:54 pm ET

The American College of Physicians says its mission is to promote the “quality and effectiveness of health care,” but it’s stepped out of its lane recently with sweeping statements on gun control. And that isn’t the only recent foray into politics by medical professionals. During my term as associate dean of curriculum at the University of Pennsylvania’s medical school, I was chastised by a faculty member for not including a program on climate change in the course of study. As the Journal reported last month, such programs are spreading across medical schools nationwide.

Why have medical schools become a target for inculcating social policy—when the stated purpose of medical education since Hippocrates has been to develop individuals who know how to cure patients?

A new wave of educational specialists is increasingly influencing medical education. They emphasize “social justice” that relates to health care only tangentially. This approach is the result of a progressive mind-set that abhors hierarchy of any kind and the social elitism associated with the medical profession in particular.

These educators focus on eliminating health disparities and ensuring that the next generation of physicians is well-equipped to deal with cultural diversity, which are worthwhile goals. But teaching these issues is coming at the expense of rigorous training in medical science. The prospect of this “new,” politicized medical education should worry all Americans.

The traditional American model of medical training, which has been emulated around the world, emphasizes a scientific approach to treatment, and it subjects students to rigorous classroom instruction. Students didn’t encounter patients until they had some fundamental knowledge of disease processes and knew how to interpret symptoms. They were expected to appreciate medical advances and be able to incorporate them into their eventual fields of practice. Medical education was demanding and occasionally led to student failure, but it produced a technically proficient and responsible physician corps for the U.S.

The traditional American model first came under attack by progressive sociologists of the 1960s and ’70s, who condemned medicine as a failing enterprise because increased spending hadn’t led to breakthroughs in cancer treatment and other fields. The influential critic Ivan Illich called the medical industry an instrument of “pain, sickness, and death,” and sought to reorder the field toward an egalitarian social purpose. These ideas were long kept out of the mainstream of medical education, but the tide of recent political culture has brought them in.

As concerns about social justice have taken over undergraduate education, graduate schools have raced to develop curricula that will steep future educators in the same ideology. Today a master’s degree in education is often what it takes to qualify for key administrative roles on medical-school faculties. The zeitgeist of sociology and social work have become the driving force in medical education. The goal of today’s educators is to produce legions of primary care physicians who engage in what is termed “population health.”

This fits perfectly with the current administrator-rich, policy-heavy, form-over-function approach at every level of American education. Theories of learning with virtually no experimental basis for their impact on society and professions now prevail. Students are taught in the tradition of educational theorist Étienne Wenger, who emphasized “communal learning” rather than individual mastery of crucial information.

Where will all this lead? Medical school bureaucracies have become bloated, as they have in every other sphere of education. Curricula will increasingly focus on climate change, social inequities, gun violence, bias and other progressive causes only tangentially related to treating illness. And so will many of your doctors in coming years.

Meanwhile, oncologists, cardiologists, surgeons and other medical specialists are in short supply. The specialists who are produced must master more crucial material even though less and less of their medical-school education is devoted to basic scientific knowledge. If this country needs more gun control and climate change activists, medical schools are not the right place to produce them.

Dr. Goldfarb is a former associate dean of curriculum at the University of Pennsylvania’s Perelman School of Medicine.

From: Nebert, Daniel (nebertdw)
Sent: Tuesday, September 17, 2019 1:37 PM
Subject: Corrupting Medical Education

This was recommended to me (to be shared with all of GEITP) by several Readers. This brief article appeared in the Wall Street Journal online, afternoon of Sept 15, out in print morning of Sept 16. It refers to an earlier article (by Dr. Goldfarb) from the week before, which can be clicked on and downloaded.

DwN

Corrupting Medical Education
The reaction to Dr. Goldfarb’s op-ed proves his point.

By The Editorial Board

Sept. 15, 2019 4:09 pm ET

Stanley Goldfarb knew what he was talking about. Last week the former associate dean of curriculum at the University of Pennsylvania medical school wrote in these pages that climate change, gun control and “other progressive causes only tangentially related to treating illness” were beginning to corrupt medical training. His piece spurred a social-media eruption that immediately proved his point.

Left-wing Medical Twitter —yes, there is such a thing—piled on, with virtue signaling that distorted Dr. Goldfarb’s argument. He didn’t write that doctors shouldn’t have opinions about political issues. He wrote that those issues shouldn’t interfere with the scientific and clinical training essential to producing doctors who can serve patients.

The most disappointing response came from Penn medical school, which sprinted for political cover. Dean J. Larry Jameson and Senior Vice Dean Suzanne Rose sent a letter to students and faculty that is a case study in progressive correctness:

“Please know that the views expressed by Dr. Goldfarb in this column reflect his personal opinions and do not reflect the values of the Perelman School of Medicine,” the letter said. “We deeply value inclusion and diversity as fundamental to effective health care delivery, creativity, discovery, and life-long learning. We are committed to ensuring a rigorous and comprehensive medical education that includes examination of the many social and cultural issues that influence health, from violence within communities to changes in the environment around us.”

Maybe we should begin to wonder about the quality of the doctors who graduate from Penn. Patients want an accurate diagnosis, not a lecture on social justice or climate change. Thanks to Dr. Goldfarb for having the courage to call out the politicization of medical education that should worry all Americans.

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Adaptive mutability of colorectal cancers in response to targeted drug therapy

Mutagenesis (process that enhances the number of DNA mutations) can drive carcinogenesis (initiation of cancer formation) and continue during cancer progression — generating intra-tumor genetic heterogeneity that enables cancer cells to adapt, via Darwinian evolution. Analyses (e.g. mutational signature characterization) have revealed specific mutational processes and their temporal activity during carcinogenesis and tumor progression. Nevertheless, many of the mechanisms that promote genomic instability in cancer are still puzzling. Authors [see attached article & editorial] show anti-cancer drugs that target tumor-causing epidermal growth factor receptor (EGFR) or BRAF (A gene that encodes B-RAF protein, which is involved in signaling pathways that enhance cell growth) signaling increase mutagenesis in colorectal cancer (CRC) cells — which can lead to the development of chemotherapy resistance to various anti-cancer drugs. Hence, the GEITP connection to gene-environment interactions (anti-cancer drug is the environmental signal; genes in the tumor cell respond to this signal by mutating, hoping these changes allow the tumor to survive). Just like an evolutionary process.

Authors [see attached article & editorial] discovered that human colorectal cancer (CRC) cell lines — following treatment with EGFR or BRAF inhibitors — down-regulated expression of high-fidelity DNA repair proteins and increased expression of error-prone DNA repair proteins, both of which lead to increases in mutation rates. Using reporter assays, authors further showed that the fidelity of DNA mismatch repair (MMR) and homologous recombination (HR) repair systems were impaired, and that DNA damage increased during drug treatment.

Genetic analysis of cell lines that had been exposed to these inhibitors revealed subclonal mutations in dinucleotide repeats, which are characteristic of defective MMR. In contrast to other cancer mutational processes — such as genetically encoded HR or

MMR defects that lead to persistent mutation acquisition or overexpression of apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) DNA cytidine deaminases, which generates mutational bursts — the mutagenesis program identified by these authors was tightly coupled to drug exposure; moreover, the mutagenesis program ceased after drug removal. This study demonstrates that nongenotoxic targeted oncogene pathway inhibitors can promote a temporally restricted increase in mutability by switching from high-fidelity to error-prone DNA repair.

In conclusion, EGFR/BRAF inhibition down-regulates MMR and HR DNA-repair genes and, at the same time, up-regulates error-prone polymerases in drug-tolerant (persister) cells. MMR proteins were also down-regulated in patient-derived xenografts (patient’s cancer tissue transplanted into mice) and tumor specimens during anti-cancer therapy. EGFR/BRAF inhibition resulted in increased DNA damage, mutability, and microsatellite instability. Thus, just like bacteria and other single-celled organisms, tumor cells evade therapeutic pressures (i.e. environmental signals that threaten their survival) by enhancing mutability (in the hopes that these new mutations will help the tumor survive). This is one mechanism for drug resistance developing in a patient who is undergoing anti-cancer therapy. Adaptation to adverse changes in the environment is also what drives evolution. 😊

DwN

Science 20 Dec 2019; 366: 1473-1480 & editorial pp 1452-1453

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Stepwise oxygenation of Earth is an inherent property of global biogeochemical cycling

Geological studies of ancient Earth have indicated that, when the planet began 4.54 billion years ago (BYA), it was basically anaerobic (i.e. very low levels of atmospheric O2). Then, the Great Oxidation Event (GOE) occurred between ~2.5 and 2.0 BYA, and scientists continue to argue about the cause. In mid-Dec 2019, these GEITP pages shared an article, “The Great Oxidation Event and the Lomagundi Event might have both occurred by tectonic plate movements about 2.5 billion years ago” — which suggested the entire oxygenation of Earth’s surface environment might be explained by one big event, tectonic plate transitions.

Others postulate the GOE might have occurred across three broad steps [see attached article]: [a] From 2.4 to 2.2 BYA, atmospheric O2 rose from trace levels to more than 10–5 of the present atmospheric level (PAL); [b] The next ~1.7 billion years of the Proterozoic Eon likely sustained atmospheric O2 levels of ~10–3 to 10–1 PAL; [c] The Paleozoic Oxygenation Event (POE) ~450 to 400 million years ago (MYA) appears to have elevated atmospheric O2 to present-day levels and established a dominantly oxygenated deep ocean, which persisted throughout the Mesozoic and Cenozoic Eras [these major oxygenation steps are entwined with evolution of progressively more complex life-forms, the first eukaryotes (organisms having pairs of chromosomes and nuclear membrane) evolved either after the GOE, or during the run-up to the GOE when O2 began to rise], whereas the Neoproterozoic Oxygenation Event (NOE) occurred between ~800 and 540 MYA — and was coincident with major eukaryote diversification and evolution of the first animals, followed by the Cambrian explosion, during which animals began to dominate marine ecosystems.

Tectonic evolution has also been considered as a potential driver of the stepwise transitions in Earth surface oxygenation. Changes in plate tectonics have been linked to the GOE through (e.g. a change in the fraction of subaerial volcanism or composition of the

crust). Some, but not all, supercontinent formation times correspond to oxygenation events, as do emplacement times of some large igneous provinces (LIPs), which are proposed to have driven ocean oxygenation through delivery of the limiting nutrient, phosphate (PO4—). However, the geologically rapid yet ultimately rare nature of Earth’s oxygenation events does not clearly correspond to either tectonic or evolutionary processes; for example, mantle dynamics and the supercontinent cycle are unlikely to produce large-scale changes on time-scales on the order of less than ~100 million years, whereas LIP emplacements are far more common than major rises in O2. Looking to biological innovations, the time scale between origination of a domain or kingdom of life (e.g. Eukarya) and its rise to global ecological dominance may also be hundreds of million-years. Furthermore, oscillations in ocean redox (reduction–oxidation) — that are apparent during the NOE — are difficult to explain through a sequence of tectonic or biological “switches” acting on the system.

It is therefore possible that Earth’s stepwise-oxygenation was not the product of individual trigger events and may instead be explained by some inherent gradient of global biogeochemical feedbacks. This hypothesis has wide implications for the evolution of life on Earth and other planets; therefore, there have been a number of attempts to explain the known stepwise O2 trajectory as a feature of Earth’s internal dynamics (e.g. it has been shown that atmospheric feedbacks might have promoted the GOE). However, no study has provided a sound theoretical basis that can explain the trajectory and timing of marine and atmospheric oxygenation over Earth’s history — without relying on either external trigger events or arbitrary switches in the model itself (e.g. assuming a transition to greater nutrient availability when O2 crosses a threshold).

Authors [see attached article] identified a set of feedbacks that exist — between the global P, C, and O cycles — which are capable of driving rapid shifts in oceanic and atmospheric O2 levels, without requiring any stepwise change in either tectonics

or evolution of the biosphere. These feedbacks replicate the observed three-step oxygenation pattern, when driven solely by a

gradual shift from reducing to oxidizing surface environmental conditions over time. Phosphorus (P) is generally considered the

ultimate limiting nutrient for marine productivity over geological time-scales, and P bioavailability exerts a key control on the

long-term rate of O2 production through oxygenic photosynthesis and organic carbon (Corg) burial. Using a theoretical model — that the observed oxygenation steps are a simple consequence of internal feedbacks in the long-term biogeochemical cycles of P, C, and O — authors show there is no requirement for a specific stepwise external forcing to explain the course of Earth surface oxygenation. They conclude that Earth’s oxygenation events are entirely consistent with gradual oxygenation of the planetary surface — after the evolution of oxygenic photosynthesis. To some of us, this makes the most sense. 😊

DwN

Science 13 Dec 2019; 366: 1333-1337

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Scientists use stem cells from frogs to build first living robots

These GEITP pages almost always share items that have the theme of gene-environment interactions. THIS article is a bit of a stretch to encompass that theme (but bioethical issues are considered near the end). However, this story is so intriguing that it just just had to be shared. Perhaps “squelchy” and “squidgy” are pretty much British terms — but that’s okay, because this article appears in The Guardian. This is the cutting edge of science fiction in the laboratory. The original article, published in Proc Natl Acad Sci USA, is far too technical for these GEITP pages. ☹

DwN

Scientists use stem cells from frogs to build first living robots

Researchers foresee myriad benefits for humanity, but also acknowledge ethical issues

Ian Sample Science editor

@iansample

Mon 13 Jan 2020

Be warned. If the rise of the robots comes to pass, the apocalypse may be a more squelchy affair than science fiction writers have prepared us for.

Researchers in the US have created the first living machines by assembling cells from African clawed frogs into tiny robots that move around under their own steam.

One of the most successful creations has two stumpy legs that propel it along on its “chest”. Another has a hole in the middle that researchers turned into a pouch so it could shimmy around with miniature payloads.

“These are entirely new lifeforms. They have never before existed on Earth,” said Michael Levin, the director of the Allen Discovery Center at Tufts University in Medford, Massachusetts. “They are living, programmable organisms.”

Roboticists tend to favour metal and plastic for their strength and durability, but Levin and his colleagues see benefits in making robots from biological tissues. When damaged, living robots can heal their wounds, and once their task is done, they fall apart, … just as natural organisms decay when they die.

Their unique features mean that future versions of these robots might be deployed to clean up microplastic pollution in the oceans, locate and digest toxic materials, deliver drugs in the body, or remove plaque from artery walls, the scientists say.

“It’s impossible to know what the applications will be for any new technology, so we can really only guess,” said Joshua Bongard, a senior researcher on the team at the University of Vermont.

The robots, which are less than 1mm long, are designed by an “evolutionary algorithm” that runs on a supercomputer. The program starts by generating random 3D configurations of 500 to 1,000 skin and heart cells. Each design is then tested in a virtual environment, to see, for example, how far it moves when the heart cells are set beating. The best performers are used to spawn more designs, which themselves are then put through their paces.

Because heart cells spontaneously contract and relax, they behave like miniature engines that drive the robots along until their energy reserves run out. The cells have enough fuel inside them for the robots to survive for a week to 10 days before keeling over.

The scientists waited for the computer to churn out 100 generations before picking a handful of designs to build in the lab. They used tweezers and cauterising tools to sculpt early-stage skin and heart cells scraped from the embryos of African clawed frogs, Xenopus laevis. The source of the cells led the scientists to call their creations “xenobots”.

A xenobot with four limbs

A xenobot with four ‘limbs’. Photograph: Douglas Blackiston

Writing in the Proceedings of the National Academy of Sciences, the researchers describe how they set the robots loose in dishes of water to keep the frog cells alive. Some crept along in straight lines, while others looped around in circles or teamed up with others as they moved around.

“These are very small, but ultimately the plan is to make them to scale,” said Levin. Xenobots might be built with blood vessels, nervous systems and sensory cells, to form rudimentary eyes. By building them out of mammalian cells, they could live on dry land.

Sam Kriegman, a PhD student on the team at the University of Vermont, acknowledged that the work raised ethical issues, particularly given that future variants could have nervous systems and be selected for cognitive capability, making them more active participants in the world. “What’s important to me is that this is public, so we can have a discussion as a society and policymakers can decide what is the best course of action.”

Traces left by xenobots as they move through a field of particulate matter

Traces left by xenobots as they move through a field of particulate matter. Photograph: Douglas Blackiston

He was less concerned about xenobots posing any threat to humankind. “If you watch the video, it’s hard to fear that these things are taking over any time soon,” he said.

But the work aims to achieve more than just the creation of squidgy robots. “The aim is to understand the software of life,” Levin said. “If you think about birth defects, cancer, age-related diseases, all of these things could be solved – if we knew how to make biological structures, to have ultimate control over growth and form.”

The research is funded by the US Defense Advanced Research Projects Agency’s lifelong learning machines programme, which aims to recreate biological learning processes in machines.

Thomas Douglas, a senior research fellow at the Oxford Uehiro Centre for Practical Ethics, said: “There are interesting ethical questions about the moral status of these xenobots. At what point would they become beings with interests that ought to be protected? I think they would acquire moral significance only if they included neural tissue that enabled some kind of mental life, such as the ability to experience pain.

“But some are more liberal about moral status. They think that all living creatures have interests that should be given some moral consideration. For these people, difficult questions could arise about whether these xenobots should be classified as living creatures or machines.”

https://www.theguardian.com/science/2020/jan/13/scientists-use-stem-cells-from-frogs-to-build-first-living-robots

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