A vaccine against Zika virus is safe and effective when administered both before and during pregnancy, according to new research published in npj Vaccines.

The purified, inactivated Zika vaccine (ZPIV) candidate, developed by Walter Reed Army Institute of Research (WRAIR), is being evaluated in animal models at Texas Biomedical Research Institute (Texas Biomed) in collaboration with WRAIR and Trudeau Institute in New York.

The vaccine candidate has previously been shown to effectively block prenatal Zika virus transmission when given to nonhuman primates prior to . This new study goes a critical step further, studying what happens when the vaccine is administered during pregnancy.

“This is a giant step forward,” says Jean Patterson, Ph.D., Professor Emeritus at Texas Biomed. “We have very strong evidence that this vaccine could protect fetal health during the next Zika outbreak.”

Mosquitoes primarily transmit Zika virus. It does not typically cause serious illness in most people; the biggest threat is to  and developing fetuses. During the 2015–2016 Zika outbreak in the Americas, there was a surge in miscarriages and babies born with extremely small heads and other severe birth defects, collectively called Congenital Zika Syndrome. Zika virus continues to circulate at low levels and has been detected in 89 countries and territories to date.

“Zika virus continues to infect people around the world and present a significant risk to maternal-fetal health,” says Stephen J. Thomas, M.D., an inventor of the ZPIV vaccine and a study collaborator. “Because of this, advancing the development of vaccine candidates and studying different use scenarios is incredibly important.”

The vaccine candidate has completed Phase 1 clinical trials in humans and was well tolerated and elicited an . But  usually exclude pregnant people, leaving key questions unanswered about whether vaccination during pregnancy would be safe and potent.

This new study is believed to be the first to evaluate a Zika vaccine during pregnancy in . Marmosets, a small nonhuman primate that typically has twins and triplets, are sensitive to Zika virus infection and closely mirror what happens in pregnant humans.

Given the drastic changes that the immune system undergoes during pregnancy, the researchers were not sure if the vaccine, when given during early pregnancy, would generate a protective immune response, such as creating protective antibodies.

“The antibody response when given during pregnancy was similar to the level we observed when administered before pregnancy,” says In-Jeong Kim, Ph.D., a principal investigator at Trudeau Institute. “That is very exciting.”

The  prevented placental damage and sufficiently blocked transmission of the Zika virus from mother to fetus. The viral load in placentas and fetuses was significantly lower in the vaccinated group versus the unvaccinated group. Growth and development of fetuses of vaccinated adult marmosets exposed to Zika virus were similar to controls not exposed to the virus. No adverse effects were detected.

What remains to be studied is whether protection will last throughout pregnancy and whether offspring born from vaccinated females challenged with the virus during pregnancy are free of Congenital Zika Syndrome.

Il cielo ci propone uno degli spettacoli più emozionanti: una eclissi solare totale.

Purtroppo, questo fenomeno spettacolare non sarà visibile dall’Italia, ma solo da Messico, Stati Uniti e una piccola parte del Canada.

Grazie però ad una rete di telescopi sarà possibile seguire “Il Cielo in Salotto”.

Per tutti gli appassionati, saranno trasmesse in streaming le immagini da vari telescopi, seguendo l’eclissi a partire dalle 19:00 ora italiana fino a conclusione del fenomeno.

Gene-edited lymphocytes and the path toward 'off-the-shelf' therapy against cervical cancer

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  (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  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 . 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 ProjectWestinghouse Time CapsulesThe Human Document ProjectThe Survivor LibraryThe Toaster ProjectThe 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.

The Origins of the Manual (1751-2014)

“Final Steps in Shaping a Goblet”, from Diderot’s Encyclopedie

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.

“Figurative system of human knowledge” from the Encyclopedie. Knowledge was divided into branches of memory, reason and imagination.

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.

Stewart Brand’s Whole Earth Catalog divided knowledge into sections based on whole systems thinking.

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.”

A Merry Prankster tarot card of Stewart Brand linking the curatorial principles of the Catalog to the formation of the World Wide Web.

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?

Stewart Brand at The Interval as the Manual For Civilization is constructed.

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.

The Interval at Long Now in San Francisco

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!

Kevin Kelly, with Alexander Rose, selects books from his personal library for The Manual For Civilization

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:

  • Long-term Thinking, Past and Future: these include books on history as well as futurism and many books by Long Now speakers.
  • Rigorous Science Fiction: especially works that build richly imagined possible worlds to help us think about the future.
  • The Cultural Canon: great works of literature, poetry, philosophy, religion.
  • Mechanics of Civilization: “how-to” books for critical skills and technology, for example books on navigation, growing and gathering food, midwifery, forging tools.

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 will have an entire wing of the library devoted to copies of book #26, because ohmygod it's the one where Jake and Cassie finally KISS!!!
Legendary web comic on the Manual

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 member Maria Popova

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.