Genes Genomics Genetics Epigenetics and the Environment

GEITP is aware that this project has been a focus of Ge Zhang [Division of Genetics, Cincinnati Children’s Hospital] for >6 years; finally, the results are published and can be shared [see attached]. 😊 More than 15 million pregnancies per year, worldwide, are affected by preterm births (i.e., <37 weeks of gestation); there are no effective ways to prevent preterm births, and premature babies suffer from more neonatal mortality and lifelong morbidities, compared with full-term babies. Genetic factors of mother and fetus explain a large proportion (~30–40%) of the variation in gestational age at delivery (thus, this topic is consistent with the “gene-environment interactions” theme of these GEITP emails). To date, there have been only a few unbiased genome-wide investigations — designed to locate these genes. Recent genome-wide association studies (GWASs) have identified some robust associations. For example, variants in genes including WNT4 (Wnt family member-4), EBF1 (EBF transcription factor-1), AGTR2 (angiotensin II receptor type-2) and KCNAB1 (potassium voltage-gated channel subfamily A regulatory beta subunit-1) have been associated with timing of birth in mothers, and a study with fetal samples discovered a locus near genes that encode pro-inflammatory cytokines associated with gestational duration. Authors hope that better characterization of causal genetic mechanisms could lead to new strategies to treat and prevent preterm births. Authors conducted a genome-wide meta-analysis of gestational duration, and spontaneous preterm birth, in 68,732 and 98,370 European mothers, respectively. The meta-analysis detected 15 loci associated with gestational duration, and four loci associated with preterm birth. Seven of the associated loci were novel: WNT3A (Wnt family member-3A), RHAG (Rh-associated glycoprotein), KCNN2 (potassium calcium-activated channel subfamily N member-2), COBL (cordon-bleu WH2 repeat protein), GNAQ (G protein subunit alpha q), GC (vitamin D-binding protein), and LINC02824 (long intergenic non-protein coding RNA 2824). The loci mapped to several biologically plausible genes, for example, HAND2 (whose expression was previously shown to decrease during gestation) was associated with gestational duration, and GC was associated with preterm birth. Downstream in silico-analysis suggested regulatory roles as underlying mechanisms for the associated loci. Linkage disequilibrium (LD) score regression found birth-weight measurements as the most strongly correlated traits — highlighting the unique nature of the spontaneous preterm birth phenotype. Tissue expression and co-localization analysis revealed reproductive tissues and immune cell types as the most relevant sites of action. The authors’ findings complement the knowledge (to date) of the genetic factors of preterm birth. 😊 DwN PLoS Genet Oct 2023; 19: e1010982

In September 2023, Princeton University’s Cyrus Fogg Brackett Professor Emeritus of Physics, William Happer, spoke at the Institute of Public Affairs (IPA) to an audience in Brisbane, Australia about the crusade against carbon dioxide and integrity in climate science. Will Happer is a member of the National Academy of Sciences (NAS), Physics Division, and has made fantastic contributions to the U.S. Defense and Space Programs.

Professor Happer is one of the world’s leading scientists and climate realists, having made extensive contributions to the debate about climate science. While in Australia, he gave similar talks in Perth, Sydney and Melbourne.

Preview of Professor William Happer IPA lecture – The Crusade Against Carbon Dioxide – September 2023

In my opinion, this is Professor Happer’s best-ever lecture on this topic and it is the best Climatology talk I have ever heard — in terms of giving a 47-min-long presentation on a complex subject in a down-to-earth, apolitical, folksy chat that is neither arrogant nor condescending nor intimidating — and which scientists in the field, as well as the lay public, will have no problem in understanding.

If you want to know the truthful scientific facts (as opposed to journalistic and politics hyperbole and hysteria), I encourage everyone to set aside an hour or two and learn the LATEST in the field. 😊 [I found that it’s easier to understand, if you click on “closed captions” (CC) — although the transcript includes a number of wrong words.] If you don’t want to know the truth, please delete without watching / listening.

His lecture (~47 minutes) can be downloaded here:

or here:

https://www.youtube.com/wath?v=v2nhssPW77I

As I understand it — here is yet another example of a grad student or postdoc (perhaps in particular because she was a female?) being ridiculed, or passed over, while it was her original idea that represented the breakthrough. But Katalin Karikó persisted and is to be congratulated. 😊

DwN

Pioneers of mRNA COVID vaccines win medicine Nobel

Katalin Karikó and Drew Weissman laid the groundwork for immunizations that were rolled out during the COVID-19 pandemic at record-breaking speed.

Ewen Callaway & Miryam Naddaf

Drew Weissman, (left) MD, PhD, seated beside Katalin Karikó,(right) PhD.

Drew Weissman (left) and Katalin Karikó (right).Credit: PixelPro/Alamy

This year’s Nobel Prize in Physiology or Medicine has been awarded to biochemist Katalin Karikó and immunologist Drew Weissman for discoveries that enabled the development of mRNA vaccines against COVID-19.

The vaccines have been administered more than 13 billion times, saved millions of lives and prevented millions of cases of severe COVID-19, said the Nobel committee.

Karikó, who is at Szeged University in Hungary, and Weissman, at the University of Pennsylvania in Philadelphia (UPenn), paved the way for the vaccines’ development by finding a way to deliver genetic material called messenger RNA into cells without triggering an unwanted immune response.

They will each receive an equal share of the prize, which totals 11 million Swedish krona (US$1 million).

Karikó is the 13th female scientist to win a Nobel Prize in medicine or physiology. She was born in Hungary, and moved to the United States in the 1980s. “Hopefully, this prize will inspire women and immigrants and all of the young ones to persevere and be resilient. That’s what I hope,” she tells Nature.
A new chapter

The COVID-19 vaccines developed by Moderna and the Pfizer–BioNTech collaboration deliver mRNA that instructs cells to create copies of a protein that is found on SARS-CoV-2 virus particles, called the spike protein. This stimulates the body to make antibodies that target the protein, as well as triggering other immune responses.

For decades, mRNA vaccines were considered unfeasible because the injection of mRNA into the body triggered an immune reaction that immediately broke down the mRNA. In the mid-2000s, working at UPenn, Karikó and Weissman demonstrated that swapping one type of molecule in mRNA, called uridine, with a similar one called pseudouridine, bypasses the cells’ innate immune defenses1.

“I’m delighted to see them recognized,” says Robin Shattock, a vaccine scientist at Imperial College London, who has worked on mRNA vaccines. “Their contribution was really fundamental in the success of the COVID-19 vaccines, and I think will underlie RNA technology for some time to come.”

“They demonstrated that changing the type of the RNA nucleotides within the vaccine altered the way in which cells see it,” said John Tregoning, a vaccine immunologist at Imperial College London, in a press statement for the UK Science Media Centre. “This increased the amount of vaccine protein made following the injection of the RNA, effectively increasing the efficiency of the vaccination: more response for less RNA.”

“This discovery has opened a new chapter for medicine,” said Nobel committee member Qiang Pan Hammarström, an immunologist at the Karolinska Institute in Stockholm, at a press conference after the prize announcement. “Investment in long-term basic research is very important.”
Vaccine revolution

There are now mRNA vaccines in development for a number of other diseases, including influenza, HIV, malaria and Zika.

“It’s really like a revolution starting since the COVID pandemic,” says Rein Verbeke, an mRNA vaccine researcher at the Ghent University in Belgium. He adds that Karikó and Weissman’s contributions were essential to the vaccines’ success during the pandemic, and beyond. “Their part was really crucial to the development of this platform.”

A COVID-19 mRNA vaccine containing unmodified RNA, developed by CureVac, based in Tübingen, Germany, was widely seen as a flop after its mediocre performance in clinical trials.

Another key component of COVID-19 mRNA vaccines was the lipid nanoparticles (LNPs) that surround the modified RNA and ease its entry into cells. Numerous scientists contributed to the development of LNPs, says Verbeke, and it would have been nice if the Nobel committee had also recognized their contributions to mRNA vaccines. The modification of mRNA and the development of LNPs “were the two major steps that were necessary to have mRNA vaccines working”, he says.

Many people were involved in developing LNPs, however, and it would be difficult to single out any one contribution, says Pierre Meulien, who worked on using mRNA to trigger immune responses in the 1990s at Transgène, a small biotech firm near Strasbourg in France. Karikó and Weissman “really created the key to success of the whole enterprise around mRNA vaccines”, he adds.

The development of mRNA vaccines and therapeutics is still in its infancy, says Shattock. Scientists and biotechnology companies are busy coming up with new applications for mRNA technology, from cancer treatments to next-generation COVID-19 vaccines. Many teams are also working on improved ways of delivering mRNA. “What we see used today is not what’s going to be used in the future,” he says. “We’re at the beginning of an RNA revolution.”

Although COVID-19 jabs put mRNA vaccines on the map, the technology’s impact is likely to reach far and wide, says Karikó. “It is just limitless.”

doi: https://doi.org/10.1038/d41586-023-03046-x

Additional reporting by Katharine Sanderson.
References

Karikó, K., Buckstein, M., Ni, H. & Weissman, D. Immunity 23, 165–175 (2005).

This technical breakthrough — boggles the mind. 😉

DwN

19 September 2023
Tasmanian tiger RNA is first to be recovered from an extinct animal

Genetic sequences from a museum specimen offer fresh clues about the physiology of thylacines, which went extinct in the 1930s.

Miryam Naddaf

Black and white photo of two striped animals in a wire and wood enclosure.

A pair of Tasmanian tigers photographed at an Australian zoo in 1933.

For the first time, researchers have sequenced RNA from an extinct animal species — the Tasmanian tiger, or thylacine (Thylacinus cynocephalus).

Using muscle and skin samples from a 132-year-old museum specimen, scientists isolated millions of RNA sequences. This genetic material provides information about the animal’s genes and the proteins that were made in its cells and tissues. The findings, published in Genome Research 1, offer hope that RNA locked up in the world’s museum collections could provide new insights into long-dead species.

Being able to look at RNA in particular “opens up a whole new potential source of information”, says Oliver Smith, a geneticist at the medical-diagnostics company Micropathology in Coventry, UK. “As opposed to looking at what a genome is, we can look at what the genome does.”
Lost species

The Tasmanian tiger was a carnivorous marsupial that lived on the island of Tasmania in southeast Australia. The last known Tasmanian tiger died in captivity in 1936, but a handful of specimens have been preserved in museums.

Researchers studied thylacine remains that had been stored at the Stockholm Natural History Museum since 1891. They collected three muscle samples and three skin samples, each weighing about 80 milligrams.

Obtaining RNA from historical samples is challenging because unlike DNA — which is highly stable and has been extracted from extinct species that lived more than one million years ago — RNA rapidly breaks down into smaller fragments. “Outside of living cells, it’s believed to be degraded or destroyed in minutes,” says study co-author Marc Friedländer, a geneticist at Stockholm University.

The team developed a protocol specifically for extracting ancient RNA from tissue samples, adapting standard methods that are used on fresher samples. Nevertheless, “it was surprising that we found these authentic RNA sequences in this mummified Tasmanian tiger”, says Friedländer.

The researchers extracted and purified 81.9 million and 223.6 million RNA fragments from the thylacine’s muscle and skin, respectively. After removing duplicates and very short sequences, they identified 1.5 million RNA sequences from muscle tissue and 2.8 million from skin.

RNA provides information about how gene expression varies between tissues, says co-author Emilio Mármol-Sánchez, a computational biologist at Stockholm University.

In the muscle samples, the research team found sequences corresponding to 236 genes, including some that code for actin and titin — proteins that enable muscles to stretch and contract. In the skin samples, they found sequences corresponding to 270 genes, including the one that encodes the structural protein keratin.
Ancient viruses

The researchers also found a small number of RNA molecules from viruses that lived in or infected the Tasmanian tiger. Being able to trace and recover these molecules opens the door to studying ancient viruses, says Hannes Schroeder, an ancient-DNA researcher at the University of Copenhagen.

The study of ancient DNA is well established, but ancient RNA sequencing is still underdeveloped, says Smith. This study, he adds, “is giving a new life into a field which is under-represented and under-rated”. He hopes to see future studies routinely combine both DNA and RNA sequencing.

doi: https://doi.org/10.1038/d41586-023-02953-3
References

Mármol-Sánchez, E. et al. Genome Res. https://doi.org/10.1101/gr.277663.123 (2023).
Article

This story is an amazing example of gene-environment interactions. For example, it explains how the “Scarecrow could function without a brain” in the movie, The Wizard of Oz. And it also explains how many politicians are able to survive in the Western World. 😊

—DwN

22 September 2023
How to train your jellyfish: brainless box jellies learn from experience

Researchers have shown that the creatures can learn to avoid obstacles using visual and mechanical cues, despite not having a brain.

Dyani Lewis

A Caribbean box jellyfish (Tripedalia cystophora)

Caribbean box jellyfish (Tripedalia cystophora) can learn to associate a particular visual cue with a bumping sensation.

A tiny jellyfish has, for the first time, demonstrated an enormous cognitive capacity — the ability to learn by association. Although it has no central brain, the finger-tip-sized Caribbean box jellyfish (Tripedalia cystophora) can be trained to associate the sensation of bumping into something with a visual cue, and to use the information to avoid future collisions.

The experiment shows a type of learning called associative learning — made famous by neurologist Ivan Pavlov’s experiments with dogs in the late-nineteenth century — in which an animal learns to associate one stimulus with another through training. “Associative learning is now considered solid evidence of cognitive capacity,” says Ken Cheng, an animal behaviour researcher at Macquarie University in Sydney, Australia. Many other animals — from humans to birds, octopuses and even insects — have the ability to learn by association.

“The box jellyfish finding is very important because it shows that a centralized nervous system, or brain, is not necessary for associative learning,” says Pamela Lyon, a cognitive biologist at the University of Adelaide, Australia.

“It’s super,” says Gaëlle Botton-Amiot, a neurobiologist at the University of Fribourg in Switzerland, who published a study in March1 showing that the sea anemone Nematostella vectensis is also capable of associative learning. Sea anemones and jellyfish both belong to a group of organisms known as cnidarians, and Botton-Amiot thinks that “this ability to do associative learning is present across probably the entire cnidarian tree”.
Natural test

The sea anemone experiment by Botton-Amiot and her colleagues involved training the animals to associate a bright light with an electric shock. But these stimuli aren’t found in the anemones’ natural environment, and therefore the observed learning might not be biologically meaningful, says Jan Bielecki, an electrophysiologist at Kiel University in Germany who co-authored the jellyfish research, published on 22 September in Current Biology 2. “We were very, very careful to make this as natural for [the jellyfish] as possible,” he says.

In the wild, T. cystophora forage for tiny crustaceans between the roots of mangroves. To mimic this environment, Bielecki’s colleagues at the University of Copenhagen placed the box jellies in cylindrical tanks that had either black and white or grey and white vertical stripes on the walls. To the jellyfish, the dark stripes looked like mangrove roots in either clear or murky water.

In the ‘murky water’ tanks, the jellyfish bumped into the wall because their visual system couldn’t detect the grey stripes very clearly. But after a few minutes — and bumps — they learned to adjust their behavior, pulsing rapidly to swim away from the wall when they got too close. “It was only when they had a combination of visual stimulation and mechanical stimulation that they would actually learn something” says Bielecki.

He adds that he was unsurprised by the results. “This is just a matter of basic survival,” he says. When the water is murky, jellyfish can’t detect obstacles clearly with their simple eyes, so they need to learn to avoid them to prevent injury. “They can’t just keep bumping into obstacles on turbid days,” Bielecki says.

“There are good lessons to learn from this study,” says Cheng. “If we pick some arbitrary task, the animal may not learn. And that just may be because you’re trying to do the wrong thing rather than the animal not having the capacity.”

“It’s great that they chose something that is really biologically relevant,” says Botton-Amiot.
Physiology probed

To better understand the mechanisms at play, Bielecki dissected out individual rhopalia — small ‘eye-brain’ complexes in the jellyfish, each containing six rudimentary eyes plus nerve centres, called pacemakers, that control the animals’ swimming pulses.

With the isolated rhopalia facing a projector screen, Bielecki could precisely record electrical activity in the nerves when the visual system perceived a visual cue — grey bars moving slowly from one side of the screen to the other. A mild electric shock to the motor neurons mimicked the bump on a jellyfish’s body. Bielecki recorded the nerve activity of the swim pacemakers that caused the rapid swim pulses in the jellies.

Just like the living box jellies in tanks, excised rhopalia could be trained to associate an electrical ‘bump’ with the appearance of a grey bar. After five minutes of training with the grey bar and the ‘bump’, the rhopalia responded to the visual cue alone by increasing their swim-pulse frequency. This confirms that the rhopalia are “where learning happens”, says Bielecki.

How T. cystophora process and coordinate the learning in each of their four rhopalia remains to be understood, says Botton-Amiot. “If you have four centres like this, how is this coordinated?” Whether the creatures retain the learning — and for how long — would also be interesting questions to investigate, she adds.

“There’s a lot more to unpack about what’s going on, in this learning,” says Cheng. Identifying the genes and biochemical pathways involved could help scientists to trace the evolutionary origins of learning, as could a better understanding of which organisms are unable to learn. “We actually need the negative data”, he says, that scientists might be shelving. He suggests that researchers should consider whether animals without nerves are capable of learning. “The more distant [evolutionary] branches we look at, the better we have an idea of when associative learning would have evolved.”

Bielecki has more practical goals in mind. He is hoping to adapt findings about how jellyfish learn at the cellular level to non-biological systems, so that robots can learn to recognize patterns. “That’s the future of the jellyfish brain,” he says. “We want to stick them on a chip.”

doi: https://doi.org/10.1038/d41586-023-02975-x
References

Botton-Amiot, G., Martinez, P. & Sprecher, S. G. Proc. Natl Acad. Sci. USA 120, 2220685120 (2023).
Article Google Scholar
Bielecki, J., Nielsen, S. K. D., Nachman, G. & Garm, A. Curr. Biol. https://doi.org/10.1016/j.cub.2023.08.056 (2023).
Article Google Scholar

MORE COMMENTS: I certainly am not dismissing most structure-activity relationship (SAR) studies. Kepone binding to the estrogen receptor was simply a very memorable exception. 😊 As I recall, the main clinical effect of chlordecone was neurotoxicity — even small children exhibited neurological symptoms from being exposed to the contaminated boots of their fathers coming home after a day’s work in the Kepone factory. Chlordecone was not federally regulated until after the Hopewell disaster (along the James River in Virginia), in which 29 factory workers were hospitalized with various ailments, including neurological problems.

Linda, I certainly agree there are many epidemiological studies showing some association of PFAS toxicity in in-vitro and cell-culture studies. However, I’m always trying to look at the Big Picture. For example, new research (just reported 24 Aug 2023 in the peer-reviewed journal Environmental Science & Technology) [https://doi.org/10.1021/acs.est.3c00343] found that Asian-Americans have (on average) 88% more PFAS body burden (bioaccumulation) than White-Americans or Black-Americans (on average). [One possible explanation might be a higher consumption of fish and seafood (which, due to being at the end of the food chain, probably accumulate more PFAS than an animal at the top of the food chain) in Asian-Americans?]

Because extensive exposure of PFAS began in the 1950s — wouldn’t we expect to see (by now) “elevated cholesterol levels, increased kidney and testicular cancer rates, both immune suppression and autoimmunity, increased risk of preterm birth, hypertension during pregnancy, low birth-weight, increased risk of type-2 diabetes (T2D) and overweight/obesity” in Asians? But clearly — 70 years later — we do not see any of these ethnic effects in Asians in the Real World. ☹

MORE COMMENTS: I’ve spent most of three days, researching PFAS. One thought I had was that, if some PFAS is/are difficult to degrade and therefore bioaccumulative — it might be possible to overwhelm some receptor(s) with a dissociation constant (Kd) of 10-2, or 10-4, when the physiological ligand for that receptor might have a (Kd) of, say, 10-9.
However, whatever findings one can demonstrate in vitro (in a test tube), or in cell culture, very often cannot be replicated (under physiological conditions) in the intact lab animal or in clinical patients. This is what I can conclude for PFAS — seeing or realizing that worldwide PFAS exposures since the 1950s — have revealed no clear-cut evidence for cause-and-effect between one or more PFAS and clinical toxicity of some organ system.

As far as trying to relate a chemical structure to a particular receptor binding site, long ago Yours Truly concluded we should forget about that. ☹ In the late 1970s, recall that Richard Palmiter reported that the insecticide/fungicide Kepone (chlordecone) could be shown to bind to the estrogen receptor(!!) — although the chemical structures of Kepone and estrogen are wildly different…!! Kepone looks like a six-sided box with Cl atoms at every possible position except for the one C=O site…!!!

kepone chemical structure from webbook.nist.gov

[By the way, in 1975 Kepone was removed from the market — due to (experimentally-demonstrated) extreme toxicity to animals and humans. Contrast THAT chemical with the hand-waving & smoke-and-mirrors that the epidemiologists are doing with the PFAS…] ☹

To bring many of our GEITP-ers up-to-speed on this “PFAS discussion” — let me try to summarize. Perfluorooctane sulfonic acid (PFOS) is one of a group (i.e., a subset) of related chemicals known as per- and poly-fluorinated alkylated substances (PFAS); collectively, these are also called perfluorochemicals (PFCs). This group of synthetic chemicals (which number almost 15,000…!!) has been commonly used in a wide range of industrial processes since the 1950s and is found in many consumer products (e.g., firefighting foam, non-stick cookware, teflon, cosmetics, and materials that protect against grease, oil, and water — such as stain-resistant carpeting and fabrics, food packaging, and water-repellent clothing).

On PubMed, requesting “PFOS toxicity review,” there are 141 reviews posted (from 2008 to 2023). Requesting “PFAS toxicity review,” there are 211 reviews listed (from 2018 to the present). Some of these reviews (of course) are listed in both searches. The reviews include both clinical studies and studies of various species of animals. The C-F bond is very difficult to break; hence, degradation (in the environment or in the body of animals) is slow, which means that all of us (in most, if not all, organs) carry a load of those PFAS that are able to bioaccumulate.

The summaries of the two most thorough epidemiological reviews are posted below. Needless to say, I notice that “associations of PFAS with serious health disorders” always seem to be “weak or nil” and “further studies” always seem to be “warranted.” ☹

[1] Association between per- and polyfluoroalkyl substances exposure and risk of diabetes: a systematic review and meta-analysis.

Gui SY, Qiao JC, Xu KX, Li ZL, Chen YN, Wu KJ, Jiang ZX, Hu CY.J Expo Sci Environ Epidemiol. 2023 Jan; 33(1): 40-55.

Background: Emerging evidence suggests that per- and polyfluoroalkyl substances (PFAS) are endocrine disruptors and may contribute to the etiology of diabetes.

Objectives: This study aimed to systematically review the epidemiological evidence on the associations of PFAS with mortality and morbidity of diabetes and to quantitatively evaluate the summary effect estimates of the existing literature.

Methods: We searched three electronic databases for epidemiological studies concerning PFAS and diabetes published before April 1, 2022. Summary odds ratio (OR), hazard ratio (HR), or β and their 95% confidence intervals (CIs) were respectively calculated to evaluate the association between PFAS and diabetes using random-effects model by the exposure type, and dose-response meta-analyses were also performed when possible. We also assessed the risk of bias of the studies included and the confidence in the body of evidence.

Results: An initial literature search identified 1969 studies, of which eventually 22 studies were included. The meta-analyses indicated that the observed statistically significant PFAS-T2DM associations were consistent in cohort studies, while the associations were almost non-significant in case-control and cross-sectional studies. Dose-response meta-analysis showed a “parabolic-shaped” association between perfluorooctanoate acid (PFOA) exposure and T2DM risk. Available evidence was rated with “low” risk of bias, and the level of evidence for PFAS and incident T2DM was considered “moderate”.

Conclusions: Our findings suggest that PFAS exposure may increase the risk of incident T2DM, and that PFOA may exert a non-monotonic dose-response effect on T2DM risk. Considering the widespread exposure, persistence, and potential for adverse health effects of PFAS, further cohort studies with improvements in expanding the sample size, adjusting the covariates, and considering different types of PFAS exposure at various doses, are needed to elucidate the putative causal associations and potential mode of action of different PFAS on diabetes.

Impact statement: A growing body of evidence suggests that per- and polyfluoroalkyl substances (PFAS) are endocrine disruptors and may contribute to the development of diabetes. However, epidemiological evidence on the associations of PFAS and diabetes is inconsistent. We performed this comprehensive systematic review and meta-analysis to quantitatively synthesize the evidence. The findings of this study suggest that exposure to PFAS may increase diabetes risk among the general population. Decreased exposure to these “forever and everywhere chemicals” may be an important preventive approach to lowering the risk of diabetes across the population. [Or, deceased exposure to PFAS may not be important in lowering the risk of diabetes?]

[2] Early-Life Exposure to Per- and Poly-Fluorinated Alkyl Substances and Growth, Adiposity, and Puberty in Children: A Systematic Review.

Lee YJ, Jung HW, Kim HY, Choi YJ, Lee YA.Frontiers in Endocrinol (Lausanne). 2021 Sep 9; 12: 683297. Free PMC article.

Per- or polyfluoroalkyl substances (PFAS), a family of synthetic polyfluorinated compounds, are widely used in consumer products. Ubiquitous exposures to PFAS, in consideration of their persistence, bioaccumulation potential, and toxicities have led to concerns regarding possible harmful effects during critical periods of development in early-life and long-term consequences on health. The potential effects of PFAS depend on various factors including the type of PFAS and the timing and level of exposure.

We performed a systematic review of the epidemiologic literature to assess the effects of early-life PFAS exposure on prenatal and postnatal growth, adiposity, and puberty in children and adolescents. For birth size, most studies indicated that prenatal PFAS exposure, in particular long-chain PFAS, may impair fetal growth, albeit there are some reports of null associations with maternal PFAS.

For growth within the first 2 years of age, prenatal PFAS exposure showed no associations with height and either null or negative associations with weight. However, postnatal PFAS exposures were inversely related to height and weight at 2 years in a cross-sectional study.

For postnatal adiposity, prenatal PFAS may mostly have negative associations with body mass index in the first 2 years of life, but positive relationships with adiposity in childhood and adolescence, although some studies showed null associations.

For time of onset of puberty, the evidence for associations between early-life PFAS exposure and pubertal development or sex hormone levels were limited and inconclusive.

From experimental studies, plausible mechanisms through which PFAS may affect early-life growth and puberty include PFAS-induced activation of peroxisome proliferator-activated receptor, alterations of thyroid or steroid hormone synthesis and metabolism, and their weak estrogenic or anti-androgenic properties.

Although the published literature suggests possible effects of PFAS exposures on early-life growth, adiposity, and puberty, current human evidence is limited in establishing PFAS-induced effects on early-life physical development. Further investigation is warranted to clarify PFAS-induced effects on growth and physical development in consideration of the critical time-window of exposure, concomitant exposure to chemical mixtures including various PFAS types, and possible non-monotonic dose-response relationship for growth and adiposity trajectories.

What is the difference between a “monotonic” and a “non-monotonic” dose-response curve? Well — they say that “a picture is worth a thousand words.” The following dose-response curves are reproduced from ResearchGate.com:

In summary, a “monotonic” dose-response curve — is a boring linear relationship between dose and response. A “non-monotonic” dose-response curve — is anything else that is not linear. ☹ Below is an excellent review:

Toxicol Appl Pharmacol 15 Jan 2018; 339: 10-23:

This study aims to evaluate the evidence for the existence of non-monotonic dose-responses (NMDRs) of substances in the area of food safety. This review was performed following the systematic review methodology with the aim to identify in vivo studies published between January 2002 and February 2015 containing evidence for potential NMDRs. Inclusion and reliability criteria were defined and used to select relevant and reliable studies. A set of six checkpoints was developed to establish the likelihood that the data retrieved contained evidence for NMDR.

In this review, 49 in vivo studies were identified as relevant and reliable, of which 42 were used for dose-response analysis. These studies contained 179 in vivo dose-response datasets with at least five dose groups (and a control group), because fewer doses cannot provide evidence for NMDR. These datasets were extracted and analyzed using the PROAST software package. The resulting dose-response relationships were evaluated for possible evidence of NMDRs by applying the six checkpoints. In total, 10 out of the 179 in vivo datasets fulfilled all six checkpoints. Whereas these datasets could be considered as providing evidence for NMDR, replicated studies would still be needed to check if the results can be reproduced to rule out that the non-monotonicity was caused by incidental anomalies in that specific study. This approach, combining a systematic review with a set of checkpoints, is new and appears useful for future evaluations of the dose response datasets regarding evidence of non-monotonicity.

Overall, humans have been eating and exposed to PFOS and PFAS through all portals of entry — since the 1950s — yet very few (if any) serious health problems can be identified and/or quantified. As Shakespeare once said, along with hand-waving and smoke-and mirrors, “It appears that there may be ‘Much Ado About Nothing’.” ☹

This topic is reminiscent of the Linear Non-Threshold (LNT) Model controversy — which assumes that every increment of ionizing radiation dose, or environmental chemical dose, no matter how small — constitutes an increased cancer risk or toxicity risk for humans. ☹
—DwN
COMMENT:
Looking at this again more thoroughly, the statement (that these fluoride compounds are toxic at parts-per-quadrillion (ppq) levels) seems hard to believe — without additional information. How are they toxic? Toxic to humans and/or animals? What is(are) the target organ(s)? What toxicology studies support this?
Also, as an analytical chemist — “analysis at the ppq level” is unknown to me, albeit I have been out of the profession for a decade. There was mention of “hundreds of epi studies.” “Hundreds?” Really? Even so, mountains of studies (based on retro-collected data for other purposes) can only be used to support a hypothesis; that is Science 101. I imagine that I am exposed to PFOA levels greater than ppq levels every time I eat anything cooked in a Teflon-coated pot or pan. Maybe that’s what gave me prostate cancer?
COMMENT:

Thanks, Linda, that is helpful. Many years ago, I did a ‘deep dive’ into all the occupational-exposure and worker-monitoring programs for perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) workers, who had enormous exposure and blood levels — relative to what is seen today. In spite of pretty decent medical records, there wasn’t anything anyone could really see. But these negative data may be a combination of “healthy worker” effects, and insensitive and/or inadequate biomedical follow-up, etc. And, there also were not any early-life-exposure-effects observed. But the dose difference (based on blood values) from what people see today is enormous; hence, my reference to a non-monotonic dose-response (NMDR) effect.

COMMENT:
Sorry friends. But I don’t agree.

While some of the PFAS concerns may involve “non-monotonic dose-response” (NMDR), most are related to hundreds of clinical epidemiology studies — backed by even more animal (rodents, birds, fish, monkeys, wildlife, domestic animals) and mechanistic data. The National Academies of Sciences, Engineering, and Medicine (NASEM) issued a consensus report, recommending medical follow up when clinical blood-levels were at, or above, two parts-per-billion (2 ppb). And they recommended intensive biomedical monitoring at 20 ppb for the sum of only seven of the more than 14 thousand (>14,000) PFAS synthetic chemicals.

All PFAS are environmentally persistent and some are biologically persistent and bioaccumulative. Hope this helps.

COMMENT: Based on my many years in drug discovery and development prior to retirement, and as a chemist — I agree completely with Fred.

COMMENT: Dan,

I completely agree with Fred. There may be some legitimate concerns over PFAS, but there is also a whole lot of hype that lacks any scientific credibility, mostly around so-called ‘non-monotonic dose-response curves,’ and endocrine disruption. As with most things, we often see elements of legitimate science — interspersed with lots of hysteria based on unsupported hypotheses.

COMMENT: Dan,
The article below states “PFAS are also toxic at extremely low levels (i.e., parts per quadrillion), posing significant risks to our health.” One part per quadrillion = picomolar concentrations.
I have not worked on PFAS myself, but I think they are rather inert (due to the C-F bonds). That is why they stick around forever. A good example is Teflon, etc. I don’t think they are generally activated to reactive intermediates, nor are they potent ligands for any receptors. Therefore, pM (10-to-the-minus-12 molar) toxicity is pretty uncommon in Toxicology.
I understand that flouride atoms are present in about 40% of new drugs and, because of the strong carbon-fluoride bond, these new drugs are usually not a problem, with a couple of exceptions… Fred

This report summarizes a promising approach to bioremediation of per- and polyfluoroalkyl substances (PFAS) — which comprise a group of “forever chemicals” which are almost impossible to break down in our environment. 😊

DwN

September 2023

woman doing science

Modified Iron Particles Could Improve Bioremediation of PFAS

A class of manmade chemicals known as PFAS — which stands for per- and polyfluoroalkyl substances — is part of what makes these consumer goods water-, stain-, and grease-resistant. PFAS are also toxic at extremely low levels (i.e., parts per quadrillion), posing significant risks to our health. If you’re wondering why they’re called “forever chemicals,” it’s because they are nearly indestructible.

Iron particles coated in a nontoxic material may enhance PFAS degradation by a certain bacterium, according to researchers funded by the NIEHS Superfund Research Program. The study could help in bioremediation efforts that harness the microbe, known as Acidimicrobium Strain A6, for cleaning up contaminated soil, sediments, and aquifers.

Distinctive PFAS properties, such as high heat tolerance and oil resistance, stem from exceptionally stable bonds between carbon and fluorine atoms. Because PFAS resist breakdown, they can accumulate in exposed organisms and ecosystems — posing as a risk to human and environmental health.

Some PFAS, such as perfluorooctanoic acid (PFOA) — implicated in immune and kidney problems, among other disorders — are particularly recalcitrant to degradation. However, prior research by Princeton University’s Peter Jaffé, Ph.D., and colleagues found that Acidimicrobium Strain A6 (or A6 for short), can break down PFOA in contaminated wastewater.

This microorganism thrives in iron-rich, acidic environments, using inorganic material as an energy source. For the present study, Jaffé’s team sought to improve PFOA breakdown by stimulating A6 activity with iron.

Priming the Process

In nature, A6 generates energy by converting the nitrogen-based compound ammonium into nitrite. During the reaction, known as Feammox, electrons are released.

Most of those electrons are transferred to iron, such as a form called ferrihydrite. In PFOA’s presence, electrons can also latch on to fluorine atoms, effectively breaking their strong bonds with carbon.

Split image showing soil colloids in ground water attached to plain ferrihydrite and PAA-coated ferrihydrite not adhering to soil colloids.

Left: Colloids, or mixtures, of negatively charged soil or sediment can trap positively charged ferrihydrite particles. Right: Ferrihydrite coated with polyacrylic acid can move easily through soil. These modified iron particles appear to stimulate A6 conversion of ammonium (NH4+) to nitrite (NO2-). Electrons generated in the process can strip fluorine from surrounding PFAS. (Image courtesy of Park et al, 2023)

Adding ferrihydrite to wastewater can stimulate bacterial breakdown of PFOA, according to laboratory studies by the team. But polluted field sites present a hurdle: negatively-charged sediment can trap the iron particles — preventing their distribution and hindering Feammox reactions from occurring.

In earlier work, the researchers found that ferrihydrite particles coated with polyacrylic acid — a biodegradable synthetic chemical — can move better through sediment samples. Based on that finding, they wondered: Could these coated iron particles promote A6 breakdown of PFOA?

To investigate, the team mixed ferrihydrite with polyacrylic acid of four different molecular weights, ranging from 2,100 to 450,000 grams per mole. The samples also contained an ammonium-based medium to encourage A6 growth. In a related experiment, they added PFOA to the mixtures.

After the samples were incubated for several weeks under acidic conditions, the researchers analyzed their contents. Samples containing coated iron showed higher total bacteria populations compared to a control with bare ferrihydrite, suggesting that polyacrylic acid may stimulate bacterial growth, according to the authors. In addition, DNA sequencing indicated that A6 was the dominant group across all samples.

The team also found significantly less ammonium in the mixtures with coated iron compared to the control. Using a powerful imaging technique, they observed that electrons were more easily transferred to coated iron than to bare iron. Their findings suggested that the coated iron facilitated Feammox reactions.

Lowering PFOA Levels

Three sets of bar charts measuring PFOA concentrations measuring controls, 2,100, 6,000, 240,000, and 450,000 per mole across 0, 30, and 40 days.

Over a 40-day period, PFOA (measured in micromoles, or mM) significantly declined in samples containing ferrihydrite coated with polyacrylic acid of 6,000 grams per mole and 450,000 grams per mole, compared to other treated samples and a control containing bare ferrihydrite. (Image courtesy of Park et al, 2023)

In two of the samples containing coated iron, the team found significant declines in PFOA concentrations, as well as significantly more free-floating fluoride — signs that PFOA was decomposing.

The team was curious whether declining PFOA levels meant that the chemical had entirely degraded or simply had broken up into smaller PFAS molecules. They found only minor levels of PFAS intermediates appearing sporadically, suggesting that in most cases, PFOA was fully breaking down.

Together, the results demonstrated that polyacrylic-coated ferrihydrite boosted A6 growth and PFOA degradation, according to the authors. However, more research is needed to thoroughly explain the underlying mechanisms, they added. Further research should also explore how to optimize coated iron for use in more complex bioremediation settings, where different water chemistries and microbial communities may affect success.

This report summarizes a promising approach to bioremediation of per- and polyfluoroalkyl substances (PFAS) — which comprise a group of “forever chemicals” which are almost impossible to break down in our environment. 😊

DwN

September 2023

woman doing science

Modified Iron Particles Could Improve Bioremediation of PFAS

A class of manmade chemicals known as PFAS — which stands for per- and polyfluoroalkyl substances — is part of what makes these consumer goods water-, stain-, and grease-resistant. PFAS are also toxic at extremely low levels (i.e., parts per quadrillion), posing significant risks to our health. If you’re wondering why they’re called “forever chemicals,” it’s because they are nearly indestructible.

Iron particles coated in a nontoxic material may enhance PFAS degradation by a certain bacterium, according to researchers funded by the NIEHS Superfund Research Program. The study could help in bioremediation efforts that harness the microbe, known as Acidimicrobium Strain A6, for cleaning up contaminated soil, sediments, and aquifers.

Distinctive PFAS properties, such as high heat tolerance and oil resistance, stem from exceptionally stable bonds between carbon and fluorine atoms. Because PFAS resist breakdown, they can accumulate in exposed organisms and ecosystems — posing as a risk to human and environmental health.

Some PFAS, such as perfluorooctanoic acid (PFOA) — implicated in immune and kidney problems, among other disorders — are particularly recalcitrant to degradation. However, prior research by Princeton University’s Peter Jaffé, Ph.D., and colleagues found that Acidimicrobium Strain A6 (or A6 for short), can break down PFOA in contaminated wastewater.

This microorganism thrives in iron-rich, acidic environments, using inorganic material as an energy source. For the present study, Jaffé’s team sought to improve PFOA breakdown by stimulating A6 activity with iron.

Priming the Process

In nature, A6 generates energy by converting the nitrogen-based compound ammonium into nitrite. During the reaction, known as Feammox, electrons are released.

Most of those electrons are transferred to iron, such as a form called ferrihydrite. In PFOA’s presence, electrons can also latch on to fluorine atoms, effectively breaking their strong bonds with carbon.

Split image showing soil colloids in ground water attached to plain ferrihydrite and PAA-coated ferrihydrite not adhering to soil colloids.

Left: Colloids, or mixtures, of negatively charged soil or sediment can trap positively charged ferrihydrite particles. Right: Ferrihydrite coated with polyacrylic acid can move easily through soil. These modified iron particles appear to stimulate A6 conversion of ammonium (NH4+) to nitrite (NO2-). Electrons generated in the process can strip fluorine from surrounding PFAS. (Image courtesy of Park et al, 2023)

Adding ferrihydrite to wastewater can stimulate bacterial breakdown of PFOA, according to laboratory studies by the team. But polluted field sites present a hurdle: negatively-charged sediment can trap the iron particles — preventing their distribution and hindering Feammox reactions from occurring.

In earlier work, the researchers found that ferrihydrite particles coated with polyacrylic acid — a biodegradable synthetic chemical — can move better through sediment samples. Based on that finding, they wondered: Could these coated iron particles promote A6 breakdown of PFOA?

To investigate, the team mixed ferrihydrite with polyacrylic acid of four different molecular weights, ranging from 2,100 to 450,000 grams per mole. The samples also contained an ammonium-based medium to encourage A6 growth. In a related experiment, they added PFOA to the mixtures.

After the samples were incubated for several weeks under acidic conditions, the researchers analyzed their contents. Samples containing coated iron showed higher total bacteria populations compared to a control with bare ferrihydrite, suggesting that polyacrylic acid may stimulate bacterial growth, according to the authors. In addition, DNA sequencing indicated that A6 was the dominant group across all samples.

The team also found significantly less ammonium in the mixtures with coated iron compared to the control. Using a powerful imaging technique, they observed that electrons were more easily transferred to coated iron than to bare iron. Their findings suggested that the coated iron facilitated Feammox reactions.

Lowering PFOA Levels

Three sets of bar charts measuring PFOA concentrations measuring controls, 2,100, 6,000, 240,000, and 450,000 per mole across 0, 30, and 40 days.

Over a 40-day period, PFOA (measured in micromoles, or mM) significantly declined in samples containing ferrihydrite coated with polyacrylic acid of 6,000 grams per mole and 450,000 grams per mole, compared to other treated samples and a control containing bare ferrihydrite. (Image courtesy of Park et al, 2023)

In two of the samples containing coated iron, the team found significant declines in PFOA concentrations, as well as significantly more free-floating fluoride — signs that PFOA was decomposing.

The team was curious whether declining PFOA levels meant that the chemical had entirely degraded or simply had broken up into smaller PFAS molecules. They found only minor levels of PFAS intermediates appearing sporadically, suggesting that in most cases, PFOA was fully breaking down.

Together, the results demonstrated that polyacrylic-coated ferrihydrite boosted A6 growth and PFOA degradation, according to the authors. However, more research is needed to thoroughly explain the underlying mechanisms, they added. Further research should also explore how to optimize coated iron for use in more complex bioremediation settings, where different water chemistries and microbial communities may affect success.

This is what I’ve told several of you. I think this (Jan 2022) volcano explains why these past 5 months (in western Oregon) have been +3 to +6 degF warmer (and more humid) than normal. And the U.S. Southwest and southern Europe had several weeks of unprecedented hot/humid summer weather…

—D

Tonga Eruption Blasted Unprecedented Amount of Water into Stratosphere

Aug. 2, 2022

This looping video shows an umbrella cloud generated by the underwater eruption of the Hunga Tonga-Hunga Ha’apai volcano on Jan. 15, 2022. The GOES-17 satellite captured the series of images that also show crescent-shaped shock waves and lightning strikes.

Credit: NASA Earth Observatory image by Joshua Stevens using GOES imagery courtesy of NOAA and NESDIS

The huge amount of water vapor hurled into the atmosphere, as detected by NASA’s Microwave Limb Sounder, could end up temporarily warming Earth’s surface.

When the Hunga Tonga-Hunga Ha’apai volcano erupted on Jan. 15, it sent a tsunami racing around the world and set off a sonic boom that circled the globe twice. The underwater eruption in the South Pacific Ocean also blasted an enormous plume of water vapor into Earth’s stratosphere – enough to fill more than 58,000 Olympic-size swimming pools. The sheer amount of water vapor could be enough to temporarily affect Earth’s global average temperature.

“We’ve never seen anything like it,” said Luis Millán, an atmospheric scientist at NASA’s Jet Propulsion Laboratory in Southern California. He led a new study examining the amount of water vapor that the Tonga volcano injected into the stratosphere, the layer of the atmosphere between about 8 and 33 miles (12 and 53 kilometers) above Earth’s surface.

Hunga Tonga-Hunga Ha’apai

This satellite image shows an intact Hunga Tonga-Hunga Ha’apai in April 2015, years before an explosive underwater volcanic eruption obliterated most of the Polynesian island in January 2022.

Credit: NASA Earth Observatory image by Jesse Allen, using Landsat data from the U.S. Geological Survey

In the study, published in Geophysical Research Letters, Millán and his colleagues estimate that the Tonga eruption sent around 146 teragrams (1 teragram equals a trillion grams) of water vapor into Earth’s stratosphere – equal to 10% of the water already present in that atmospheric layer. That’s nearly four times the amount of water vapor that scientists estimate the 1991 Mount Pinatubo eruption in the Philippines lofted into the stratosphere.

Millán analyzed data from the Microwave Limb Sounder (MLS) instrument on NASA’s Aura satellite, which measures atmospheric gases, including water vapor and ozone. After the Tonga volcano erupted, the MLS team started seeing water vapor readings that were off the charts. “We had to carefully inspect all the measurements in the plume to make sure they were trustworthy,” said Millán.

Hunga Tonga-Hunga Ha’apai volcanic eruption

An image from Jan. 16, 2022, shows the ash plume from the Hunga Tonga-Hunga Ha’apai volcanic eruption that occurred the day before. An astronaut took a photograph of the plume from the International Space Station.

Credit: NASA

A Lasting Impression

Volcanic eruptions rarely inject much water into the stratosphere. In the 18 years that NASA has been taking measurements, only two other eruptions – the 2008 Kasatochi event in Alaska and the 2015 Calbuco eruption in Chile – sent appreciable amounts of water vapor to such high altitudes. But those were mere blips compared to the Tonga event, and the water vapor from both previous eruptions dissipated quickly. The excess water vapor injected by the Tonga volcano, on the other hand, could remain in the stratosphere for several years.

This extra water vapor could influence atmospheric chemistry, boosting certain chemical reactions that could temporarily worsen depletion of the ozone layer. It could also influence surface temperatures. Massive volcanic eruptions like Krakatoa and Mount Pinatubo typically cool Earth’s surface by ejecting gases, dust, and ash that reflect sunlight back into space. In contrast, the Tonga volcano didn’t inject large amounts of aerosols into the stratosphere, and the huge amounts of water vapor from the eruption may have a small, temporary warming effect, since water vapor traps heat. The effect would dissipate when the extra water vapor cycles out of the stratosphere and would not be enough to noticeably exacerbate climate change effects.

The sheer amount of water injected into the stratosphere was likely only possible because the underwater volcano’s caldera – a basin-shaped depression usually formed after magma erupts or drains from a shallow chamber beneath the volcano – was at just the right depth in the ocean: about 490 feet (150 meters) down. Any shallower, and there wouldn’t have been enough seawater superheated by the erupting magma to account for the stratospheric water vapor values Millán and his colleagues saw. Any deeper, and the immense pressures in the ocean’s depths could have muted the eruption.

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The MLS instrument was well situated to detect this water vapor plume because it observes natural microwave signals emitted from Earth’s atmosphere. Measuring these signals enables MLS to “see” through obstacles like ash clouds that can blind other instruments measuring water vapor in the stratosphere. “MLS was the only instrument with dense enough coverage to capture the water vapor plume as it happened, and the only one that wasn’t affected by the ash that the volcano released,” said Millán.

The MLS instrument was designed and built by JPL, which is managed for NASA by Caltech in Pasadena. NASA’s Goddard Space Flight Center manages the Aura mission.
News Media Contact

Jane J. Lee / Andrew Wang

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Yours truly certainly remembers hearing in medical school that “forceful events such as coughs (i.e., the Valsalva Maneuver) can momentarily reverse blood flow and jolt cancer cells loose, into the vicinity of the spine” — where they might form new tumors. I always had hoped that one day there might be a more logical molecular explanation. ☹

DwN

13 September 2023
Breast cancer often spreads to spine — newly discovered stem cell might explain why

A stem cell that contributes to vertebra formation also encourages the growth of tumours that move to the backbone from elsewhere

Saima Sidik

Coloured MRI scan of the side view of a person’s neck, in brown, white and grey with a streak of purple.

A scan (artificially coloured) of upper vertebrae reveals cancer that spread from a breast tumor.

Scientists have discovered a new type of stem cell that gives rise to the backbone — and that helps to drive the frequent metastasis of breast tumors and other cancers to the spine1.

Certain cancers, including those in the breast, prostate and lung, spread preferentially to the spine, but the reasons have been unknown. One theory from the 1940s proposed that forceful events such as coughs (Valsalva Maneuver) can momentarily reverse blood flow and jolt cancer cells into the vicinity of the spine, where they form new tumors(!!)

This idea “is still the classic dogma that’s taught in medical schools”, says Matthew Greenblatt, a pathologist at Weill Cornell Medicine in New York City and a co-author of the latest study. Greenblatt and his team’s results, “I would argue, overturn this very old paradigm”, he says.

The work appears on 13 September in Nature.
Growing a spine

Spines are unique to vertebrate animals, and the spinal vertebrae don’t carry some of the proteins often thought of as characteristic of bones. These features led Greenblatt and his colleagues to suspect that they form through a different mechanism than other bones.

Working in mice, scientists in Greenblatt’s laboratory isolated stem cells from both the vertebrae and what are known as the long bones, such as the femur in the leg. They found that the stem cells from the two locations expressed markedly different sets of genes. The scientists inserted the vertebral cells into the muscles of mice and observed that the cells produced progeny reminiscent of the range of cells found in the spine. This and other evidence led them to conclude that they had uncovered vertebral skeletal stem cells, or vSSCs.

Greenblatt and his colleagues “clearly and beautifully show” that vSSCs and long bone stem cells are “very different”, says bone biologist Noriaki Ono at the University of Texas Health Science Center at Houston, who supplied mice for the study but was otherwise not involved in it.

Until now, many scientists have been “by and large, considering all the bones as the same organ”, says cancer biologist Xiang Zhang at Baylor College of Medicine in Houston. “This study brings our understanding to a new level.”
Bad actor

The authors’ finding made them wonder whether the new type of stem cell could account for some of the unexplained patterns in cancer metastasis. The team zeroed in on a protein called MFGE8, (milk fat globule EGF and factor V/VIII domain-containing), which is secreted by vertebral stem cells. In mouse experiments, deleting the gene for the protein cut the chance that cancer cells would spread to the animals’ spines by about two-thirds.

The researchers isolated vSSCs from people undergoing spinal surgery and found that human vSSCs secreting MFGE8 were more likely to interact with cancer cells than vSSCs that were not secreting the protein. One protein probably can’t explain the entire phenomenon, Ono says, but it seems to be an important component.

The study’s implications could reach beyond cancer. For example, spinal fusions — procedures that bridge two or more vertebrae to relieve pain from conditions such as scoliosis and arthritis — often fail — for as-yet undetermined reasons, says study co-author Sravisht Iyer, a spinal surgeon at the Hospital for Special Surgery in New York City. He hopes further work on vSSCs will increase the success rate of these operations.

doi: https://doi.org/10.1038/d41586-023-02851-8

Read the associated News & Views editorial, ‘Stem-cell clues to why vertebrae attract tumours’
Reference

Sun, J. et al. Nature https://doi.org/10.1038/s41586-023-06519-1 (2023).

This recently-published paper [see attached Hu et al. paper] has been all over the news this past week. Human ancestors (hominins) diverged from gorilla and chimpanzee ancestors between 8 million and 5.5 million years ago. One of these lineages ultimately evolved into present-day gorillas and chimps, whereas the other line evolved into early human ancestors (hominids). Further evolution of the latter continues to be studied with frequent new paleontological data, but it is clear [see figure below; H.denisova and H.floresiensis were not yet established when this graph was made] that there were many (at least 24) fits and starts in southwestern and southeastern Africa. The ultimate “survivors” that migrated out of Africa (in several “waves” before the successful wave ultimately survived) included Homo sapiens, Homo denisova and Homo neandertalensis (among a few other minor ones); there is evidence these three sublines interbred (as previously discussed in these GEITP pages).

It is now generally agreed upon that modern man (Homo sapiens) appeared some 300,000 years ago. The Pleistocene is the geological epoch that lasted from ~2.58 million to 11,700 years ago, spanning the Earth’s most recent Glacial Period (~110,000 to 11,700 years ago). From ice-core data over the last 800,000 years (in Antarctica and Greenland), we know there have been about ten Glacial Periods (~100,000 years) interspersed with Interglacial Periods (~15,000 years long). When Earth awakened from its last Glacial Period (11,700 years ago), the area we now call Cincinnati was under about 3 miles of glacier ice; obviously, it was cold and began to get warmer, as glaciers receded in both the north and south poles…

Earth’s climate system began to change during the Middle Pleistocene transition, which is associated with a severe cooling phase ~900,000 years ago. How this change might have affected human populations is difficult to determine, because human fossil and archaeological records are relatively sparse for this period and lie beyond the reach of ancient DNA recovery. Authors Hu et al. [see attached] used a new method of analysis called FitCoal to project current human genetic variation backwards in time — to estimate the size of populations at specific points in the past.

Their data suggest that human ancestors suffered a severe population bottleneck that started ~930,000 years ago and lasted for almost 120,000 years; this adversity is estimated to have reduced the number of breeding individuals to ~1,300(!!), bringing human ancestors close to extinction. Hu et al. postulate that the proposed bottleneck correlates with a chronological gap in the African and Eurasian fossil records that may have led to evolution of a new human species, ancestral to Homo sapiens. They favor H.heidelbergensis as this ancestral species, probably emerging in Africa by 800,000 years ago [depicted as #3 or #5 in the graph above].

Two lineages of large-brained humans have long been recognized in the later Pleistocene: H. sapiens and Neanderthals (H. neandertalensis). A third group — Denisovans — was identified more recently from ancient DNA in fossils and sediments at Denisova Cave in Siberian Russia. Considering how the inferred bottleneck might have affected human evolution, inevitably leads to debate about the nature of the last common ancestor of H. sapiens, Neanderthals, and Denisovans, and when and where this ancestor lived.

It is not yet clear whether the last common ancestor lived in Europe, Asia, or Africa. Authors attributed the East Asian fossil record from that time to the more ancient human species H.erectus. However, there is evidence from sites (e.g., Yunyang, China), of a distinct species that is morphologically closer to later humans from Eurasia and Africa such as H.sapiens and Neanderthals, suggesting their ancestral lineage(s) might already have diverged from H. erectus by the time of the Yunyang fossils — which are dated at 1,100,000 to 800,000 years ago.

Estimates using genomic data from H.sapiens, Neanderthals, and Denisovans calibrate the last common ancestor to have existed between ~700,000 and 500,000 years ago — which would relate the inferred bottleneck to this ancestral population (wherever it lived) — with comparable signals expected from Denisovan and Neanderthal genomes, as well as from those of H.sapiens.

However, some recent studies of dental and cranial variation in fossilized skulls place the last common ancestor earlier, between about 1,200,000 and 800,000 years ago — which might mean that already-separated basal lineages of Neanderthals and Denisovans avoided the bottleneck, or suffered it to a lesser extent. Morphological analysis of fossils suggests that the last common ancestor might be H.heidelbergensis (as favored by Hu et al.), H.rhodesiensis, H.antecessor, or H.bodoensis. 😊

DwN

Science 1 Sept 2023; 381: 979-984 & editorial pp 947-948