“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.
‘So much evidence I feel like it’s coming in through a fire hose’
By Joe Kovacs
Sidney Powell on the Fox Business Network on Sunday, Nov. 15, 2020. (Video screenshot)
An attorney helping President Trump challenge the results of the 2020 election says she’s astonished by the amount of evidence of vote fraud that took place, alleging “millions of votes” were shifted to Democrat Joe Biden by software specifically designed to benefit the Democratic nominee.
“President Trump won by not just hundreds of thousands of votes, but by millions of votes that were shifted by this software that was designed expressly for that purpose,” attorney Sidney Powell told Maria Bartiromo on “Sunday Morning Futures” on the Fox Business Network.
“We have sworn witness testimony of why the software was designed. It was designed to rig elections,” Powell said of the Smartmatic software in Dominion voting machines.
“They did this on purpose, it was calculated, they’ve done it before. We have evidence from 2016 in California, we have so much evidence I feel like it’s coming in through a fire hose,” Powell continued.
“I’ve got lots of ways to prove it … but I’m not gonna tell on national TV what all we have. I just can’t do that.” WATCH:
Bartiromo wondered: “You have a very small timeframe here, the elections are supposed to be certified in early December. Do you believe that you can present this to the courts and be successful within just this couple of weeks?”
“First of all, I never say anything I can’t prove. Secondly, the evidence is coming in so fast I can’t even process it all,” Powell responded.
“This is a massive election fraud, and I’m very concerned it involved not only Dominion and its Smartmatic software, but that the software essentially was used by other elections machines also. It’s the software that was the problem. Even their own manual explains how votes can be wiped away. It’s like drag and drop Trump votes to a separate folder and then delete that folder.”
“It’s absolutely brazen how people bought the system, and why they bought the system. In fact, every state that bought Dominion for sure should have a criminal investigation or at least a serious investigation of the officers in the states who bought the software. We’ve even got some evidence of kickbacks essentially.”
Powell named names, including Peter Neffenger, the former administrator of the Transportation Security Administration under Barack Obama.
Powell said Neffenger is “president and on the board of directors of Smartmatic. And it just so happens he’s on Mr. Biden’s presidential transition team, that’s going to be non-existent, because we’re fixing to overturn the results of the election in multiple states.”
Peter Neffenger (Official photo)
“He was fully briefed on it. He saw it happen in other countries it was exported internationally for profit by people that are behind Smartmatic and Dominion.”
Powell also said the CIA must have known about the problem with the voting machines, and she called for the immediate firing of CIA Director Gina Haspel.
“It’s really an insidious, corrupt system and I can’t tell you how livid I am with our government for not paying attention to complaints, even brought by Democrats,” Powell said. “Nobody in our government has paid any attention to it which makes me wonder if the CIA has used it for its own benefit in different places. And why Gina Haspel is still there in the CIA is beyond my comprehension. She should be fired immediately.”
President Donald J. Trump talks to members of the press along the South Lawn driveway Thursday, Sept. 24, 2020, prior to boarding Marine One en route to Joint Base Andrews, Maryland, to begin his trip to North Carolina and Florida. (Official White House photo by Tia Dufour)
Meanwhile, President Trump remained steadfast on Sunday in his refusal to concede the election in any way to Biden.
“He only won in the eyes of the FAKE NEWS MEDIA,” Trump tweeted. “I concede NOTHING! We have a long way to go. This was a RIGGED ELECTION!”
The controversial business magnate is supporting the controversial candidate for Speaker of the Texas House.
By Adam Cahn
Tilmann Fertitta
Dade Phelan’s presumptive speakership of the Texas House has already raised eyebrows, given his support for left-wing social causes and questionable commitment to law enforcement. But an upcoming fundraiser for Phelan is sure to raise eyebrows further.
According to an event invitation seen by Texas Scorecard, Houston Rockets owner Tilmann Fertitta will host a fundraiser for Phelan on November 30 at the former’s Post Oak Hotel at Uptown Houston. According to its website, the Post Oak is Houston’s only five-star hotel, where rooms start at $467 per night. Tickets to Fertitta’s event with Phelan range from $1,000 for an individual to $25,000 for so-called “platinum” hosts.
More notably, Fertitta attracted national attention during the 2019 controversy over the NBA’s relationship with the Chinese dictatorship. Then-Rockets General Manager Daryl Morey made a seemingly innocuous tweet of support for pro-constitutional liberties protests in Hong Kong, but following economic threats from the Chinese dictatorship, Fertitta publicly threw Morey under the bus:
Lest there be any doubt about where Fertitta stands on China, he doubled down on his position at a White House meeting in May:
In addition, Fertitta’s support for Phelan is noteworthy, given the NBA’s recent infatuation with anti-law enforcement activism.
Members of the Texas House of Representatives will officially vote for their next speaker on January 12, 2021.
“In a society where the press is not holding those who govern accountable, we will have no chance to learn the truth.” – Alexander Nanau
On November 30, 2015, a fire broke out at Bucharest’s Colectiv nightclub. The free concert celebrating metal band Goodbye to Gravity’s latest album featured a pyrotechnic display during the performance. A spark from one of the fireworks caused the fire to spread quickly, soon engulfing the entire room. Twenty six people died on-site. A further 38 died in hospitals around Romania and neighbouring countries. Protests against the government’s lack of regulation erupted, leading to the government’s resignation.
Collective is a Romanian documentary film directed and co-written by Alexander Nanau. It was featured at the Venice Film Festival, the Toronto International Film Festival and this year’s Sundance Film Festival. The film has been submitted by Magnolia Pictures and Participant for the 2021 Academy Awards (Best Documentary). The Romanian Film Center/CNC Romania recently confirmed that Collective will be Romania’s official Oscar entry for Best International Feature. In the film, Nanau follows the crack team of journalists at the Romanian newspaper Gazeta Sporturilor as they uncover a vast health-care fraud that enriched politicians and moguls in the wake of the Colectiv nightclub fire.
The Global Search for Education is pleased to welcome Alexander Nanau.
“A young generation took to the streets against the corrupt authorities and the corrupt political class. It felt like change was coming.” – Alexander Nanau
Alex, in your own words, can you please explain to us what happened on November 30, 2015?
The Collectiv club fire should not have happened or, even if it happened, it should not have cost so many lives. The Collectiv club in Bucharest was a popular club where there were a lot of concerts. But one of the main reasons why so many people died on the spot is that the Romanian fire department allowed the club to function even though there were no fire exits. What we realized and what the film is about is the aftermath of that. Many more people, thirty-seven in total, continued dying after the fire in hospitals. The Romanian government, together with doctors and the health-care system, lied to everybody that they were capable of treating burn patients when they actually couldn’t take care of their patients because they didn’t have burn units. They refused to fly the young burn patients out of the country into burn clinics where they could have been rescued. Our film takes a look at the journalistic investigation after the fire that uncovered more information, including the mass manipulation by the Romanian authorities. The government claimed that Romania was as well prepared as a country like Germany to take care of patients. They journalists found out that the company that was producing disinfectants for about 350 Romanian hospitals was diluting the disinfectants. This meant that not only these burn victims, but hundreds to thousands of Romanian patients over the last ten years were infected by hospital bacteria because the disinfectants were diluted. It is a bit like The Third Man which was made into a film with Orson Welles, where he was selling diluted penicillin.
So the Romanian government refused to get some of these burn victims out of the country and into other hospitals where they could have been treated?
Yes, their discourse was we have a great health care system, we have the best specialists, we can treat these patients as well as the German health care system, there won’t be a better treatment for them than in Romania. It’s the kind of behavior that we see today around the world where the populistic discourse leads to death. We always ask ourselves “why did you do that?” And then we find out it’s because by keeping patients in the country they can spend the money in an illicit way, and actually steal it.
“We realized we were witnessing a story that goes into the heart of the relationship between citizens and those in power.” – Alexander Nanau
The CEO of the pharmaceutical company Hexi Pharma that was diluting the disinfectants ends up losing his life. What was the cause of death?
He had a car accident. He was alone in his car and he drove into a tree.
The timing of your movie is very relevant with the COVID-19 pandemic and world leaders needing to address better health care systems and better health safety measures. What specific parallels do you see between the story of the Colectiv nightclub fire and what’s going on right now worldwide with the coronavirus pandemic?
I think that the important thing is the lack of responsibility of those that govern the lives of the citizens that elected them. Secondly, it’s about corruption. The journalistic investigation in the film moves like a thriller which leads us to the facts. We discover that everything is linked to corruption and to laundering money from the health care system. Another link to the pandemic is that at any time something like a fire, or a virus or any other disease can suddenly impact all our lives and that’s the point where we realize how much we depend on the functioning of the societies we live in. In a society where the press is not holding those who govern accountable, we will have no chance to learn the truth.
“People have reacted very emotionally and have said, “oh, it’s like it is in our country, it’s not just a Romanian story.” – Alexander Nanau
Your film illustrates the fallout of societies that do not function properly.
Yes, I think there is also the link between the universality of the Collectiv story and what’s happening to all of us right now, and that’s the total loss of humanity. These people are not human anymore. We started to make the film because we saw a turning point in Romanian society. A young generation took to the streets against the corrupt authorities and the corrupt political class. It felt like change was coming. When we started to dive into the whole corruption and revelation we were shocked to realize the level of the lack of humanity amongst these decision makers to a whole nation that was traumatized by this event. They knew they would send victims to their death because they knew about the infections in Romanian hospitals due to the diluted disinfectants.
What key element of this real life story inspired you to tell it? What has been the audience reaction to this story so far, of those that you have screened this movie to and those who have seen this movie?
It was the fact that we saw there was a change in the street. A new generation wanted to claim back their society from a corrupt political class. Once we started, we realized we were witnessing a story that goes into the heart of the relationship between citizens and those in power. We wanted to understand how the relationship between power and citizens works, and the point of view of investigative journalists seemed the best point of view to tell it through, to understand this relationship, to understand how information flows from the power towards the citizens, and how citizens can react to it, and how citizens can take care of, or protect, or influence their own community and society. People have reacted very emotionally and have said, “oh, it’s like it is in our country, it’s not just a Romanian story.”
Could you elaborate a little more on “the change in the streets?”
After the fire, we had mass demonstrations that were actually the biggest demonstrations since the Revolution in ’89, and it was just young people demonstrating against the corrupt political class and demanding a change. Demanding the government to step down and to have a politically independent government until reelections.
What do you want audiences to take away from this movie?
Normally I don’t make the films with an idea in my head as to what I want people to take away. I think that the most important question for me is, “how do I influence the community or society I’m living in? And what kind of society do I want to live in? And am I courageous enough to be true to myself and to stand up when I see corruption or when I see something really bad and wrong happening? Making this film is like holding a mirror in front of my face and asking myself if I’m bold enough to be myself and to stand up to things that I believe in, and to be a better human being.
What’s next for you? What are you working on now, in terms of future projects? Is there anything you’ve got your eye on right now that you’re planning?
Yeah, there are two, three projects that we’re developing but I never talk about projects when they’re in development. I’m superstitious, let’s say. Regarding Collective, the film will be released by Magnolia Pictures and Participant, in theaters and on VOD, on November 20th, and it will be released at the same date in the UK and France and Europe. It is now up for the European Film Academy Awards and, most probably, it will also try to run with all the other documentaries for the Academy Awards in the United States.
Thank you Alex
(Dallin Agatone contributed to this article)
C.M. Rubin and Alexander Nanau
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.
Strict lockdowns have devastated millions of families’ incomes while failing to bring success in suppressing covid mortality.
Mitch Nemeth
During the early onset of covid-19 in the spring, government officials across the political spectrum widely agreed that government intervention and forced closure of many businesses was necessary to protect public health. This approach has clearly failed in the United States as it led to widespread economic devastation, including millions of jobs lost, bankruptcies, and extremely severe losses in profitability. Nor have states with strict lockdowns succeeded in bringing about fewer covid deaths per million than states that were less strict.
Consequently, a few months into the pandemic, some governors weighed the competing economic costs with covid-19 containment and slowly reopened their economies. Of course, these governors did not mandate businesses reopen; however, they provided businesses the option to reopen.
Hysteria ensued as many viewed easing restrictions as akin to mass murder. The Atlantic famously dubbed Georgia governor Brian Kemp’s easing of restrictions as “human sacrifice” and referred to Georgians as being in a “case study in pandemic exceptionalism.” Instead, we should view the lockdowns as a case study in the failure of heavy-handed approaches in containing a highly infectious virus.
Now that we are nine months into this pandemic, there is a clearer picture of how state government approaches varied widely. It is clear that “reopened” economies are faring much better overall than less “reopened” economies. “Fueled by broader, faster economic reopenings following the initial coronavirus rash, conservative-leaning red states are by and large far outpacing liberal-leaning blue states in terms of putting people back to work,” writes Carrie Sheffield. This follows logically especially when considering that human beings learn to adapt very quickly. Now, we have learned much more about treating this virus and about who is most at risk from infection.
Not Everyone Can #StayHome
Even so, many proponents of lockdowns still contend that every covid infection is a failure of public policy. But this position is largely a luxury of white-collar workers who can afford to work from home. Lockdowns have been described as “the worst assault on the working class in half a century.” Martin Kulldorff, a biostatistician, says, “the blue-collar class is ‘out there working, including high-risk people in their 60s.” Kulldorff’s colleague Jay Bhattacharya notes that one reason “minority populations have had higher mortality in the U.S. from the epidemic is because they don’t often have the option…to stay at home.” In effect, top-down lockdown policies are “regressive” and reflect a “monomania,” says Dr. Bhattacharya. With this in mind, it is easy to see why more affluent Americans tend to view restrictive measures as the appropriate response.
For many Americans, prolonged periods of time without gainful employment, income, or social interaction are not only impossible but potentially deadly. Martin Kulldorff notes that covid-19 restrictions do not consider broader public health issues and create collateral damage; among the collateral damage is a “worsening incidence of cardiovascular disease and cancer and an alarming decline in immunization.” Dr. Bhattacharya correctly notes that society will be “counting the health harms from these lockdowns for a very long time.”
Mixed Messages
Bhattacharya emphasized the politicization of these restrictions: “When Black Lives Matter protests broke out in the spring, ‘1,300 epidemiologists signed a letter saying that the gatherings were consistent with good public health practice,’” while those same epidemiologists argued that “we should essentially quarantine in place.” Such a contradiction defies logic and undercuts arguments about the lethality of this virus. If this novel virus truly were as devastating to the broader public as advertised, then political leaders supporting mass protests and riots during a pandemic seem to be ill founded. This contradiction has been cited in countless lawsuits challenging the validity and constitutionality of covid-19 restrictions.
Separately, these often heavy-handed restrictions have targeted constitutionally protected rights like the freedom of religion. Supreme Court Justice Samuel Alito criticized the Nevada governor’s restrictions saying, “that Nevada would discriminate in favor of the powerful gaming industry and its employees may not come as a surprise…We have a duty to defend the Constitution, and even a public health emergency does not absolve us of that responsibility.” This scathing criticism, however, did not gain the support of the Supreme Court as a 5–4 majority deferred to the governor’s “responsibility to protect the public in a pandemic.”
The Worst State and Local Offenders
Such deference may be politically beneficial for the Supreme Court, but it presents a much more significant problem for basic freedoms. For one, many of these covid restrictions have been issued by state governors or administrative agencies rather than through democratic means. Michigan governor Gretchen Whitmer has been targeted for her continued sidestepping of democratic channels and for her top-down approach.
These covid restrictions are somewhat meaningless without ample enforcement and resources, so many major American cities have created task forces for enforcing these covid restrictions. For example, Los Angeles mayor Eric Garcetti has threatened to shut off public utilities for those who host massive house parties. Garcetti wants to treat private gatherings similarly to the bars and nightclubs he has forced closed. Not only is this ridiculous, but it is also authoritarian; there have been few checks on his ability to weaponize public utilities this way. The New York City Sheriff’s Office recently “busted a party of more than 200 people who were flouting coronavirus restrictions.” Their crime? Deputies found around two hundred maskless individuals “dancing, drinking and smoking hookah inside.” In typical government fashion, the owner of the venue was “slapped with five summonses…for violation of emergency orders, unlicensed sale of alcohol and unlicensed warehousing of alcohol.” What would we do without the government?
California governor Gavin Newsom has long been a part of this effort to restrict freedoms under the guise of public health. Governor Newsom and the California Department of Public Health released new “safety” guidelines for all private gatherings during the Thanksgiving holiday. According to Newsweek, “all gatherings must include no more than three households, including hosts and guests, and must be held outdoors, lasting for two hours or less.” Given Newsom’s interventionist tendencies, it is likely that these restrictions will be enforced. How will the government determine how many households are at a Thanksgiving meal and who will enforce the two-hour window? These are questions that journalists should ask.
Meanwhile, the varying levels of economic recovery between red states and blue states demonstrate how top-down policy can be a failure. Strict lockdowns have devastated millions of families’ incomes while failing to bring success in suppressing covid mortality. This failed experiment must be brought to an end.
Mitchell Nemeth is a Risk Management and Compliance professional in Atlanta, Georgia. He holds a Master in the Study of Law from the University of Georgia Law School, and he has a BBA in Finance from the University of Georgia. His work has been featured at the Foundation for Economic Education, RealClearMarkets, Merion West, and Medium.
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.
Remember when you were young, and you could tackle a full day on activity and keep moving forward completely unbothered? Moreover, it seemed that your desire to find a romantic partner was unsatiable, and you couldn’t get enough of the dating scene and the ups and downs associated with young love.
Now that you are a bit older and wiser, these moments have a rose-tinted-glasses type effect on your memory. Although we chalk these fond memories up as nostalgic, they can become a regular part of our adult life as well. The underlying component behind the memories from our past is simple to understand: elevated human growth hormone (HGH) levels.
Why Adults Should Consider Hormone Replacement
The difference between a young person in their prime and a seasoned adult is dictated by hormone production. When we’re in our teens and early twenties, we don’t have a care in the world about our health, testosterone or human growth hormone levels. We wake up, tackle the world, go to bed and repeat the process the next day.
If you’re getting older and want to recapture the fun and excitement that you experienced in the early portion of your life, we encourage you to consider growth hormone therapy. Be candid with yourself and answer these question honestly:
Have you gained unwanted weight over the years?
Do you have trouble packing on lean muscle?
Were you much stronger when you were younger?
Has the idea of sex become an afterthought, or worse, ignored completely?
Do your bones and joints ache at random?
Have feelings of anxiety and dread become commonplace?
Are you tired and forced to tackle your day with brain fog?
While many individuals associate these experiences with something that inevitably comes with age, they’re all signs of low HGH levels.
The Pros
Luckily for us, hormone therapy has been successfully used for years as a means of recapturing our youth. While results may vary between patients, most individuals notice a spike in their sexual desire within a few weeks of treatment. From here, the world becomes their oyster.
More importantly, HGH accelerates fat loss and muscle growth fairly quick in hormone-replacement patients. But the most important benefit that often goes undiscussed is the mental boost that healthy HGH levels give the patient.
When a patient undergoes treatment and begins to experience healthy-range growth hormone levels, their mood and overall wellbeing soar to new heights. While the research is still ongoing, we can safely say that your joy and quality of life will increase once treatment begins.
Typical Results
The first benefit that people notice once their growth hormone therapy starts is how tight and youthful their skin beings to look. Among the whole hgh results timeline, HGH, when introduced into the body, stimulates collagen production within the system.
When this occurs, side effects such as supple skin, improved complexion and hydration occur. In conjunction with this, aching joints and bones seem to dwindle in the presence of elevated collagen levels.
While improved skin tone and elasticity are the first benefits that a patient may experience, here are other surprising benefits that HGH therapy can provide:
Improved sex drive
Increased bone mass
Easier to build muscle
Impressive fat loss
Increased range of motion in joints
Removed brain fog
Emotional stability and regulation
An abundance of energy
High-quality workouts
Decreased recovery times
While running the risk of sounding like a terrible cliche, human growth hormone therapy can produce massive results.
The Cons
While there are a plethora of benefits for introducing human growth hormone into our body, it’s not all sunshine and rainbows. In a small percentage of patients that have undergone HGH therapy, negative side effects have occured.
Out of these side effects, the growth of male breast tissue — gynecomastia — seems to be the most prevalent. However, this side effect seems to affect men in their senior years.
While the negative aspects of growth hormone are still being discovered, here are some areas that readers should be aware of:
Type-2 diabetes risk
Risk of carpal tunnel syndrome
Joint pain
Insulin resistance
Excessive swelling in the limbs
Pain at the injection site
Muscle wasting disease
Bottom Line
While human growth hormone is not a miracle compound, it seems to benefit more patients than other methods of youth retention. Whether you’re a man or a woman, an abundance of HGH in your system can drastically improve your quality of life.
For readers that want to recapture their youth and experience the joy that filled their late teens and early twenties, growth hormone may be a logical approach. If you want to improve your sex drive, get in great shape and improve the complexion of your skin, ask your doctor about human growth hormone therapy today.
Countless schools have had to close their gates because of the pandemic. They simply could not risk the health and safety of the students, the faculty, and the staff. Instead, they have had to switch to remote learning with profound consequences for those involved. While some are happy to be home with their families in relative safety, others are having a hard time transitioning to this new mode of study. The heavy dependence on technology is a burden on those who may not have the resources or the know-how to face the challenges that they encounter. Fortunately, useful software tools are available online including MyCleanPC.
One of the most common issues that students face is computer slowdown. They are completely dependent on their laptops and desktops in completing their schoolwork. They cannot afford to have a slow system that frustrates them at every turn. Imagine having to wait for several minutes just for the machine to boot up. The same thing could happen when trying to launch programs and doing intense work. These issues are particularly frequent with older machines. Buying a new laptop can help but that’s out of the budget range for most students. It would be best to look for other solutions to speed up the existing computer.
Understanding why machines slow down will help immensely. Several things can lead to this unfortunate situation including low disk space, excessive startup programs, active malware, registry problems, and so on. If each of these could be solved, then the speed of the computer can drastically improve. Wait times can shorten from minutes to seconds. Students can read all of the pages that cover their exams and reports. They can pass their assignments before the deadlines. They can create their presentations and videos in time for their next classes. MyCleanPC has the power to automate troubleshooting and boost speed in one click.
MyCleanPC looks for all unnecessary files that can be erased without problems. Your important documents, pictures, videos, spreadsheets, and personal files will still be there but the clutter will be gone. By getting rid of these, you can free up a massive amount of space on the hard drive. This lets your system function smoother since it uses free space as temporary storage when opening programs and doing various tasks. Instead of crawling through every click, your machine will feel snappy and responsive. Instead of frustrating you at every turn, it will be helping you accomplish whatever you set out to do which is exactly how it should be.
MyCleanPC also has a built-in Startup Manager which makes it a breeze to edit the settings for your startup programs. These are the software that automatically opens up when you turn on the machine. This feature is definitely convenient as you don’t have to keep opening items that you always need. However, it can backfire if you include too many programs on the list. If you have an unusually long boot-up time, then this may be the culprit. Open the MyCleanPC manager and trim the startup programs on the list. Leave only what is essential.
The MyCleanPC software is available for download through the official website at https://www.mycleanpc.com/ so there is no need to look for a CD at stores. Students can try it for free and diagnose their system. This will show the issues that can be resolved by the program. You can unlock the full features by activating the software online. The process is fast and easy. Anyone can get their system up and running quickly with just a few clicks. It’s perfect for college students who want their computer to be the ideal learning companion.
Joe Biden may have declared victory, but whether he or Donald Trump officially wins the presidency may remain undetermined for weeks, even months, and even then we may see the election brought before the Supreme Court.
Who knows?
What we do know is that this election has delivered a mess not seen since 2000, when the Supreme Court had to rule on whether Bush or Gore had won the race. We’ll see recounts and accusations of voter fraud, and as time drags on, the bitter acrimony that already divides our country will only deepen.
A contested election weighted by accusations of deceit and ballot irregularities was the last thing this country needed. When tens of millions of voters believe the election was stolen from their candidate, our American Republic is in serious danger.
Here are some proposals for the future that might help end some of these troubles.
First, declare the first Tuesday in November a national holiday. Voting is a primary right and duty of the American citizen, and we should honor that right by giving Election Day the same status as Independence Day, Martin Luther King Day Jr., or Presidents’ Day. I’ve read of frustrated voters having to leave the polls without depositing a ballot because of work obligations. Making Election Day a legal holiday would ease that situation.
Require voter identification. We need an ID to drive a car, obtain a library card, and board an airplane. It’s absurd not to demand ID for voting.
Limit the availability of early voting to one week directly ahead of the election. The number of days and weeks given to our elections is not only ridiculous, but also allows for more fraud.
We should say “Never again” to mail-in ballots. This year the excuse for this procedure was avoiding the COVID-19 virus, which is ridiculous when we consider the new normal of our everyday lives. If wearing masks and social distancing work in Walmart and Kroger, then why wouldn’t they work in polling locations?
While mail-in ballots should be a thing of the past, absentee ballots for military serving overseas, for citizens living abroad, and for those who are traveling or too ill to leave their homes on Election Day should remain in place.
Shorten the election season. Cut it by two-thirds. Many of us have come to dread this relentless, lengthy ordeal. These campaigns are divisive and incredibly expensive, in part because the United States has the longest election process of any country in the world by far. In 2015, for example, NPR reported that the national election campaigns in the USA were 596 days compared to Great Britain’s 139 days and Canada’s 78 days. The difference? Most other countries in the world have laws limiting the length of such campaigns.
It’s time to do the same here.
Prosecute those who commit fraud during an election year. The people who try to vote more than once, those who create false ballots, and those who refuse to permit legitimate monitors from another party to enter polling places should be hauled before a judge and face stiff fines and time in prison. These cheaters are undermining American democracy.
For a number of years America has endured a culture war – a battle, depending on which side you stand – between good and evil, between right and wrong. Our election procedures just widen that divide, pushing us apart rather than making us citizens of the same land.
So let me leave my readers with a question: Why is it that a yutz like me with little direct experience in politics can come up with these proposals? Why aren’t those in our government considering these or similar alternatives to avoid the next train wreck coming down the tracks? Is this truly the best they can do? Or are they just that corrupt?
As the National Inquirer used to ask, “Enquiring minds want to know.”
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Image Credit:Edward M. Kennedy Institute-Eric Haynes, CC BY-NC-ND 3.0
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, “PrPSC,” 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 “PrPC,” where the “C” stands for cellular. The PrPC 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 PrPC version and convert it into another PrPSC type of protein. The PrPC harbors mainly alpha-helices. The PrPSC consists primarily of beta-strands. See Figure 36, which depicts a secondary structure format.
Figure 36. Differences between secondary structures of the normal PrPC protein and scrapie prion PrPSC. (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 PrPSC configuration.
Figure 37. PrPSC induces a conformational change in PrPC.
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 PrPSC, or transmission to the patient occurs. The PrPSC then aggregates abnormally into giant molecular complexes, converging on brain cells’ membrane surfaces. The normal PrPC that’s anchored to phosphatidylinositol glycan molecules on cell surfaces are converted to the pathological PrPSC shape. The neuron compensates by making more PrPC. 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 PrPSC, which then migrate to other cells to start the process over again.
Sometimes the PrPSC 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 PrPSC aggregates, the process fails. Instead of PrPSC 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.
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?
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.
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?
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?
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.
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