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the-feminist-philosopher · 2 years

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Debunking the Trans-Exclusionary's Pseudoscience: a thread

Yes, all embryos start with the same template. No, this template is not "female." Ovary and testis development require complex genetic regulation. Neither can really be said to occur by "default."

"We have just begun to glimpse into the mechanisms underlying ovarian development. Convincing evidence challenges us to reconsider the existing paradigm that describes ovarian development as a default system. The default concept was first proposed in the early 1950s when Jost performed the groundbreaking experiments to demonstrate mechanisms of sex differentiation of reproductive tracts (Jost, 1947, 1953, 1970). The term “default” was not originally intended to describe the developmental status of the ovary. Instead, it is referred to the female reproductive tract or the Mullerian duct based on the fact that the female reproductive tract forms in both XX and XY individuals in the absence of gonads. Indeed, now it has become evident that early ovarian development is an active process involving intrinsic cell fate decisions and complex crosstalks between germ cells and somatic cells. Most intriguingly, the appearance of testicular structures in XX individuals where Sry and its downstream components are absent..." -Yao 2005

Sex determination in mammals involves the development of a bipotential gonad into either a testis or ovary. Studies have suggested that at the start of mammalian reproductive development, both male, sperm-carrying reproductive tracts and female, egg-delivering reproductive tracts are present. Depending on the sex of the embryo, one set of tracts usually disintegrates as development proceeds.

Ovarian development is centered on beta-catenin protein stabilization by WNT4 secretion, and this is believed to inhibit the expression of SOX9 (which is pivotal in male sexual development).

Do not let them fool you. Ovarian development is a very active process. Nothing can be said to happen by "default."

Continuing to spread this narrative actually contributes to spreading the patriarchal idea of "male" as inherently active and "female" as inherently passive.

Sex differentiation is a feature of the patriarchy that posits that “men are men” and “women are women” and the two ought be and fundamentally are separate from each other. It is responsible for the social prescription that each group must stay within certain bounds of public and private life as well as certain bounds of behavior and certain bounds of presentation. One such social prescription is assigning to men the role of Actor and Aggressor and to women the role of the passive Recipient of aggression. This gendered association decreases the perception of women as empowered agents (and even human). This social prescription also encourages men to act on behalf of women from making financial or relationship decisions, to deciding when and where and how a woman has sex, to the definition and social prescription of "woman" and "female," and to the reproductive alienation of those assigned female.

Please, for the love of fuck, do not spread the myth that the vagina has a natural spermicide. Does a "female" system cull most sperm? Yes. Because our species developed the ability to cull potentially "off" offspring that would be detrimental to species survival. In evolution, if it hurts, it goes. If it's disadvantageous, but has limited benefit, it stays. If it doesn't hurt, it also stays. The two-tailed sperm swimming in circles- for example- isn't staying.

Yes, there are women with immune infertility whose immune system attacks sperm. Yes, white blood cells will kill off lots of sperm. Yes, lots of sperm will literally get "lost" or "caught" in linings. And, yes, lots of sperm die because of the acidity of the vagina. HOWEVER, when the egg follicles mature and prepare for ovulation, the pH of cervical fluid rises, bridging the gap between the acidic vagina and the alkaline sperm. The egg literally releases hormones to better allow for fertilization while the semen forms a gel which provides protection for the sperm from the acidic environment of the vagina. In fact, contractions in the reproductive tract can propel sperm toward the oviducts. And there's also a reason there are about 200 million sperm in a single ejaculation.

The vagina DOES NOT have a built-in spermicide. PLEASE, please, wrap it before you tap it. DO NOT let misinformation like this convince you that your vagina will just kill the sperm and reject any and all pregnancies. The body both helps you get pregnant or helps you avoid it depending on the compatibility or survivability of the sperm and the pregnancy material. If there's something real screwy (including being malnourished), it's not making it. BUT that doesn't mean you CANNOT get pregnant.

SPERM can survive in the female genital tract for up to FIVE whole days. Sperm are very-very tiny and they can, and will, make it. Additionally, bleeding and getting pregnant are not mutually exclusive. You CAN get pregnant while on your period. Don't take risks because of misinformation like this.

I'm scared to know how this person thinks people become pregnant.

I-- didn't even know what to make of this when I read it. What a way to stigmatize female genital tracts as an "other" by describing it as "reptilian." So, I want to take a moment to talk about the vagina dentata and the patriarchal association of women with the monstrous, often snakes or other reptiles.

While not all of them do, many vagina dentata folk tales explicitly articulate male fears of castration in the act of PiV sexual intercourse. These myths will warn of the necessity of violently or forcefully removing the teeth from women’s vaginas to transform her into a nonthreatening sexual partner. In most cases, these myths can be read as the patriarchal attempt to render female sexuality non-threatening and strip it of it's "danger" (temptation) to men. There is one author I remember reading who spoke of a connection between this myth and the practice of FGM and rape epidemics.

These myths seemed to act as a cautionary tale to men to beware where they stick it, least they lose their dick. Unless, they first forcibly broke the teeth (rape) or neutralized the temptation (marriage) or removed a woman's "promiscuousness" (genital mutilation).

The Greek figure of a Gorgon is representative of this concept, as is the mermaid. The "devouring mother" in many religions and mythologies often took the form of a serpent or a snake woman. The fearful aspects of the feminine were also sometimes represented by a woman with a phallus. But, once all her vagina teeth were knocked out by the male hero (sometimes a son), the devouring mother would lose her masculine characterization in these tales, transforming from a Terrible Mother (a manifestation of the Great Mother archetype) to something desirable to men (the Kindly mother). Many of these myths served to portray the feminine as terrifying as well as something negative.

Now, I'm pretty sure that she's referring to the squamous cells, which *look like* fish scales. The only context most people have likely heard this term used is in reference to cancer. For context, it's these thin, flat cells that you likely looked at under the microscope in 9th grade biology class:

These cells are found in the tissues that form the surface of the skin, the passages of the respiratory and digestive tracts, and the lining of the hollow organs of the body (such as the bladder, kidney, and uterus, including the cervix). They can be keratinized or nonkeratinized. Reptile scales are keratinized. No, your genital tract is not "reptilian." It is very much mammalian and human.

Another thing I want to tackle is the teleological argument briefly touched on in this post. Teleology is the idea that something has a telos- a purpose, goal or final end. Evolution does not have a purpose. It makes no conscious decisions or sets any goals. There's no final end to evolution. Our insistence that evolution has an end and an overarching purpose is a remnant of Social Darwinism. Menstruation in mammals has no inherent purpose or end. Menstruating makes no decisions and it sets no goals. A vagina, similarly, has no inherent purpose or end-goal.

When educating people on reproductive tracts, many people may use teleological phrasing, saying that the vagina's purpose is to receive a penis or hold sperm until it can pass into the uterus or provide a passage for childbirth.

Unfortunately, our language is limiting. Because *function* can mean something has a certain *purpose.* So, I want it to be clear that I use "function" to mean something which carries on an action, rather than something with a set objective or end to be attained. In this case, saying that an organ has a function is thus very different from talking about it's purpose. Through evolution, we developed tissues and organs with specialized functions. These organs can carry on specific actions. For a vagina, these actions include 1.) providing passage for blood and mucosal tissue from the uterus, 2.) providing passage for sperm to the uterus, and 3.) providing passage for live birth.

Now, I am being very careful with my language full-well knowing that if I simply say, "The function of a vagina is also to provide passage for live birth," a trans-exclusionary will shoot back, "So, you think the purpose of female organs is to give birth?" This retort, and the fact the featured poster says "[f]ar from every woman gives birth [and] [m]any women have no desire for penetrative sex," makes it clear that "rad fems"- including the featured poster- are making teleological arguments.

Because I am saying that, during the course of evolution, we developed organs that carry on specific actions. I am not saying they were *designed* for a purpose, but that they developed to operate specifically and perform specialized functions. During the course of evolution, we developed kidneys to filter blood of toxins and turn waste into urine. This does not mean the kidneys were planned nor does that mean that a kidney designs to find impurities in our blood. Kidneys do not have a goal or an ambition or an aim.

Their equivocation on "function" and "purpose" serves to hide teleological arguments behind "scientific" sounding language as well as turn their assumption that we're operating with teleological statements around on any dissidents. This way, when someone points out that species developed reproductive tracts which perform reproductive functions, they can accuse you of reducing a woman's "purpose" to childbearing and taking dick.

However, their insistence that *they're* operating only based on "the science" allows them a degree of plausible deniability when women, feminists, and LGBTQ+ activists and allies tell them that their definition of a woman ironically does exactly that: reduces a woman to a reproductive purpose. Women and feminists and queer activists alike have noticed that the transphobe is operating off of teleological assumptions and trying to hide behind science and "biology" to mask this. They recognize that "a woman is an adult human of the sex that can bear offspring and produce ova" is an also an "ought" statement: a woman ought to be someone who bears children and produces eggs.

It might *seem* grammatically declarative. However, when we are naming something, we are also categorizing it, saying it performs at least one function sufficiently enough to meet the requirements of the description, and saying it performs that function well enough to be named one thing instead of another. We are fitting it within certain bounds, and thus giving it social meaning and value.

A mutual (@/dark-and-sparkles) gave this example:

"This is a chair," doesn't simply describe a chair or declare that a chair is present. A chair is an object with a specific form, function, and social meaning; when we are naming something a "chair," we are evaluating it on its ability to serve our purposes as a chair. If it didn't perform these functions well, we either would see it as faulty (another socially loaded description) or wouldn't pick it out as a chair at all."

Making linguistic and categorical distinctions can have teleological implications.

No organ has a primary "purpose." Organs have basic functions and features which operate specifically. So, yah, not every woman will give birth or have penetrative sex. But those social decisions mean absolutely nothing when we're talking about how- during the course of evolution- we developed certain organs to carry on reproductive functions and that these organs carry on these actions in the event of reproduction. These social decisions do mean something, however, if you are addressing a teleological argument that posits that because a female reproductive tract has the capacity for pregnancy, that means it's *purpose* is to produce children.

They're arguing that the *purpose* of the female genital tract is not to produce children because its purpose is instead to pass tissue from the uterus. Neither is correct because organs have no final ends. (And they call themselves monists.)

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As for the rest of this section...

I first find it ironic that they spent the paragraphs above arguing that we should not conceptualize a uterus in terms of its fertility and a relationship to sex, only to say that a uterus is essential to one's health in areas such as fertility and sex drive.

Now, I want to be clear that "greater risk" does not me you WILL get dementia or depression or "other serious inflictions" if you have a hysterectomy. Yes, a hysterectomy *may* increase *the risk of* cardiovascular events, certain cancers, the need for further surgery, early ovarian failure and menopause, depression, and dementia. It is important to note that most studies on this examine possible associations, causality, and hypotheses instead of causality. Part of this increase in health risks- like cardiovascular complications, memory complications, and metabolic changes- is hypothesized to have to do with the earlier onset of menopause because some of these potential long-term risks are common with the onset of menopause. Earlier onset of menopause is thought to lead to greater risk. People who start menopause earlier without a hysterectomy as well as people who start their periods later (also not something achieved through surgery), and people with a longer reproductive period also have an elevated risk in many of these same categories.

Absolutely none of these facts "prove" one sex's superiority over the other. Because there is no "superior" sex.

(Also, would the OP take a similar stance on birth control, which women also use to treat similar conditions which a hysterectomy is used to treat? Because birth control carries many of the same health risks. Is the moral here, "Don't undergo treatments if they carry health risks" or have we run into the Raymond effect? Where a "whole" [natural] state is "better" than an "altered" state? So, a hysterectomy would make someone "incomplete"/"broken" and keeping the reproductive trace makes someone "whole" and "complete." Based on the rest of the paragraph and post, I'm guess it's another iteration of Raymond's argumentum ad naturam.)

I also have no idea how any of this relates to challenging ideas of male supremacy. How does "Getting a hysterectomy could be detrimental to your health" combat ideas of male supremacy? Male dominant society is all about creating a system where people with a uterus and ovaries keep them and use them to become mothers. This point is really unrelated to combating those ideas. Does she think arguing that getting a hysterectomy could lead to health problems down the line supports some "power of the uterus" argument? Because a hysterectomy is a medical procedure designed to treat severe and emergency health conditions.

An example: My mother bled every day for months on end with cramping and bleeding so heavy, she was passing out. She asked for a hysterectomy and the first doctor asked "Are you sure. You're young and could have more babies yet." She got an ablation that didn't work. She went to a second doctor who told her that the uterus absolutely needed to come out. The only thing that ended her bleeding was the hysterectomy. When you go to the Mayo Clinic website and they list "heavy periods" as a common reason for a hysterectomy, this is what they mean. They aren't referring to the couple hours you utilize a heating pad or that time you attached a TENS unit to your back for cramping.

Another example: Doctors found an aggressive cancer in my grandmother's reproductive tract. So, she got a hysterectomy. The surgery was effective. From subsequent testing, it seems the cancer did not spread, and so my grandmother is still with us. I'm seeing her for dinner in two days.

These are reasons women get hysterectomies.

So, I don't know why the OP has seemingly taken issue with a medical procedure designed to treat severe medical conditions and problems. Does the issue maybe instead lie with someone like myself who elected to get a hysterectomy because I didn't want the potential to bear offspring? Or does the issue instead lie in someone, again, like myself who gets a hysterectomy for "gender" affirming reasons, namely, to never bleed again? In which case, let's have that conversation about bodily autonomy.

Next, your body does not "fall apart" when you remove your uterus. Do organs shift around? Yes. Does this mean you'll pee more? For a while, yes. Most complications arise not from the mere absence of a uterus, but from damage during the surgery itself. Doctors might nick something, for example. Like with all major surgeries, there is a risk of clotting afterwards. But, no, the uterus does not help hold the body together. Your body will not fall apart in its absence. Unless the OP is talking about a prolapse, which is not caused by a hysterectomy, but a cause for a hysterectomy. A prolapse certainly *will* cause such "serious complications" as fecal incontinence and bladder control issues because other pelvic organs prolapsed too. Is there a risk of prolapse after a hysterectomy? Yes. That risk is some 1%-15%, with the risk being highest in individuals whose hysterectomy was necessitated by a prolapse. In fact, hysterectomy is not a risk factor for prolapse when preoperative prolapse is taken into account.

As for that last point... "women have better cognition and memory than men and their reproductive organs are the reason for that." For a group that claims to reject the idea of "female" and "male" brains, they sure are willing to embrace it. I know that a hysterectomy uniquely impacts spatial memory in rats, but I am unsure whether this holds true for humans too. I also know that high estrogen- a hormone secreted by the ovaries- in older female mice can improve spatial memory consolidation, and that this effect can be weakened by progesterone, but I am unsure whether this holds true for humans too. I do know that in one of our closer evolutionary cousins, the estrogen steroid hormone, Estradiol, enhances "some aspects of spatial working memory in aged monkeys despite many years of estrogenic deprivation." I also know that estrogen increases the risk of breast and uterine cancers.

You can read an overview about the role of sex in memory function here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028920/. Here's a snapshot of this overview:

I am always cautious to automatically attribute such things as memory to sex difference; to claim that the reason this happens is purely biological. And the reason for that is because I know characteristics considered an inherent and immutable part of sexual dimorphism in humans are physical conditions reinforced by a patriarchal gender system. For example, a woman's weight and height will increase under systems of greater gender equity (There was a study done in Chile on height and greater gender equity and there was a study done in India on weight and gender oppression). I also know that women have a better memory than men in middle age, but decline faster, and it is believed that these difference will shrink in the future because education levels for women have been increasing over the last several decades, leading to higher cognitive reserves and less risk for dementia.

“…there are unnecessary and potentially inaccurate linkages made when binary categories of sex are exclusively drawn on to interpret sex-associated biology. The use of binary categories of sex in this way can inadvertently contribute to the normalization of culturally recognized 'typical’ biologies and undermine capacities to see variation even within these categories defined as 'normal.’ When used in this way, the categories themselves are interpreted as proxy for pathways and thus biological differences are concluded to be 'sex-based,’ as opposed to driven by some other mechanism.”

DuBois, L. Z., & Shattuck‐Heidorn, H. (2021). Challenging the binary: Gender/sex and the bio‐logics of normalcy. American Journal of Human Biology, 33(5), e23623.

One's reproductive organs are not a reason or cause for superiority over the other sex. This is literally just reproducing the exact same forces of socialization that the patriarchy does, something which these women claim to be critical of but then embrace if it means gaining power for themselves.

#I have several more posts like this lined up #but it may take a while #to post them all #I can only include so many links and pictures in a single post #txt #feminism

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foggynightdonut · 17 days

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Water: The Origin of Life from Water to the Molecules of Life by Joseph C. Collins

Overview

Description

How was it possible for the simple molecules which arrived on the early earth to be transformed into the extremely complex forms which compose living cells? If we are to believe the Second Law of Thermodynamics and the Laws of Probability, spontaneous assembly would seem to have been absolutely impossible! Based on that Second Law, systems move spontaneously from order toward disorder – not the other way around. Furthermore, there are simply too many options of bonding between atoms to have accidentally produced the molecules of life. However, the process did not occur in air - most likely, it occurred in saline water: an environment which we now know has such intrinsic properties of quantized order that it not only reverses the direction of spontaneity but provides the quantized entanglement properties which permits it to direct the formation of spatial structures and integrate their functions. First: recent studies have provided evidence that the largest ordered unit in liquid water is a Trimer with three molecules hydrogen-bonded together and that as many as six water molecules may form oriented linear elements on surfaces. Although these ordered forms last for only about 10-12 seconds, a million millionth of a second, they, like those which form at interfaces between water and air and water and oil, impose linear and planar order on molecular surfaces. Second: motions of water molecules adjacent to ions and surfaces are governed by Quantum Mechanics, not Newtonian Physics – water molecules jump from one preferred probability position to another. As water molecules on surfaces move from conditions of low-entropy order to higher-entropy disorder, they absorb quantized units of energy from those surfaces to drive bonding within toward higher levels of order. Third: water molecules adjacent to the surfaces of natural molecules like proteins, nucleic acids and polysaccharides exhibit the Nuclear Magnetic Resonance doublet peaks of ice, not the singlet peaks of liquid water. Since doublets are produced by water molecules in linear elements, water molecules appear to exist as transient linear elements in specific orientations on ordering surfaces. Again, they last for only 10-12 seconds, but they form so continuously and rapidly that they impose linear and planar order on surfaces. Fourth: ultra high-speed irradiation of liquid water with neutrons has provided evidence that the protons of water molecules exhibit the same dual Quantum Mechanical Particle and Wave Properties as electrons in metals – they couple together to produce Entanglement. Just as entanglement coupling between electrons provides communication at extended distances in metals, proton coupling ties water molecules together at extended distances in living cells. Thus, living cells must be considered as gigantic molecules with transient linear waves, which last about 10-15 seconds, circling the molecules and tying them all together. Thus, Transient Linear Hydration on surfaces as well as Quantized Hydration Patterning in the free, unbound water around vital molecules occur so rapidly, relative to the movement of the molecules, that the molecules continually experience order around them. The purpose of the book is to present an accurate graphic presentation of how the major classes of molecules in living cells might well have formed in a spontaneous fashion and how they function in such a coordinated manner today. Indeed, it was energy of the sun and the increase in entropy of surface water which functioned symbiotically to bring forth the molecules of life. If life should cease and the conditions which brought it forth are repeated, it will appear once more.

About the author

Dr. Collins received his degrees in Chemistry from Wayne Unversity and the University of Wisconsin. After employment at General Motors Research, Central Research at E. I. DuPont and Sterling Withrop Research Institute, he accepted an appointment as Associate Professor at Illinois Wesleyan University. In 1967, he returned to Sterling Winthrop to direct Medicinal Chemistry and Developmental Research until he retired in 1987 to devote full time to his driving interest in the role of water in the living cell. He has a number of publications and patents to his credit and has had a synthetic organic reagent for selectively converting primary alcohols to aldehydes, "The Collins Reagent," named after him. However, the study of natural molecular shape and surface hydration has been a major interest for many years.

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twiainsurancegroup · 5 months

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star-ayurveda · 7 months

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Ayurvedic Treatment for Kidney Stones

https://starayurveda.com/ayurvedic-treatment-for-kidney-stones.php

Kidney stones are small, hard deposits that form inside your kidneys. This condition is also called as renal lithiasis / calculi.

The stones are formed of minerals & acid salts. When the urine becomes concentrated, allowing minerals to crystallize and stick together and can affect any part of your urinary fact from kidneys to bladder.

Knowing the type of stone helps determine the cause and may dine cheers in how to reduce the risk of getting more kidney stones. Types include.

Calcium stones − occurs in form of calcium oral ate these are commonest. These stones may occur in the form of calcium phosphate also oxalate is a naturally occurring substrate found in foods like some fruits, vegetables, nuts, chocolates, high doses of vit d, intestinal bypass sundering

Struvite stones- these stones are formed in response to infection. Uric acid stones − these stones are formed due to inadequate intake of water and seen in those who eat high protein diet. Cystine stones-these stones frees in people with a hereditary disorder. Others.

Cause: there is no definite cause; several factors may increase your sisal. Kidney stone free when you urine contains more crystal forming substances such as calcium,oxalate & uric acid − than the fluid in your urine can debate.

Symptoms: a stone may not cause symptoms until it moves around within your kidney.

Sense pain in the side & back, below ribs.

Pain that spreads to the lower abdomen and groin.

Pain that comes in waves & fluctuates in intensity

Pain on urination

Pink, red or brown urine

Clouding or foul smelling urine

Nausea & vomiting

Persistent urge to urinate

Urinating more offen than usual

fever and chills

Ayurvedic treatment for kidney stones includes Panchakarma, a detoxification therapy that aids in the release of accumulated toxins, as well as the cleansing and restoration of the body's intrinsic healing potential. Ayurvedic Kidney Stone Treatments might provide remarkable outcomes in a short period of time. The drugs contain a unique blend of herbs that naturally dissolve kidney stones.

As it in said “prevention is better than cure, we not only have the cure for this condition in ayurveda, we also focus on prevention by changing /modifying once life style which may be a major factor in causing recurrent Renal caliculi ayurvedic medicines not only cures the disease, but also maintains the health of a person which prevents a disease from occurring again.

#kidneyhealth #kidney stones #kidney stone symptoms #health #health and wellness #healthcare #ayurvedic #ayurvedictreatment

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prose2passion · 3 months

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I do love intrinsically disordered proteins but pinning them down to do a crystal structure is kind of against the spirit? NMR structures giving dynamic representations have served the field well.

#science #proteins #intrinsically disordered proteins #structural biology #protein structure

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jhavelikes · 8 months

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α-Synuclein is an important drug target for the treatment of Parkinson’s disease (PD), but it is an intrinsically disordered protein lacking typical small-molecule binding pockets. In contrast, the encoding SNCA mRNA has regions of ordered structure in its 5′ untranslated region (UTR). Here, we present an integrated approach to identify small molecules that bind this structured region and inhibit α-synuclein translation. A drug-like, RNA-focused compound collection was studied for binding to the 5′ UTR of SNCA mRNA, affording Synucleozid-2.0, a drug-like small molecule that decreases α-synuclein levels by inhibiting ribosomes from assembling onto SNCA mRNA. This RNA-binding small molecule was converted into a ribonuclease-targeting chimera (RiboTAC) to degrade cellular SNCA mRNA. RNA-seq and proteomics studies demonstrated that the RiboTAC (Syn-RiboTAC) selectively degraded SNCA mRNA to reduce its protein levels, affording a fivefold enhancement of cytoprotective effects as compared to Synucleozid-2.0. As observed in many diseases, transcriptome-wide changes in RNA expression are observed in PD. Syn-RiboTAC also rescued the expression of ~50% of genes that were abnormally expressed in dopaminergic neurons differentiated from PD patient–derived iPSCs. These studies demonstrate that the druggability of the proteome can be expanded greatly by targeting the encoding mRNAs with both small molecule binders and RiboTAC degraders.

Decreasing the intrinsically disordered protein α-synuclein levels by targeting its structured mRNA with a ribonuclease-targeting chimera | PNAS

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scientificinquirer-blog · 9 months

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Overlooked parts of proteins revealed as critical to fundamental functions of life

According to textbooks, proteins work by folding into stable 3D shapes that, like Lego blocks, precisely fit with other biomolecules.Yet this picture of proteins, the “workhorses of biology,” is incomplete. Around half of all proteins have stringy, unstructured bits hanging off them, dubbed intrinsically disordered regions, or IDRs. Because IDRs have more dynamic, “shape-shifting” geometries,…

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#North America #proteins

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jcmarchi · 10 months

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Hard to Drug: Protein Droplets Reveal New Ways to Inhibit Aggressive Form of Prostate Cancer - Technology Org

New Post has been published on https://thedigitalinsider.com/hard-to-drug-protein-droplets-reveal-new-ways-to-inhibit-aggressive-form-of-prostate-cancer-technology-org/

Hard to Drug: Protein Droplets Reveal New Ways to Inhibit Aggressive Form of Prostate Cancer - Technology Org

Many of the most potent human oncoproteins belong to a class of proteins called transcription factors, but designing small molecule drugs that target transcription factors is a major challenge, especially when treating aggressive forms of prostate cancer.

Surgeon during a surgery – illustrative photo. Image credit: National Cancer Institute

An international team of researchers from the Institute for Research in Biomedicine in Barcelona, the Max Planck Institute for Molecular Genetics, BC Cancer (University of British Columbia) and other institutions has now discovered a potential way to target the androgen receptor, the most prominent oncogenic transcription factor in prostate cancer, based on its propensity to form droplets also known as condensates.

The results described in this publication set the basis for the foundation of Nuage Therapeutics, a spinoff of the Institute for Research in Biomedicine and ICREA.

Super-resolution (τ-STED) imaging of the androgen receptor in human prostate adenocarcinoma cells. Image credit: MPI for Molecular Genetics

Transcription factors play essential roles in turning the genetic information encoded by genes into proteins in all cells and organisms. These regulatory proteins bind DNA, turn genes on or off, and control the rate at which DNA is transcribed into mRNA, which is needed for protein synthesis. Because of their central role in transcriptional control, many diseases can be traced back to dysregulated transcription factors.

Inhibiting their activity, especially in cancer, offers therapeutic potential, but many transcription factors have a trick up their sleeve. Their activation domains are intrinsically disordered, meaning that the chains of amino acids that make up the domain lack a clear three-dimensional structure. The lack of a stable 3D structure makes it virtually impossible to design drugs that bind to the activation domains.

A research team led by Xavier Salvatella and Antoni Riera at the Institute for Research in Biomedicine, ICREA and the University of Barcelona, Denes Hnisz at the Max Planck Institute for Molecular Genetics and Marianne D. Sadar at BC Cancer (University of British Columbia, Canada) – focused on the tendency of intrinsically disordered proteins to form so-called biomolecular condensates.

They found that the mechanisms involved in condensation could be exploited to inhibit androgen receptor activity in prostate cancer. “The rationale we have followed to optimize an inhibitor of the androgen receptor could be exploited to inhibiting other transcription factors, opening up new possibilities to address unmet medical needs,” says Xavier Salvatella.

Cellular droplets, a new approach to targeting transcription factors

Biomolecular condensates resemble proteinaceous blobs floating on water under a microscope. The condensates form in a process called liquid-liquid phase separation, similar to how oil droplets coalesce when mixed in water.

“We had previously observed that the androgen receptor forms biomolecular condensates when you add even a tiny amount of an activating molecule, such as testosterone, to cells” says Shaon Basu, now a computational biologist at the Charité and one of the study’s first authors together with Paula Martínez-Cristobal at the Institute for Research in Biomedicine.

The scientists hypothesized that there could be a link between the activation of the androgen receptor and its propensity to form droplets.

Working with biophysicist Xavier Salvatella, they used nuclear magnetic resonance techniques to identify several short pieces within the intrinsically disordered activation domain that are essential for phase separation. Moreover, the same short pieces turned out to be also necessary for the gene-activating function of the receptor.

“We discovered short sequences in the activation domain that tend to be disordered when the protein is soluble, and surprisingly, these regions seem to form more stable helices when the protein is concentrated in condensates,” explains Hnisz. The short helices create transient binding pockets that can be targeted with inhibitors when the receptor is in condensates.

Improving compounds for the treatment of prostate cancer

Working with the labs of Antoni Riera and Marianne Sadar, the team then improved an experimental small molecule inhibitor to fit almost perfectly into the transient binding pocket. They then tested in cell and mouse models whether these changes would increase the efficacy in an aggressive, late-stage form of prostate cancer.

“We modified the chemical features of the compound to match the features of androgen receptor condensation, resulting in a tenfold increase in the potency of the molecule in castration-resistant prostate cancer,” says Paula Martínez-Cristobal, also first author of the study.

“This is really important, because castration-resistant prostate cancer is an extremely aggressive cancer that is resistant to the current first-line therapeutics,” she adds.

However, more research is needed before these findings can be translated into new and safe therapeutics, the authors agree. The team hopes that the basic mechanisms they have discovered may be applicable to other transcription factors, opening the door to targeting these important molecules in many different diseases.

“We believe that the idea that there are certain sequences within intrinsically disordered protein domains that adopt a transiently stable structure in condensates is universal and likely generalizable to transcription factors,” concludes Hnisz.

Nuage Therapeutics

Founded by Xavier Salvatella, Mateusz Biesaga, Denes Hnisz and Judit Anido, the biotech company Nuage Therapeutics develops drug screening assays to target intrinsically disordered proteins that undergo biomolecular condensation, thus providing new treatments for diseases currently considered difficult to treat.

The findings now published laid the groundwork for the foundation of this company in September 2021. The potential of its science led to a €12M Seed financing round on June 2023.

Source: MPG

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