Michael F. Shaughnessy

1) Susan Lindquist—When was she born, where was she born, and what about her early formative years? 

Dr. Susan Lee Lindquist McKenzie is famous for her discoveries involving protein folding, molecular chaperones such as heat-shock proteins, prions in yeast microbes, and cancer. On June 5, 1949, Lindquist was born in Chicago, Illinois, into the home of Iver and Eleanor (Maggio) Lindquist, who were first-generation immigrants. Their aspirations for her future involved being a homemaker. Providentially, Lindquist would carve out her future by studying microbiology and biology in some of the country’s finest higher learning institutions.

Lindquist’s parents valued education, yet their daughter’s expectations were low, as was customary of the times. Lindquist herself admits to not having any career goals in her youth. Lindquist’s fifth-grade science teacher was her inspiration and influenced her way of thinking big and questioning style. Lindquist also learned techniques to cope with mild dyslexia and earned a scholarship to college. She earned her bachelor’s degree in microbiology from the University of Illinois at Urbana—Champaign in 1971.

2) Her Ph.D. was from Harvard—who did she study under, and what was her main field of interest?

Lindquist earned her Ph.D. in biology in 1976 from Harvard University. She worked in the laboratory of molecular biologist Matthew Stanley Meselson. There she studied the fruit fly, Drosophila melanogaster, and its heat-shock proteins (Hsps)—proteins synthesized more quickly in larger quantities following cellular exposure to sudden rises in temperatures.

After earning her Ph.D., Lindquist conducted her postdoctoral research in the laboratory of Hewson Swift at the University of Chicago. In 1978, she was employed in the U of C molecular genetics and cell biology department, where she remained until 2001. Lindquist flourished in this environment and became a Howard Hughes Medical Institute Investigator and full professor in 1988 and the Albert D. Lasker Professor of Medical Sciences in 1999.

3) First, prions—what are they—why are they important?

Prions are infectious agents that cause a constellation of slowly progressive degenerative diseases of the brain. Surprisingly, the prion particles consist entirely of protein. As causative agents of ailments, it was thought early on after their discovery by Stanley Prusiner that the prions were viruses. Viruses are known to harbor nucleic acid enclosed by a protein coat. Instead, it was found that these contagious prion agents lacked any form of nucleic acids. Therefore, the prions are named as such because they are proteinaceous infectious entities.

The prion diseases constellation has been renamed transmissible spongiform encephalopathies (TSE). One notorious prion disease is colloquially called “mad cow disease,” known as bovine spongiform encephalopathy (BSE). Due to neurological pathology, the cattle infected by the prions and exhibiting BSE appear to have gone mad. Other potentially susceptible mammals include elk, deer, mice, cats, minks, sheep, and humans.

The sheep version of the prion disease is called “scrapie.” In addition to neurological manifestations, the sheep have an uncontrollable desire to scrape themselves against objects like fences, poles, or trees until they bleed. The prion disease-causing agent is called prion protein, “PrP^SC,” in which “SC” denotes scrapie, the pathogenic form of the PrP. The standard non-pathogenic form is called the cellular prion protein. It is designated as “PrP^C,” where the “C” stands for cellular. The PrP^C form functions to chaperone the folding of a protein into its standard shape. However, a primary function of the PrPSC is to bind the healthy PrP^C version and convert it into another PrP^SC type of protein. The PrP^C harbors mainly alpha-helices. The PrP^SC consists primarily of beta-strands. See Figure 36, which depicts a secondary structure format.

https://commons.wikimedia.org/wiki/File:PRPCvsPRPSC.jpg

Figure 36. Differences between secondary structures of the normal PrP^C protein and scrapie prion PrP^SC. (Labels have been translated to English.)

Humans can be susceptible to the prions either by infection, genetic inheritance, or sporadically. The human prion versions of the illness acquired by infection are called Creutzfeldt-Jakob disease (CJD) and variant CJD. Another transmissible human version is called kuru, which emerged in New Guinea. The kuru form of the prion disease is transmitted by a cannibalistic foodborne mode in which natives of New Guinea consume their dead relatives’ brains, who succumbed to the agent. The prions embedded in their victim’s brain tissue is transferred to the cannibals, who then can acquire the kuru. Carlton Gajdusek took the Nobel prize for discovering that kuru was infectious and for developing a technique for diagnosis.

The genetic versions of the human TSE diseases include familial-CJD (f-CJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome, and fatal familial insomnia (FFI). The f-CJD, GSS, and FFI disorders can involve mutations in the PrP molecule that destabilize the protein structures. The destabilized prion molecule spontaneously converts to the pathological PrP^SC configuration.

https://commons.wikimedia.org/wiki/File:Prion_Replication.png

Figure 37. PrP^SC induces a conformational change in PrP^C.

While the molecular basis of the disease pathology is far from understood, a general mechanism has emerged. See Figure 37. First, the genetically mutated prion agent produces the PrP^SC, or transmission to the patient occurs. The PrP^SC then aggregates abnormally into giant molecular complexes, converging on brain cells’ membrane surfaces. The normal PrP^C that’s anchored to phosphatidylinositol glycan molecules on cell surfaces are converted to the pathological PrP^SC shape. The neuron compensates by making more PrP^C. They form long chains consisting of repeating units outside the cell. The repeats create an extracellular component called an anionic glycosaminoglycan. Then, the long chains break from the action of phagocytes and shearing forces, releasing smaller aggregates of PrP^SC, which then migrate to other cells to start the process over again.

Sometimes the PrP^SC molecules get taken up by brain cells and accumulate, reaching high intracellular concentrations. The buildup is problematic because when phagocytosis attempts to eliminate the accrued PrP^SC aggregates, the process fails. Instead of PrP^SC eradication, abnormal brain tissue vacuolation occurs. The vacuolation somehow produces the diseased brain’s spongy-like texture.

Lindquist’s involvement with prions concerned her discovery of their presence in yeast microbes. Her findings were important discoveries because yeast cell harboring prions served as a useful laboratory model system for close study of the prions’ effects in living cells. Her studies of prions in yeast organisms showed that normal cellular proteins were associated with host cells’ prion biology. In particular, Lindquist showed how the folding of protein structures of ordinary versus prion proteins had similarities in their biochemical mechanisms.

4) Heat shock proteins—what exactly are these, where are they located, and why are they important?

Heat shock proteins are found in all taxa of living organisms, from bacteria to humans. These specialized proteins are produced at a rapid rate in cells that are exposed to higher-than-normal temperatures. For a cell’s proteins to function correctly, they must be folded into specific three-dimensional shapes; otherwise, misshaped proteins cannot work. The life of the cell will be in peril.

As soon as a protein is made fresh off the translational machine, the new protein molecule arranges its linear primary sequence of amino acids into an adequately shaped 3-D configuration. Some of these 3-D shaped proteins assemble into larger quaternary complexes, forming functional molecules necessary for life. Appropriately folded proteins are an essential requirement for the living cell. Such proteins can function only when a specific molecular structure is assumed.

Presumably, the heat shock proteins function to protect cellular proteins from denaturing. When temperatures are elevated, the heat will cause proteins to unfold or misfold, causing denaturation. A denatured protein will cease to function correctly and could even be destroyed by a cell. The heat shock proteins can protect cellular proteins from denaturation after exposure to heat. Lastly, for proteins that become unfolded or heat-denatured, the heat shock factors will recover the unfolded proteins and restore them to their original shapes. Such re-shaped proteins can reacquire their cellular function, allowing the cell to continue living.

As the ribosome and its translational machinery make new proteins, the newly constructed proteins are initially unfolded. Neighboring molecules and the cell’s internal environment can influence the new proteins’ nascent nature to form misfolded structures. Thus, an improperly folded protein can malfunction or associate with inappropriate molecules to form abnormal complexes, producing deviant cellular behavior that can be detrimental to the cell.

Today, we understand that these heat shock proteins serve a general biological role called molecular chaperoning. Molecular chaperones are proteins that assist the proper folding of newly made proteins into their correct molecular shapes. Molecular chaperones positively influence a cell’s life expectancy by helping new proteins form their appropriate 3-D shapes so that they can function normally.

https://commons.wikimedia.org/wiki/File:Heat_Shock_Response_Diagram.png

Figure 38. The diagram depicts molecular and cellular actions if stress is introduced to the cell.

In Figure 38, the effects of heat stress on a cell are shown. Stress induces the heat shock factor, HSF-1, which can form molecular chaperones. Cellular stresses, such as heat, can cause proteins to misfold as they denature. The molecular chaperones can influence misfolded proteins to fold correctly. However, if the misfolding is excessive, the protein will be completely degraded by a complex proteasome or through a process called autophagy, which is a debris elimination mechanism in cells.

Several of these molecular chaperones, known at the time as heat shock factors, were discovered by Lindquist during the 1980s. She first studied the heat stress behavior in fruit flies, in Drosophila melanogaster, at Harvard. Lindquist measured mRNA levels in flies that were exposed to high temperatures. As a postdoctoral fellow under Hewson Swift at the University of Chicago, Lindquist examined the translation’s efficiency in the new RNA messages in the heat- flies. She found that the protein synthesis patterns were not affected detrimentally but were altered in their translational programs. As an independent investigator and faculty at the University of Chicago, Lindquist studied the regulation patterns of protein synthesis and the intracellular locations of the proteins that emerged after heat exposures in the fruit flies.

She then compared the protein expression patterns observed in fruit flies with those in the yeast microbe called Saccharomyces cerevisiae. Lindquist discovered specific differences in heat stress responses between the fruit fly and yeast. In yeast, she found that particular RNA molecules disappeared from the microbial cells. In contrast, other RNA messages were faithfully translated into proteins. This expression phenomenon was in stark contrast to the protein expression patterns she had observed in the fruit flies. The flies had a control mechanism at play to increase specific protein production while suppressing the expression of other proteins in flies exposed to heat. In due course, Lindquist would go on to make new vital discoveries in the yeast microbes.

5) We are all vaguely familiar with yeast—but what was Susan Lindquist’s specific interest in yeast?

https://commons.wikimedia.org/wiki/File:20100911_232323_Yeast_Live.jpg

Figure 39. Saccharomyces cerevisiae — baker’s yeast.

In yeast cells, see Figure 39, Lindquist made other startling discoveries involving heat shock proteins. One of these proteins was called Hsp90. In addition to observing that the rise in Hsp90 occurred after heat stress and helped unstable proteins fold correctly, Lindquist further discovered novel functions. She showed that Hsp90 had roles in signal transducing and developmental biology. The Hsp90 molecule worked on a completely different set of unstable mutated proteins to permit their functions to be carried out. Thus, Lindquist discovered that the Hsp90 allowed the evolution of new traits conferred by the newly stable mutated proteins. The discovery was of great importance because a heat shock protein, a chaperone, made it possible for new evolutionary adaptations to occur in novel environments.

https://commons.wikimedia.org/wiki/File:PDB_1uyi_EBI.jpg

Figure 40. Molecular protein structure of the ATPase domain in the Hsp90 chaperone, registered with 1uyi code.

Lindquist studied the molecular mechanism of Hsp90. She and colleagues examined the amino acid sequences of the Hsp90 and found homology to a critical enzyme called ATPase, see Figure 40. It was further discovered that all Hsp proteins studied thus far harbor the ATPase domain. These ATPases contain two nucleotide-binding domains, called NBDs. These new findings pointed to ATP’s hydrolysis as a biochemical mechanism for driving the protein folding abilities of molecular chaperones. Interestingly, the ATPase domain structure has been conserved in other proteins, such as histidine kinase and DNA topoisomerase II enzymes.

Lindquist made another new significant discovery involving yeast microbes. This new finding concerned another heat shock protein, a chaperone protein called Hsp104, involved in yeast stress tolerance from heat exposure. This particular discovery would shake the foundations of prion biology, a field for which Lindquist had not previously been a member. In Lindquist’s laboratory, Hsp104 untangled inactive protein aggregates, restoring their functions. While the protein function restoring the ability of a heat shock protein was not a novel result on its own, the kind of protein that was reactivated was novel. That was an incredible achievement. Lindquist discovered that Hsp104 disentangled tangled prions!

The work was met with fierce resistance by many investigators. However, Lindquist would spend the next decades providing concrete experimental evidence for yeast proteins’ prion-like behavior. The discovery had shed light on the prion hypothesis, which implied a protein-based mode of genetic inheritance.

One unclear observation involving yeast was an inherited genetic element called [PSI⁺] first described by Brian Cox in 1965. The [PSI⁺] trait was a colorful yeast phenotype that did not obey standard Mendelian genetics. Lindquist showed that the [PSI⁺] genetic element was a prion-like aggregation of a protein called Sup35. The Sup35 molecule is a sub-unit of a translation-release factor that makes ribosomes stop protein synthesis when reaching nonsense codons on mRNA.

Hsp104 binds to Sup35 as it is freshly made, producing a partially folded transition state, which then aggregates to form the [PSI⁺] element. Thus, as part of the [PSI⁺] complex, the Sup35 is effectively sequestered from the translational machinery. Accordingly, the sequestered Sup35 cannot terminate translation. Therefore, the translational machinery reads through the termination codon of mRNA to produce a longer protein than is usual.

However, without [PSI+] complex formation, Sup35 reverts to its normal functional state, terminating translation at the stop codon on mRNA. To precisely regulate the Sup35 incorporation into the [PSI⁺] element, the Hsp104 concentration must be present in precise amounts—too little or too much would mess up the [PSI⁺] complex formation.

As the years went by, Lindquist would discover additional prion-like behaving proteins, showing how prion-like aggregations regulated their activities. Lindquist and her laboratory students and scientists would find dozens of prions and molecular chaperones from yeast cells.

6) We must mention that Lindquist served as a mentor to many female scientists. Professor Lindquist went out of her way to provide a warm welcome to up and coming colleagues. Can you name a few?

Dr. Susan Lindquist mentored generations of female students and postdoctoral fellows throughout her scientific career. Lindquist was a tremendously encouraging advocate for female colleagues, many of whom looked up to her as an influential and positive role model. Many of these fledgling scientists went on to become quite prominent independent investigators. For instance, Dr. Bonnie L. Bassler, a noted molecular biologist interested in bacterial quorum sensing at Princeton University, attributed much of her success to Lindquist’s mentorship. Dr. Bassler would become Squibb Professor, an endowed post, and chair of the molecular biology department at Princeton.

Another mentee, Dr. Dianne K. Newman, an endowed Binder and Amgen professor of biology and geobiology at Caltech, was motivated by Lindquist’s example of a stellar scientific investigator. Lindquist deeply inspired Newman. Likewise, Dr. Brit D’Arbeloff recalled that Lindquist’s career advice influenced her and her husband to pursue their investigations at the Whitehead Institute.

Lindquist’s publications were inspiring to young molecular biologists. Neurobiologist Dr. Cori Bargmann remembered reading Lindquist’s creatively brilliant scientific 1998 paper on Hsp90 functioning like a capacitor for directing molecular evolution as one of her favorite articles. The report would influence many to study misfolded proteins and their relationships to human neurodegenerative illnesses.

Many of Lindquist’s students and mentees were quite appreciative of her efforts to train them in the scientific method. Lindquist was awarded the Vanderbilt Prize for Women’s Excellence in Science and Mentorship 2014. It is an utmostly fitting tribute to a fine scientist.

She was honored in other ways. She was bestowed the President’s National Medal of Science in 2009, awarded by President Barack Obama. She was awarded the Dickson Prize in Medicine in 2003, the Otto-Warburg Prize in 2008, the Genetics Society of America Medal in 2008, the FASEB Excellence in Science Award in 2009, the Max Delbrück Medal in 2010, the Mendel Medal in 2010, the E.B. Wilson Medal in 2012, the Vallee Visiting Professorship in 2015, and the Albany Prize in 2016.

Lindquist was also elected as a member of the prestigious National Academy of Sciences, the National Academy of Medicine, the American Philosophical Society, the American Academy of Arts and Sciences, and the British Royal Society.

7) She was the Director of the Whitehead Institute—from 2001 to 2004—What exactly is the Whitehead Institute, see Figure 41, what gets researched there? And what did she investigate there?

https://commons.wikimedia.org/wiki/File:Whitehead_Institute_at_night_-_from_Flickr_3504665133.jpg

Figure 41. The Whitehead Institute for Biomedical Research (left building) in Cambridge, Massachusetts.

From 2001 until 2004, Lindquist became a biology department professor at the Massachusetts Institute of Technology (MIT). While there, she served as the Director of the MIT-affiliated Whitehead Institute for Biomedical Research until her death. She guided over 100 postdoctoral fellows at the Whitehead Institute, graduate students, and undergraduates to fruitful research careers.

In her laboratory, Lindquist examined the transcriptional response to heat stress and investigated induced proteins: molecular chaperones. She was captivated because, although all eukaryotic cells placed at an extreme temperature perish, those same cells survived if first exposed to an intermediate temperature. Lindquist’s laboratory showed a genetic program that responds to this, and other stresses are activated in all cells. Thus, she embarked on her career studying heat-shock factors whose functions made the difference between life and death after stressor exposures.

Lindquist and her laboratory at Whitehead pioneered new studies devoted to folding newly formed proteins in the cell. She had discovered a variety of heat shock factors, called Hsp, with each one given a number attesting to their molecular weights. For instance, she found that the chaperones, such as Hsp90, enhance and buffer potentially detrimental outcomes from genetic variation. Thus, the heat shock chaperone factors drove evolutionary processes. These evolution-based systems ranged from cellular transformation during malignant cell tumorigenesis to the emergence of microbial resistance factors against antimicrobial agents.

Lindquist’s scientific contributions also definitively established the cellular and molecular bases for protein-based avenues of inheritance, to transfer new traits to subsequent generations of organisms, a controversial hypothesis. Lindquist also implied that the molecular chaperones and the prions each confer unique but potential mechanisms for Lamarckian-like modes of inheritance.

The molecular processes involved in folding proteins can occasionally go awry. The consequence of aberrant folding, called misfolding, has been invoked to explain neurological disorders such as Alzheimer’s disease, cystic fibrosis, Parkinson’s disease, and Huntington’s disease chorea. Protein misfolding can also play roles in illnesses of cancer. Specific proteins that have malformed their molecular structures, such as the prions, actively seek and attack the brain’s neurons to confer transmissible spongiform encephalopathies. Consequently, these abnormalities produce diseases Creutzfeldt-Jakob in humans and scrapie in sheep and mad cow disease in bovines.

8) Although she never received a Nobel, she seemed to enjoy her research, the collegiality and cordial relationship Lindquist had with colleagues—What was she like as a person?

https://commons.wikimedia.org/wiki/File:Professor_Susan_Lindquist_ForMemRS.jpg

Figure 42. Susan Lindquist.

A distinctive and characteristic attribute that has been noted about Lindquist was her mentorship. Her mentees reported that Lindquist took great care to teach younger people to write and communicate scientific findings. Her colleagues recognized Lindquist as a talented and gifted scientific communicator. She possessed a rare ability to explain molecular biology unambiguously.

Lindquist, Figure 42, was remembered as a bit absentminded when it came to everyday things. For example, in 2006, there was a meeting about Protein Folding in Vermont. Lindquist had accidentally left her computer at home. Since her colleagues were already on their way to the conference and could not bring her laptop, an alternate plan to deliver the forgotten laptop involved a helicopter. Luckily, the computer arrived just in time, and the conference-goers watched in astonishment as Lindquist retrieved her computer.

The positive influence of Dr. Susan Lindquist was powerful. She was recalled fondly by Dr. Rita Colwell, who became the first female Director of the prestigious National Science Foundation. Dr. Colwell would write that Lindquist will be long remembered for her significant mentorship towards younger female scientists. Her commitment to advancing education in the STEM fields was unparalleled. Further, Colwell stated, Dr. Lindquist would be commemorated for many scientific contributions for the ultimate betterment of humanity.

9) Sadly, she passed at age 67—and again, sadly, from cancer—what had she spent a lot of her time studying? 

Before her death, Lindquist studied cancer. On October 27, 2016, she died in Boston, Massachusetts, from ovarian cancer at 67 years of age.

Intriguingly, her work with the heat shock proteins had a direct relationship to studies of cancer. During tumor cell formation, the protective effects of the heat shock proteins are subverted. Thus, compromising molecular chaperones’ functions can facilitate carcinogenesis by converting benign tumors to malignant ones.

Conversely, molecular chaperones, such as Hsp90, present in tumorous tissues, permit mutated proteins to maintain function. The refolding of mutant proteins can allow cancers to regulate imbalanced signaling that is induced by oncogenic proteins. Investigators are actively pursuing studies on cancer cell function by using Hsp90 inhibitors.

These modulatory agents, as they become available, are applicable in cancer chemotherapy. Thus, improving the Hsp90 chaperone inhibitors’ pharmacological activities is an active field of anti-cancer therapy. New work that combines conventional anti-cancer agents with Hsp90 inhibitors is a promising avenue. Maybe these chaperones can guide cancer cells to become normal cells.

Learn more about Dr. Lindquist’s work in her own words. Some of her lectures and interviews are listed below.

• Lecture Series for iBiology, 2016 Susan Lindquist: Protein Folding, Prions, and Disease
• Profile of Susan Lindquist, The Scientist, Jan 2016: Fearless About Folding
• Vanderbilt Prize Lecture to honor a scientist with stellar research and outstanding mentorship, Nov 2015:  From Yeast Cells to Human Neurons: Powerful Discovery Platform for Combatting Neurodegenerative Diseases
• iBiology Lecture, Susan Lindquist, June 2015:
  Susan Lindquist: Protein Folding and Disease
• CSHL 2015 Symposium Interview Series with Susan Lindquist, May 2015:
  80th Cold Spring Harbor Symposium on Quantitative Biology, 21st Century Genetics: Genes at Work
• ISSCR, Vancouver, June 2014:
  From Yeast Cells to Human Neurons — Modeling Complex Protein Folding Diseases
• Molecular Frontiers Symposium, Stockholm, May 2014:
  From Yeast Cells to Patient Neurons: A Powerful Discovery Platform
• AAAS Plenary Lecture, February 2014:
  From Yeast Cells to Patient Neurons: A Powerful Discovery Platform for Parkinson’s and Alzheimer’s Diseases
• BBC World-Changing Ideas Interview, May 2013:
  Simpler Solutions for Unlocking Secrets of Ageing Minds
• E.B. Wilson Award Lecture, ASCB, December 2012:
  Hsp90 Chaperone Scultpting Evolutionary Change: A Quantitative Genetic and Proteomic View
• Interview About E.B. Wilson Award, ASCB, December 2012:
  Interview with Susan Lindquist
• A Celebration of Science Lecture, Washington D.C., September 2012:
  The Protein Folding Problem
• Molecular Frontiers Symposium, Stockholm, May 2011:
  Lamarck Redux: Prions, Hsp90, and the Inheritance of Environmentally Acquired Traits

Stew Peters

According to a new Gallup poll, more than half of Americans will refuse to comply with new virus lockdowns. In the new poll, 49% of respondents said they’ll be very likely to stay home, when in the spring time that number was 67%, according to a CNN poll. 

Coronavirus? What’s this thing you speak of? I vaguely remember a virus that went around in early 2020. That was the year the Democrats tried to cheat Donald Trump out of a second term in the White House. Do you remember? Yeah, I seem to recall a doctor that put the fear of God into elderly people and citizens that had underlying health conditions, and then do you remember how we later found out that doctor had a financial stake in the game and it later came to light that he didn’t even believe what he was saying as he told the entire country they should wear a mask, but then he went to a major league baseball game and as the cameras panned the stadium, there he was. There he was right next to his buddies with no mask on.

Yeah, that was the game I think he threw out the first pitch. Oh yeah, the COVID, that’s what they called it.

And then, what was that woman’s name? That crazy one? Remember her, the Speaker of the House? Nancy…Nancy Pelosi yes, she REALLY shed light on the importance of lockdowns and masking I mean she was the one that proved how dangerous the virus was for anyone that wanted to get together over the summer, go out to eat or have some drinks with your buddies, remember she was a mask nut job! She was like Lenin with those masks I think she even had some masking police my God she was REALLY convinced that virus was going to take us all down I mean she shut down restaurants and gyms… in California, you couldn’t even get a haircut, I mean she shut down salons!…and then, she was busted and exposed as a complete fraud and a liar after a hair salon owner leaked footage of her getting her wig blown out with no mask on. Yeah, that was crazy…those were crazy times. 2020…what a year.

Do you think this new information we’re seeing in these sliding restriction compliance numbers could have something to do with the the forgotten details?

Could this be a reaction to the little things the media leaves out as they blast COVID relentlessly through our televisions and into our living rooms reminding us that over 80 million people have been infected and 200,000 have died? Tragic, of course, but I don’t believe you. I’ll get to that in a minute, but I mean…So, when people do that math and realize the survivability is over 99%, when they realize that they actually have a better chance of becoming a millionaire from a scratch off, do you think they may be ready to roll the dice with the virus to prevent losing everything they’ve ever worked for? I mean, the likelihood that your business will close down permanently without any customers is about the same percentage…about 99.9%. Restaurants and bars don’t seem to do well when they’re not serving food and slinging drinks. My barber tells me she can’t make any money without someone sitting in her chair. I was blown away. I couldn’t believe it when I heard that kids weren’t learning as much as a result of not being in school…that really shocked the hell out of me!

Suicides are going through he roof as people lose it all, kids aren’t able to report to their school counselor how their uncle is touching their pee pees or how their mom puts her cigarette out on their sister when she’s drunk…. Yeah, child abuse and youth deaths are tragically becoming a part of this ‘new normal’ these progressives keep telling me I’m supposed to accept and I’ll have to get used to. Yeah, the ‘new normal’. The new normal that forced an immigrant woman to shut the doors on her newly opened business after she risked it all to flee her third world country to escape real oppression, and start her new life in the United States because we have a Constitution that guarantees her the protection from a tyrannical government, the promise of equality and the right to be free…do you think any of this weighs on the minds of these people giving the middle finger to radical power hungry liberal Democrats like Tim Walz in Minnesota or Gretchen Whitmer in Michigan? 

When Americans realize that these mandates really have nothing to do with safety and health, but everything to do with compliance and control, is it really supposed to shock or disturb us when they tell the government to get bent? 

Am I supposed to believe the same media that suppressed the biggest story in our lifetime about how a father used his son as a money mule to cash out on a Ponzi scheme with foreign adversaries to this country as he compromised the national security of America and sold us out as the Vice President of the United States? The same media that prematurely called an election for the highest office in the world, ignoring the fact that no state had certified their poll numbers, massive fraud is suspected and men married to Democratic senators sit on the board of directors of a computer company that supposedly mistakingly glitched taking votes away from Donald Trump and giving them to Joe Biden? 

You know, so forgive me if I don’t cower before my master, cover my face with a mask that isn’t backed up by any scientific data, close down my business and lock myself inside for the winter because I’m told to by the same people who’ve attempted multiple times to unseat a duly elected president by manufacturing lies about racism, misogyny and Ukrainian phone calls while corrupt establishment deep state politicians organize a fourth attempt at a coup de’ etat.

Meanwhile, the president they blame for the virus was the only one willing to act immediately to curb the spread when he shut down travel from the country that manufactured the damn thing and the same president that deregulated the hell out of drug makers so rather than six years of bureaucratic red tape and lobbyist pay to play to get medicine on the market, a vaccine is ready to go in just months…only to be shut down by sickos like Andrew Cuomo, who has said he’s actually ready to let front line medical workers and your grandmother die rather than allowing them to acquire the vaccination as he trades lives for political optics.

I don’t know about you, but I’m part of the majority. You can throw me in jail.

Source: Do What You’re Told Hypocrisy

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“What I like most about the film, in relation to its production process, is discovering how the different parts are related to each other.” – Alex Piperno

In Alex Piperno’s Window Boy Would Also Like to Have a Submarine, doors never lead to where they’re supposed to. A young sailor on a cruise ship off the coast of Patagonia stumbles upon a magical doorway that leads to a woman’s apartment in Montevideo.  Meanwhile, a group of Filipino farmers discover an abandoned shed in the valley that holds supernatural powers.  These two stories will merge in Piperno’s film and allow people in different parts of the world to enter one another’s spaces.  

Alex Piperno, was born in Montevideo.  He studied Film Directing at the Universidad del Cine de Buenos Aires.  Following a series of short films, Piperno directed the Hubert Bals Fund supported Window Boy Would Also Like to Have a Submarine.  His feature debut had its world premiere at the Berlinale in 2020. The film was nominated for the International New Talent Competition at the Taipei Film Festival, The International Competition at Jeonju Film Festival, and the Best First Feature Award at the Berlin International Film Festival.

The Global Search for Educationis pleased to welcome the film’s Director, Alex Piperno. 

“As a spectator, my favorite part is the end of the film, when everything ends up mixing and that leads to catastrophe.” – Alex Piperno

Alex, tell us what you like most about your film and also what audience feedback you’ve received.  Is there anything in your production process that you would do differently?

What I like most about the film, in relation to its production process, is discovering how the different parts are related to each other. They are not ideas that I came up with. I experienced that discovery and surprise in the process, and that is my greatest joy as a director. This happened during the script writing, but also during shooting, editing and sound design. In each of the stages, with different materials, I discover how old notes enter in relation to other notes, how frames leave doors open for someone to enter or not, how a shot in one scene works differently in another scene, what happens when this or that sound comes in, and thus the film becomes a system of opacities and transparencies that drives me crazy and keeps me fascinated during the different stages. As a spectator, my favorite part is the end of the film, when everything ends up mixing, and that leads to catastrophe.

Regarding the feedback from the audience, the Q&A experience at the Berlinale was deeply moving for me. The conversation with the audience was warm, stimulating, and extensive, and while I had no prior thoughts, it was unsettling for me to discover the spectators appropriating the film. There may be no other way, but it is my first film and I have not experienced that feeling before. After so many years, with so many moments of uncertainty and loneliness, putting the film on the table like a fruit and seeing how each one grabbed his own piece was wonderful. And I especially remember this: I would enter the theatre towards the end of each screening and I would wait at the entrance, and at one point, always the same, I would hear the audience giggling. It was not a time to laugh, I thought so, but the audience was laughing. There I understood that I had nothing more to do with the film and that was a great relief.

In relation to what things in the production process would I do differently: everything.

People have referred to your movie as “a globalized fairytale”. In what ways do you think the characters and the locations in your movie might inspire the audience to reflect on some of these relevant societal themes?  

I think the film does not talk about but works with. It is true that its materials are peripheral characters and places located in the antipodes, that these places become close and that the world ends up turning inside out like a sock. But the characters cannot communicate with each other, that is, the distance between them is not elided. I don’t know if I am interested in globalization as a topic. I do know that I am interested in the characters that watch, and I understand that in order to watch they have to be outside the thing, on the periphery. I also know that when I went to the cruise ship and framed the tourists, I felt a lot of rejection, and that when I panned to one side and the space was empty, I felt much better. I know that in a film, I prefer silence to bustle, that I like characters who do not know what to do and who are ashamed of themselves and are pushed by circumstances. I know that I hate the idea of work and that I am moved by the poetic function of language, that is, impertinence, humor, surprise, diagonals, frame within frame compositions. All this will make one type of film appear instead of another.

“In relation to what things in the production process would I do differently: everything!” – Alex Piperno

Funding and especially funding during a pandemic – what lessons did you learn from the process?  What advice would you give to other young filmmakers trying to raise money for their first film?

The development of the film began at the end of 2011. I had screened that year the short film The Inviolability of the Domicile which is based on the man who appears wielding an ax at the door of his house during the Cannes Critics’ Week, which I imagine must have helped the project to be considered more carefully. The film was selected in a script workshop called Taller Colón along with other projects by Latin American directors, who later became very dear friends. The following year the film obtained its first development funds, from ICAU (Uruguay) and the Hubert Bals Fund, which was essential for me to dedicate myself seriously to its development. I had decided to be the majority co-producer on the Uruguayan side and I conceived the film as a co-production between Uruguay and Argentina. I associated with my beloved Lukas Rinner, who at that time was taking his first steps with his production company Nabis Argentina. We began to be selected for different laboratories and markets, such as Bafici Bal, San Sebastián Co-production Forum and Berlinale Script-station, among others. The truth is that we had no idea how to produce a feature film, much less this one in particular.

Years passed and we could not obtain any production funds. Then we applied to the Uruguay and Brazil co-production fund and obtained our first production fund. Meanwhile, we continued applying to national and international funds without luck. My life had been reduced to trying to carry this film forward and I felt that the film was getting stuck in a well and myself with it. We were still applying to laboratories. The search for financing for production lasted until 2017.

In 2014 Lukas shot his first feature film and we decided that it was best for him to open up about the project. He was replaced by Argentine producers Esteban Lucangioli and Araquén Rodríguez, from Pelícano production company. In those years we obtained INCAA production fund (Argentina), IBERMEDIA co-production fund, NFF + HBF from Netherlands (joining the project the producer Frank Hoeve, from Baldr Film), a municipal production fund from Montevideo (Uruguay) and, at the last moment, ICAU production fund (Uruguay), which finally allowed us to start the production. The staged shooting strategy, which was the condition of possibility of the film and that extended from 2017 to 2019, also involved going through a severe devaluation of the Latin American economy. The funds obtained in our national institutes, which are granted in local currency and staggered in installments, were devalued in some cases above 70%. The film was made possible with the entry of the Philippine producer Armi Rae Cacanindin to the co-production team, and with a very significant effort in time and money from all the production companies, to which I am eternally grateful.

This whole process was very formative for me. It was a ten-year process of many “first times”. 

An incredible journey for sure.

Yes, I had to learn how to write a film, how to produce a film, how to direct a film. Naturally, having had the experience, I would do things differently. For example, the most important thing is to find your own way and defend it from common sense. Cinema is such a normed, hierarchical, collective and expensive discipline that it can pass over you. The crew need urgent definitions that many times I cannot give them and it is necessary to be able to deal with that, with the chronometer running and without fully understanding what I am doing. I was very afraid that the common sense of the shooting would win me over, because I knew that would be a disaster for the film. Finding out what my times and priorities were and learning to trust them in the midst of that fire was the hardest thing for me. So it seems to me very important to be able to invent a production system that can be solidary with the way one has to face a film. Because the traditional way of production rejects any possibility of doubting, playing or making mistakes, and at the end of the day, these are our most valuable working tools.

“The traditional way of production rejects any possibility of doubting, playing or making mistakes, and at the end of the day, these are our most valuable working tools.” – Alex Piperno

Where can audiences see Window Boy Would Also Like to Have a Submarine?

The film was released in the last days of the pre-covid era and we had a beautiful schedule of international festivals and premieres in confirmed theaters that exploded in the air and we still continue putting together the broken pieces of all this. The film is now available on IFFR Unleashed, the VOD platform of the Rotterdam Festival, exclusively for the Benelux territory. We continue to prioritize the screenings in festivals and theatres, because the film is, as it is said – or as it used to be said – a film “to watch in the theatre”. 

Thank you Alex

C.M. Rubin and Ben Stassen

Thank you to our 800 plus global contributors, artists, teachers, entrepreneurs, researchers, business leaders, students and thought leaders from every domain for sharing your perspectives on the future of learning with The Global Search for Education each month.

C. M. Rubin (Cathy) is the Founder of CMRubinWorld, an online publishing company focused on the future of global learning, and the co-founder of Planet Classroom. She is the author of three best-selling books and two widely read online series. Rubin received 3 Upton Sinclair Awards for “The Global Search for Education.” The series, which advocates for Youth, was launched in 2010 and brings together distinguished thought leaders from around the world to explore the key education issues faced by nations.

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Better caviars are unbelievable eaten with toast, blinis, or unsalted wafers. While using different sorts of caviar, they should be presented with inside the requesting for intensity of the flavor, beginning with a milder-taste, for example, White Sturgeon and moving onto the ones which are more important phenomenal, for example, Sevruga.

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Bit by bit directions to decorate caviar

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The result of the U.S. presidential election marks the triumph, not of the Democrats and a senile senator, but of the Puritan current over the Jacksonians. It does not reflect the political views of American citizens and masks the crisis of civilization in which their country is sinking.

Source: U.S. Presidential Election: Open your eyes!, by Thierry Meyssan

‘Tucker Carlson Tonight’ host accuses America’s hypocritical lawmakers of not following own coronavirus rules

Source: Tucker Carlson: The elites want COVID-19 lockdowns to usher in a ‘Great Reset’ and that should terrify you | Fox News

Source: How America’s Cities Became Bastions of Progressive Politics – American Greatness

Source: California School District Bans ‘To Kill a Mockingbird,’ ‘Huckleberry Finn,’ Other Classic Novels

11.13.20 – AIER

“Even a Military-Enforced Quarantine Can’t Stop the Virus, Study Reveals”

Jeffrey A. Tucker

Excerpts from this article:

The New England Journal of Medicine [11.11.20 — https://www.nejm.org/doi/full/10.1056/NEJMoa2029717 ] has published a study that goes to the heart of the issue of lockdowns. The question has always been whether and to what extent a lockdown, however extreme, is capable of suppressing the virus. If so, you can make an argument that at least lockdowns, despite their astronomical social and economic costs, achieve something. If not, nations of the world have embarked on a catastrophic experiment that has destroyed billions of lives, and all expectation of human rights and liberties, with no payoff at all. 

AIER has long highlighted studies that show no gain in virus management from lockdowns. Even as early as April, a major data scientist said that this virus becomes endemic in 70 days after the first round of infection, regardless of policies. The largest global study of lockdowns compared with deaths as published in The Lancet found no association between coercive stringencies and deaths per million. 

To test further might seem superfluous but, for whatever reason, governments all over the world, including in the US, still are under the impression that they can affect viral transmissions through a range of “nonpharmaceutical interventions” (NPIs) like mandatory masks, forced human separation, stay-at-home orders, bans of gatherings, business and school closures, and extreme travel restrictions…

A study conducted by Icahn School of Medicine at Mount Sinai in cooperation with the Naval Medical Research Center sought to test lockdowns along with testing and isolation. In May, 3,143 new recruits to the Marines were given the option to participate in a study of frequent testing under extreme quarantine. The study was called CHARM, which stands for COVID-19 Health Action Response for Marines.

Of the recruits asked, a total of 1,848 young people agreed to be guinea pigs in this experiment which involved “which included weekly qPCR testing and blood sampling for IgG antibody assessment.” In addition, the CHARM study volunteers who did test positively “on the day of enrollment (day 0) or on day 7 or day 14 were separated from their roommates and were placed in isolation.”

What did the recruits have to do? The study explains, and, as you will see, they faced an even more strict regime that has existed in civilian life in most places. All recruits, even those not in the CHARM group, did the following.

All recruits wore double-layered cloth masks at all times indoors and outdoors, except when sleeping or eating; practiced social distancing of at least 6 feet; were not allowed to leave campus; did not have access to personal electronics and other items that might contribute to surface transmission; and routinely washed their hands. They slept in double-occupancy rooms with sinks, ate in shared dining facilities, and used shared bathrooms. All recruits cleaned their rooms daily, sanitized bathrooms after each use with bleach wipes, and ate preplated meals in a dining hall that was cleaned with bleach after each platoon had eaten. Most instruction and exercises were conducted outdoors. All movement of recruits was supervised, and unidirectional flow was implemented, with designated building entry and exit points to minimize contact among persons. All recruits, regardless of participation in the study, underwent daily temperature and symptom screening. Six instructors who were assigned to each platoon worked in 8-hour shifts and enforced the quarantine measures. If recruits reported any signs or symptoms consistent with Covid-19, they reported to sick call, underwent rapid qPCR testing for SARS-CoV-2, and were placed in isolation pending the results of testing.

Instructors were also restricted to campus, were required to wear masks, were provided with preplated meals, and underwent daily temperature checks and symptom screening. Instructors who were assigned to a platoon in which a positive case was diagnosed underwent rapid qPCR testing for SARS-CoV-2, and, if the result was positive, the instructor was removed from duty. Recruits and instructors were prohibited from interacting with campus support staff, such as janitorial and food-service personnel. After each class completed quarantine, a deep bleach cleaning of surfaces was performed in the bathrooms, showers, bedrooms, and hallways in the dormitories, and the dormitory remained unoccupied for at least 72 hours before reoccupancy.

The reputation of Marine basic training is that it is tough going but this really does take it to another level. Also, this is an environment where those in charge do not mess around. There was surely close to 100% compliance, as compared with, for example, a typical college campus. 

What were the results? The virus still spread, though 90% of those who tested positive were without symptoms. Incredibly, 2% of the CHARM recruits still contracted the virus, even if all but one remained asymptomatic…

And how does this compare to the control group that was not tested and not isolated in the case of a positive case?  

Have a look at this chart from the study:

New England Journal of Medicine

Which is to say that the nonparticipants actually contracted the virus at a slightly lower rate than those who were under an extreme regime. Conversely, extreme enforcement of NPIs plus more frequent testing and isolation was associated with a greater degree of infection. 

…No national news story that I have found highlighted the most important finding of all: extreme quarantine plus frequent testing and isolation among military recruits did nothing to stop the virus. 

…with this Marine study, you have a near homogeneous group based on age, health, and densities of living. And even here, you see confirmed what so many other studies have shown: lockdowns are pointlessly destructive. They do not manage the disease. They crush human liberty and produce astonishing costs, such as 5.53 million years of lost life from the closing of schools alone. 

The lockdowners keep telling us to pay attention to the science. That’s what we are doing. When the results contradict their pro-compulsion narrative, they pretend that the studies do not exist and barrel ahead with their scary plans to disable all social functioning in the presence of a virus. Lockdowns are not science. They never have been. They are an experiment in social/political top-down management that is without precedent in cost to life and liberty. 

Source: Pandemic ‘fuelling numbers of children out of school’ – BBC News