Cervical cancer is among the most common malignancies affecting women worldwide. In 2020 alone, approximately 600,000 women were diagnosed with this disease, and over 314,000 died from it. In 99% of the cases, cervical cancer cells harbor human papillomavirus (HPV), and thus, HPV vaccines are an effective way to mitigate the risk of developing this disease. Unfortunately, such preventive measures are useless against established cancers, which are generally incurable once they become metastatic or relapsing.
Fortunately, scientists have made substantial progress in developing a promising therapeutic strategy for cervical cancer: rejuvenated cytotoxic T lymphocytes (rejTs). These lymphocytes can be engineered to target HPV-specific antigens that are expressed predominantly in cervical cancer cells, constituting a type of targeted immunotherapy. Ideally, rejTs would be produced from induced pluripotent stem cells (iPSCs) gathered from the patient themselves. However, this process is not clinically feasible in terms of both time and cost.
Against this backdrop, a research team including Chief Professor Miki Ando, graduate student Yoshiki Furukawa, and Assistant Professor Midori Ishii from Juntendo University School of Medicine, Japan, has recently achieved a breakthrough by developing robust iPSC-derived rejTs for cervical cancer treatment. Their work was published in Cell Reports Medicine.
The team sought to address one of the key roadblocks for allogeneic iPSC-derived rejTs, which refers to rejTs produced from ‘standardized’ iPSCs rather than derived from the patient’s cells. Prof. Ando explains, “In immunocompetent cervical cancer patients, the dominant problem is the rejection of foreign T lymphocytes by the recipient’s CD8+ T lymphocytes or natural killer (NK) cells.” The patient’s immune system tends to attack the therapeutic HPV-specific rejTs before they can neutralize cancer cells.
The research team used CRISPR-Cas9 two-step “scarless” gene editing on iPSCs derived from an HPV-specific cytotoxic T lymphocyte clone to overcome this issue. The first modification was the deletion of all HLA class I antigens from the cells. The role of these surface proteins is to present peptides to CD8+ T lymphocytes, which promptly eliminate any cells displaying foreign or anomalous peptides. After the modification, the cells are essentially able to evade detection by CD8+ T lymphocytes.
The second modification involved introducing the limited expression of two specific HLA antigens, namely HLA-A24 and HLA-E. This enabled the engineered cells to evade attacks from NK cells, which specifically target cells lacking these surface antigens. By selecting HLA-A24, the engineered cells are naturally compatible with a significant portion of South American, Eastern Asian, North American, and European populations.
After implementing these modifications using CRISPR-Cas9, the researchers induced the differentiation of the iPSCs into T lymphocytes and tested their ability to fight cervical cancer cells while evading allogeneic immune responses both in vitro and in vivo. These experiments yielded very promising results, as the generated rejTs did not trigger attacks from either CD8+ T cells or NK cells while simultaneously achieving strong cytotoxicity against tumor cells.
Compared to the control group, mice engrafted with cervical cancer cells and injected with the gene-edited rejTs survived longer and exhibited significantly reduced tumor sizes and proliferation index. To gain further insights into the enhanced therapeutic effects of the rejTs, the researchers conducted single-cell RNA sequencing analyses. These analyses revealed that the population of rejTs was highly enriched with tissue-resident memory T cells, which establish residence in the mucosa of the cervix and provide stronger protection.
Prof. Ando remarks, “We found that the enhanced cytotoxicity against cervical cancer occurred through TGFβ signaling and increased CD103 expression.”
Taken together, the results of this study showcase a powerful method to make iPSC-derived rejTs a viable option to treat one of the most common forms of cancer. Prof Ando concludes, “The HLA-engineered HPV-rejTs obtained using our method provide a sustainable and promising approach toward successful ‘off-the-shelf’ T cell therapy, which could help in overcoming cervical cancer. We are planning on conducting an investigator-initiated clinical trial in 2024.”
The promise of a technologically advancing future is predicated on millennia of accumulated knowledge. How can we retain that knowledge?
The Long Now Foundation has been involved in and inspired by projects centered on that question since launching in 01996. (See, for example, The Rosetta Project, Westinghouse Time Capsules, The Human Document Project, The Survivor Library, The Toaster Project, The Crypt of Civilization, and the Voyager Record.) For years, Executive Director Alexander Rose has been in discussions on how to create a record of humanity and technology for our descendants. In 02014, Long Now began building it.
The Manual For Civilization is working toward a living, crowd-curated library of 3,500 books put forward by the Long Now community and on display at The Interval. To stack the shelves, we solicited book recommendations from Long Now members and supporters, special guest curators like Long Now founders Stewart Brand and Brian Eno, past Seminar speakers like George Dyson and Neal Stephenson, subject experts Maria Popova and Violet Blue, and volunteer curators like Alan Beatts, Michael Pujals, and Heath Rezabek.
The physical collection in The Interval grounds the catalog, and also provided the size constraint of the number of books. But the Long Now community is global, and the reality is that few Long Now members have had the opportunity to peruse our Bay Area-bound library.
Today, we’re getting ready to digitalize the Manual so that the library can be shared with the world. We are partnering with the Internet Archive, who have created a special collection for the Manual, and, for the first time, we are sharing a selection of the titles in our collection as a temporary browse-only catalog on Libib (currently showing about 800 of the currently 1400 selections). To help make this digitalization effort happen, we will need to raise approximately $100,000 to scan all the books and post them online making the library accessible to everyone. If you are interested in helping support this effort, please contact nick@longnow.org.
Framing the library’s focus as “restarting civilization” may seem apocalyptic or predictive on its face, but that is not the intention. Rather, the hope is to create a curatorial principle that inspires valuable conversation that reframes how we think about where civilization has come so far, where it might go in the future, and what tools are necessary to get it there.
In that sense, The Manual For Civilization is the latest in a centuries-long genealogy of ambitious projects to catalog and, crucially, democratize the most essential human knowledge. Inherent in each project—from Denis Diderot’s famous Encyclopedie to Long Now Co-Founder Stewart Brand’s countercultural bible Whole Earth Catalog to The Manual—is a theory of civilization. There is also, as will be discussed further below, a bias depending on which curatorial principle is emphasized and of course, who does that curation.
When Diderot began editing the Encyclopedie in 01751, the ideas of the Enlightenment held sway only amongst learned philosophes. Power rested in the hands of the clerics. Diderot considered the Encyclopedie as a deliberate attempt to “change the way people think” by democratizing the ideals of the Enlightenment. Controversially, the Encyclopedie’s central organizing principle was based on reason, rather than the authority of the church. In the entry for encyclopedia, he wrote:
The goal of an encyclopedia is to assemble all the knowledge scattered on the surface of the earth, to demonstrate the general system to the people with whom we live, & to transmit it to the people who will come after us, so that the works of centuries past is not useless to the centuries which follow, that our descendants, by becoming more learned, may become more virtuous & happier, & that we do not die without having merited being part of the human race.
Diderot would continue editing the Encyclopedie over the next fifteen years, amassing thousands of entries and enlisting the help of some of the Enlightenment’s most brilliant minds as contributors, including Voltaire, Rousseau, and Montesquieu. Diderot’s 35 volumes were describes as constituting a:
tremendous storehouse of fact and propaganda that swept Europe and taught it what ‘reason,’ rights,’ ‘authority,’ ‘government,’ ‘liberty,’ ‘equality,’ and related social principles are or should be. The work was subversive in its tendency, not in its advocacy: it took for granted toleration, the march of mind exemplified by science, and the the good of the whole people….The eleven volumes of plates were in themselves a revolutionary force, for they made public what had previously been kept secret by the guilds, and they supported the philosophe doctrine that the dissemination of knowledge was the high road to emancipation.
Two hundred years later, while reflecting on the legacy of the Whole Earth Catalog (01968), Stewart Brand wrote that the Catalog and the Encyclopedie shared a similar aim: to hand “the tools of a whole civilization to its citizens.” Like the Encyclopedie, Brand wrote, the Whole Earth Catalog sought to decentralize authority and redistribute it to individuals through access to knowledge, or tools. Diderot’s Encyclopedie, wrote Brand, “was the leading tool of the Enlightenment.”
Though the first commune-bound readers of the Whole Earth Catalog— those “bands of adventurous malcontents who were setting out to reinvent civilization”— did not exactly restart civilization, their process held “surprising value.” Brand wrote that as the decades passed, the Catalog’s true legacy was glimpsed in the personal computer revolution that followed, which was informed by the same process:
The personal-computer revolution was a direct result of that value system. It was initiated and carried to fruition by youthful longhairs, on purpose, with striking consistency between what was intended and what was accomplished. The impulse was to decentralize authority—to undermine the high priests and air-conditioned mainframes of information technology and hand their power to absolutely everybody.
“Here are the tools to make your life better. And to make the world better,” Brand wrote in his foreword to the Millennium Whole Earth Catalog (01994)—the last edition published. “That they’re the same tools is our theory of civilization.”
In the inaugural Whole Earth Catalog, Brand declared that “We are as gods and might as well get good at it.” But we are as gods only because of our ancestors’ diligence. The promise of a technologically advancing future is predicated on millennia of accumulated knowledge. Civilization has taken a lot of work to build, and it demands a great deal of know-how to sustain. And as modern life increasingly encourages specialization, familiarity across that accumulated knowledge’s breadth can wane. Our ability to collaborate is a strength, but beyond a point we risk losing comprehension of the infrastructure—both physical and intellectual—that supports our modern lives. How can we retain that knowledge?
These questions inspired Long Now to build The Manual For Civilization. In developing the experience of The Interval, we integrated the Manual of Civilization book collection into the design layout as two floors of bookshelves that would face outward in The Interval space. The first floor shelves would be open and accessible for browsing, and the upper shelves would be accessible by staff, reached from the front by a tall ladder, or from the opposite side, since the shelves are open to the Long Now office above.
As the opening date of The Interval approached in the summer of 02014, we knew we had a lot of empty shelves to fill, but had already started assembling the catalog as well as physical copies of books. In one pre-opening party, we had a bucket brigade of supporters passing physical books in the door, up the spiral staircase, to people on ladders who arranged the books on shelves, about 1,000 volumes that evening!
We’ve had over 2,500 submissions and recommendations to the collection so far, with approximately 1,400 approved for inclusion in The Manual by our director Alexander Rose. Currently, 1,007 physical books reside in the Manual’s bookshelves. 861 titles from the collection are available to view on Libib.
Our plan is to solicit more book lists and recommendations until the list grows to about 5,000 from which we will edit the collection down to the 3,500 or so volumes that can fit on the shelves. We began the collection by using four broad categories to structure the collection:
Beyond these categories, we are exploring other ways to organize and catalog the collection, and to locate books on shelves. With any scheme though, we want to preserve the experience and delight of serendipitous discovery, of going to the bookshelf to look for one thing, and discovering three or four other things you are curious about.
We also hope to open up the discussion so that we can have an ongoing conversation about which books are in and out of the collection at any point in time, and why. With any curatorial principle comes a bias. This bias is problematic, but can be mitigated in a variety of ways. Wikipedia, for example, makes it possible for anybody to edit and contribute to its catalog. In the case of the Manual, we are committed to evolving our curatorial principle over time, the hope being that as we move through the Long Now, this living collection is responsive, adaptive and open.
We’ve already had a few valuable learning experiences. When the Manual launched, Long Now member and Brainpickings founder Maria Popova contemplated Stewart Brand’s selections for the Manual, and had “only one lament:”
One would’ve hoped that a lens on rebuilding human civilization would transcend the hegemony of the white male slant and would, at minimum, include a more equal gender balance of perspectives — of Brand’s 76 books, only one is written by a woman, one features a female co-author, and one is edited by a woman. It’s rather heartbreaking to see that someone as visionary as Brand doesn’t consider literature by women worthy of representing humanity in the long run. Let’s hope the Long Now balances the equation a bit more fairly as they move forward with the remaining entries in their 3,500-book collaborative library.
Long Now immediately reached out to Popova and invited her to contribute her own list for the Manual. In selecting it, she found it especially challenging to reconcile the curatorial constraints of the Manual with her desire to offer a diverse and balanced representation of essential human knowledge:
I faced a disquieting and inevitable realization: The predicament of diversity is like a Russian nesting doll — once we crack one layer, there’s always another, a fractal-like subdivision that begins at the infinite and approaches the infinitesimal, getting exponentially granular with each layer, but can never be fully finished. If we take, for instance, the “women problem” — to paraphrase Margaret Atwood — then what about Black women? Black queer women? Non-Western Black queer women? Non-English-speaking non-Western Black queer women? Non-English-speaking non-Western Black queer women of Jewish descent? And on and on. Due to that infinite fractal progression, no attempt to “solve” diversity — especially no thirty-item list — could ever hope to be complete. The same goes for other variables like genre or subject: For every aficionado of fiction, there’s one of drama, then 17th-century drama, then 17th-century Italian drama, and so on.
The inherent biases in catalogs like the Manual must be acknowledged, and ideally mitigated through open conversation, if such catalogs are to persist over the long term. Over time, we believe that the conversation about what goes into Manual will become as rich and interesting as the collection in the Manual itself.
New documentary exposes what ‘Oppenheimer’ left out about the impact of nuclear testing on Native, Hispanic people
Generations of New Mexicans — mostly Native Americans and Hispanics — have become ill with cancer after being exposed to catastrophic levels of radioactive fallout from the Trinity nuclear bomb testing.
Now, a new documentary film, “First We Bombed New Mexico,” tells the counter-narrative to the award-winning “Oppenheimer” film, of generations still feeling the impacts of the tests and of government betrayal with tragic consequences.
The film, directed and produced by New Mexico-based filmmaker Lois Lipman, alleges a government cover-up of monumental proportions – bigger than Watergate, bigger than arms for Iran, bigger than government experiments on people of color.
Inspired by New Mexico cancer survivor Tina Cordova, Lipman told ICT she made the film to unearth the story and make the public aware of a compensation bill looming in government to help the families who continue to be ignored.
Congress has until June 7, 2024, to expand the Radiation Exposure Compensation Act, known as RECA, to families harmed in New Mexico and in other areas impacted by radiation. The act has provided reparations for Nevada Cold War nuclear test victims since 1990, so why was New Mexico left out? Many blame environmental racism.
“We feel it’s urgent to get this social justice story known,” Lipman told ICT, “and to put public pressure on legislators to understand what this is about and to lend their support to extending RECA (before it expires) to include ignored Downwinders and the post-1971 Uranium miners.
The Senate overwhelmingly voted last summer to include the expansion of the bill in the annual defense authorization act, but in December, the Republican leadership removed it.
“That was a huge disappointment for many,” Lipman said. “So, the pressure is back on to possibly slip RECA in some legislation so it is extended before it finally expires.”
The film premiered at the Santa Fe International Film Festival in October, and is currently making the rounds of the festival circuit.
Cordova, who is featured in the film, is a cancer survivor and co-founder of the Tularosa Basin Downwinders Consortium, an organization started 18 years ago that works to advocate bills through the government and organize peaceful protests.
“My father developed oral cancer without any risk factors,” Cordova, who is Hispanic, says in the film. “He didn’t smoke, didn’t drink, didn’t use chewing tobacco. Had no viruses. The doctor told us this just didn’t happen. But they also told us they see this a lot here.”
She says government leaders need to admit what they have done.
“I can tell you what I believe to be true,” she said. “They have a very difficult time admitting that they harmed American citizens, that they killed American babies afterwards, that’s a very difficult thing to admit to. But that is the truth and that is what happened. The only way that we will ever get past this history is if we finally admit what took place, acknowledge the harm that was done and atone for that harm.”
The radiation exposure stems from the Manhattan Project, which developed the nuclear weaponry that ended World War II. Trinity was the code name for the first detonation of a nuclear weapon, conducted by the U.S. Army at dawn, 5:29 a.m., on July 16, 1945, at a site located 35 miles southeast of Socorro, New Mexico, on the plains of the Alamogordo Bombing Range, known as the Jornada del Muerto, near the Mescalero Apache reservation. The surrounding communities were never warned, never acknowledged, and never helped afterwards. Generations of cancers followed.
New Mexico’s Democratic governor, Michelle Lujan-Grisham,is among those interviewed in the documentary.
“No one should have to fight so hard to get restitution when you are victimized by your government,” she says. “They absolutely knew about the radiation exposure. Lots more science about it today, but they knew.”
Lipman, an American journalist who was based in London for many years, learned of the story after moving to New Mexico.
“I had a big career living in London,” Lipman told ICT. “I worked for ‘60 Minutes’ and the BBC and traveled around the world, making award-winning films, developing them and field producing them. And then I took a break and moved to New Mexico, which I fell in love with. I had a very strong feeling that I need to use my skill to make a difference.
“I discovered this story in New Mexico that had never been told and was bigger than anything I’d ever worked on,” she said, “which was that the U.S. government detonated Oppenheimer’s Trinity bomb as close as 12 miles from New Mexico residents, most of them Native American and Hispanic, and now they have had generations of cancer.
“They have never been helped and they need to be helped,” she said. “I also found government documents that have been top secret that explain all of this. I channeled and struggled with how to tell the story, then I met Tina and clearly Tina is our engine. Through Tina we learned this story.”
The film shows Cordova rallying communities and gathering devastating health information while residents try to continue living normal lives.
“The government continues to say today that no one lived here, and no one was harmed when the bomb was detonated, but nothing could be further from the truth,” Cordova says in the film. “In 18 years, we’ve discovered so very many times … how our government looked away from us. They have never come back. They’ve never done any kind of meaningful study of the impact on us and I’m the fourth generation in my family to have cancer since 1945.”
“I have a 23-year-old niece. She’s a beautiful young woman going to college in California in San Jose. She’s studying art. She wants to work at Pixar. She was diagnosed with thyroid cancer a year ago,” Cordova said.
“That’s the cancer that I had, and the first thing they asked me when I was diagnosed was, ‘When were you exposed to radiation?’ I come from a multi-generational family of cancer patients. I wish I could say we were unique. We’re not. We’ve documented hundreds of families just like mine that are displaying four and five generations of cancer here. It’s a true travesty that our government has looked away from us.”
Cordova says some members of Congress contend it’s going to cost too much to atone for the exposure. The state of New Mexico is unique, since that is where the uranium was mined, where the nuclear bombs were developed, where it was detonated, and now where they store nuclear waste.
“There’s a lot of employment, industry and big business associated with that,” she says. “And so many people believe you just don’t bite the hand that feeds you. You just don’t discuss the hard truths about what that means. At one of the very first town hall meetings we ever held, a woman told me, ‘You’re not going to be satisfied until they close down the Air Force base.’ And I said, ‘That’ll never happen.’”
Cordova says in 1945, the government depended on the Native and Hispanic communities to be uneducated, unsophisticated, and unable to stand up for themselves. Many of them were uranium miners, who went into the mines without adequate protective gear.
That is the Oppenheimer legacy in New Mexico, she said.
“This happened through no fault of our own,” Cordova says. “We did nothing except simply live in the same place for hundreds if not thousands of years. We’ve occupied this land. These are our homelands, and everything has been taken from us because I can clearly tell you that without your health you have nothing,”
LARAMIE, WYOMING—According to a statement released by the University of Wyoming, a small, tube-shaped bead unearthed at Wyoming’s La Prele Mammoth site has been dated to about 12,940 years ago by Todd Surovell of the University of Wyoming and his colleagues. Previous studies have shown that a young mammoth was butchered at the La Prele Mammoth site; the bone bead was recovered about three feet away from a collection of other artifacts. Analysis of collagen extracted from the bead with mass spectrometry indicates that it was made from the bone of a hare, while the shape of the bone suggests it came from a hare’s paw. Marks on the outside of the bead, which was likely used to decorate clothing or was worn as jewelry, are consistent with marks made by people working with stones or their teeth, Surovell explained. The bead is the first evidence that hares were used by the Clovis people, who were named for the archaeological site in New Mexico where their distinctive stone tools were first unearthed, he added. Read the original scholarly article about this research in Scientific Reports. For more on archaeology at La Prele, go to “Excavating a Mammoth Hunters’ Campsite.”
