Last week, Jennifer Doudna and Emmanuelle Charpentier, winners of the Nobel Prize for Chemistry in 2020 for developing CRISPR gene editing technology, belatedly traveled to Stockholm to enjoy the pageantry and ceremonies that were postponed two years ago because of the COVID pandemic. But as scientists celebrate the revolutionary development of CRISPR-Cas9 genome editing just ten years ago, they continue to develop new technologies for manipulating DNA.
CRISPR is a superb programmable scissors but has certain drawbacks. After making a double-stranded break in DNA, it is up to the cell’s DNA repair pathways to rescue and effectively fix that broken DNA. Because the repair pathways evolved to fix broken DNA quickly, it’s hard to use these nucleases to introduce a new sequence or gene into the genome, install a specific type of edit, or change one base to another or many bases all at once. For years, genome engineers have been trying different tricks to increase the efficiencies of these repair pathways to achieve specific goals, without any clear breakthroughs.
A few years ago, Jacob Rubens, senior principal at Flagship Pioneering, and his colleagues asked whether nature, instead of creating mechanisms for breaking DNA, had evolved schemes for writing DNA. “It didn’t take long before we came to mobile genetic elements—sequences of DNA that exist for the sole purpose of copying and pasting themselves from one location in the genome to another,” Rubens told GEN Edge. “We didn’t know that these are the most abundant genes in nature!”
It turns out that there’s more real estate in genomes that codes for this mobile genetic element machinery than any other protein class—transporters, metabolic enzymes, etc. “It’s not surprising considering these elements are just copying and pasting themselves everywhere,” said Rubens. “But Mother Nature has been evolving these systems for billions of years, and we were surprised to discover that almost no one had thought about how they could be adapted as tools for genome engineering, even though their sole purpose is to write DNA.”
Rubens and his team opened a thousand-page textbook called Mobile DNA III that was edited by Nancy Craig, one of the leading researchers in the field. It contains dozens of chapters on different types of mobile genetic elements. Yet, Rubens said that almost all the relevant work within the space of biotechnology could fit into just a couple of those small chapters. They focused on a single type of mobile genetic element known as a DNA transposon, which has some applicability in biotechnology but had been somewhat limited.
Rubens and his team found that there are many other types of biochemistries that could become biotechnologies but that had not been studied. This gave them some ideas about different types of mobile genetic elements suitable for genome engineering because of their features and abilities. And that’s how Tessera Therapeutics was born. The company name has two origins: “tessares” is Greek for the number 4, as in four nucleotides in the genome. And a tessera is a tile in a mosaic. So, the name for the company comes from a view that every nucleotide is like one tile in the mosaic of life.
“We put a couple of million dollars into seeding the company in 2018 and hired our first scientists, finding some fantastic people with experience in gene editing companies like Editas, Intellia, and Beam to come aboard,” said Rubens. For example, Tessera was able to recruit the likes of Senior Vice President Cecilia Cotta-Ramusino from Editas and Chief Medical and Development Officer David Davidson from bluebird bio. Chief Scientific Officer (CSO) Michael Holmes, who was one of the star scientists at Sangamo and developed the concept of genome editing with zinc finger nucleases with Fyodor Urnov, joined from Ambys Medicines. Tessera’s Scientific Advisory Board is stacked, with Board Director Melissa Moore (previous Moderna CSO), gene transfer pioneer Luigi Naldini, Innovative Genomics Institute (IGI) co-director and co-founder of KSQ therapeutics and Maze therapeutics Jonathan Weissman, and the infamous George Church, to name a few.
“We began to conduct some experiments and realized there was a lot of potential here and what it would take to truly build a breakthrough company. We realized that what it was truly going to take to build the biggest version of this company was not just trying different types of mobile genetic elements but systematically exploring the types of elements that had interesting biochemistries for the functions that we wanted.”
Harnessing mobile genomic elements
Over the next few years, the team at Tessera built the capability to make thousands of mobile element sequences per month in DNA and RNA formats, put them on human cells, and measure tens of thousands of different changes in the genome monthly in different cell types to figure out which of these systems work for their purposes.
Tessera has invested heavily in high-throughput DNA and RNA manufacturing to do massive amounts of high-throughput screening. Rubens said that it is routine for Tessera to make thousands of DNA plasmids each month, which are typically turned into hundreds of different RNAs. These RNAs are then put into cells using automated cell-handling machinery for transfections and cell passages.
Next, they use machines to extract the nucleic acids from the cells and test for three key properties that are important for a good genome engineering technology: efficiency (the percent of alleles or cells in the population that are effectively edited); specificity (the location of those edits in the genome); and fidelity (does the appropriate outcome occur at the intended site?).
There are different automated pipelines for each run at Tessera. The most important one currently is the assay that measures efficiency, called amplicon sequencing—the same type of sequencing reaction for figuring out the SARS-CoV-2 variants in patients. With a targeted polymerase chain reaction and sequencing, it is possible to survey the genome to see where changes are made by the machinery that writes genes. Very soon, Tessera will have end-to-end automation to do 20,000 sequencing reactions per month.
Rubens says that Tessera has also built the data science infrastructure to ingest data from a variety of experiments and to leverage the differences in the performance of these systems to inform how they change the compositions that matter, whether those are the amino-acid sequences of the gene writers or the RNA sequence or DNA sequence of the templates, to make them work more effectively towards those parameters that they measure.
RNA writing medicines
Of course, Tessera is not merely a technology company. It plans on creating medicines, starting with a few particular patient populations – and several oncology applications (both yet to be disclosed).
Tessera’s technology, called RNA gene writers, is based upon a type of mobile element called a non-LTR retrotransposon. These use a mechanism to write genes into the genome called target primed reverse transcription, which Rubens thinks will be a hot topic over the next few years. The method relies upon four key steps: binding RNA, binding DNA, nicking DNA, and then priming reverse transcription (Fig. 1).
According to Rubens, Tessera saw right away that the mechanism had some interesting aspects. First, it’s very programmable in that it’s possible to target genome sites for editing or integration. Second, it only makes use of an RNA template (Fig. 2). This makes it possible to make systems that can write whole genes into the genome by sending RNA to the cell. This is done by sending an mRNA that codes for the gene writer and a template RNA. The gene writer then grabs the template RNA and writes it into the genome.
“That opens up amazing possibilities because it permits us to bring together the very best of mRNA and lipid nanoparticles (LNPs) with the very best of gene therapies—the manufacturability of mRNAs and LNPs, the scalability, and the re-dosability with the longevity of viral vector gene therapies,” said Rubens.
There are two major potential clinical applications for Tessera’s technology:
- Writing—adding entire genes to the genome with their promoters and other parts necessary for expression; and
- Rewriting—to make edits to the genome (small substitutions, insertions, and deletions).
In the short term, Rubens said one area of focus is writing chimeric antigen receptors (CARs), which are cells that reprogram immune cells to target cancer.
“The vast majority of people developing CAR-T therapies take cells out of a patient’s body and treat the patient with some toxic drugs that clear out their endogenous T-cells. Then they engineer the patient’s cells with a lentiviral vector and reinfuse that into patients,” Rubens explained. “By doing CAR-T engineering with just RNA, we can not only do this faster, but we can also do it in vivo with mRNA and lipid nanoparticles.”
Regarding their rewriting technology, Tessera aims to make small genomic substitutions. “Right now, we’re primarily focused on two areas: liver-targeted editing applications, such as phenylketonuria (PKU), where we’ve shown really exciting progress by editing 40% of the [mutant] alleles in a liver with clear curing of PKU phenotype in the ENU2 mouse model of this disease, said Rubens.
The other example is sickle-cell disease (SCD). Rubens continued: “We’re the only ones (that we’re aware of) that is developing a therapy for sickle cell disease, where we can just deliver RNA into a cell and correct the allele that causes the disease to wild-type sequence. Not only that, but because it’s all RNA and in LNPs, we’ve made huge strides in delivering it to hematopoietic stem cells inside the body. So, like the CAR-T example, we no longer have to take the cells out of a patient’s body, engineer them, and return them.”
This is important because the biggest burden of SCD—in the United States at least—falls on patients who can’t take weeks off work to go through the therapy required to receive a cure. Most SCD patients live in sub-Saharan Africa. “If we want to be able to help them, we need to be producing drugs at the same cost of goods at which we’re producing the current virus vaccines—the price of a fancy T-shirt—and that’s uniquely enabled today by our RNA writing technology,” said Rubens.
In recent conference presentations, Tessera scientists have shared some primary proof-of-concept data from animals for liver rewriting and T-cell therapies. “We are engineering T cells outside the body and delivering them to monkeys, as well as delivering to T cells and hematopoietic stem cells inside of monkeys,” said Rubens. “So, it is very real, and we’re going to hopefully share more soon.”
DNA writing medicines
When launched in 2018, the team at Tessera also began working on serine integrases and discovered 75,000 serine integrases. Unlike the approach that the groups of (twinPE) have taken, Tessera has been searching for serine integrases that target native sites on the human genome (similar to a recently published approach from Patrick Hsu’s group at the Arc Institute). In a screen of some 750 enzymes, Tessera found a handful that were very efficient and quite specific at integrating genes into the genome without having to do the first step of the PASTE process using prime editing to write a landing pad.
Tessera has developed a simpler version of these systems. With a related class of DNA gene writers, the company has shown that the combination of DNA gene writers and adeno-associated viruses (AAVs) has potential, at least in mice and non-human primates, to make gene expression more permanent by writing it into the genomes of the animals.
By writing an AAV into the genome of dividing cells such as the liver, Tessera can make the AAV express permanently. This is critical for certain applications, such as treating newborn patients with AAV gene therapies. Because the liver divides over the first 18 years of the patient’s life, they typically aren’t candidates for these gene therapies today.
“We’ve shown in mice that we can make 40% of their hepatocytes express the payload we delivered over the lifetime of these animals, compared to just 2–3% in the mice that receive the control AAV,” said Rubens. “And we’ve demonstrated something similar in non-human primates now, but we haven’t really shared that data publicly yet.”
Tessera has also shown an ability to integrate AAVs into the genomes of adult mice. “When those AAVs integrate into the genome, we’ve shown that they express at an 85-fold higher level,” said Rubens. “That means we could reduce the AAV dose by 85-fold to achieve the same level of therapeutic protein expression. This would likely solve a lot of the problems that AAV has in facing dose-limiting toxicities that we hear about all the time in the clinic, as well as the manufacturability issues. We’ve also shown that this property is translatable from the mice to the non-human primates.”
A Marathon long sprint
What started in a small basement in Kendall Square with a few former alums of these genetic medicine companies is 275 people today with close to 90,000 square feet of space at a facility in Somerville, Massachusetts, where Flagship has a few different companies co-located.
“We expect to have proof of concept that our technologies work in non-human primates shortly, and just a couple of years after that, we expect to put our first drugs in the clinic,” said Rubens. “It’s been a quick sprint from the fundamental idea, the perfect concept, to starting to make compositions that matter, that someone might use to help people, which has been fascinating to watch.”real estate pandemic genome genetic therapy rna dna africa
Trans To Be Banned From Female Hospital Wards In UK
Trans To Be Banned From Female Hospital Wards In UK
Authored by Steve Watson via Summit News,
The UK Health Secretary is to issue a proposal…
The UK Health Secretary is to issue a proposal to ban trans patients from female hospital wards in the UK, as well as reinstating ‘sex specific’ language in National Health Service materials, according to reports.
The Daily Mail reports that “Steve Barclay will unveil the plans to push back against ‘wokery’ in the health service amid concerns that women’s rights are being sidelined.”
Daily Mail: "Trans women patients 'to be banned from female wards' under plans to be announced by Health Secretary Steve Barclay today"https://t.co/dPU9wbKEZL— Emily Wilding Davison (@Wommando) October 3, 2023
The proposal would see only people of the same biological sex sharing wards, with care coming from doctors and nurses of the same sex, when it comes to intimate health matters.
“We need a common-sense approach to sex and equality issues in the NHS. That is why I am announcing proposals for clearer rights for patients,” Barlcay stated, adding “It is vital that women’s voices are heard in the NHS and the privacy, dignity and safety of all patients are protected.”
He added “And I can confirm that sex-specific language has now been fully restored to online health advice pages about cervical and ovarian cancer and the menopause.”
As we previously highlighted, the word ‘women’ was removed from such materials and replaced with non-gendered terms to be “more inclusive”:
A source close to the Health Secretary told the Telegraph that “The Secretary of State is fed up with this agenda and the damage it’s causing, language like “chestfeeding”, talking about pregnant “people” rather than women. It exasperates the majority of people, and he is determined to take action.”
“He is concerned that women’s voices should be heard on healthcare and that too often wokery and ideological dogma is getting in the way of this,” the source added.
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Sweden’s Deadly Gun Violence
Sweden’s Deadly Gun Violence
Swedish Prime Minister Ulf Kristersson is calling on the military to assist the police with tackling the rise…
Swedish Prime Minister Ulf Kristersson is calling on the military to assist the police with tackling the rise in gang-related violence in the country, as fatal shootings and bombings claimed the lives of 12 people last month.
As Statista's Anna Fleck reports, in the latest move, the Swedish government said on Friday that it would authorize future military assistance to the police, following a meeting between Krisstersson and the heads of both forces on how to reduce violence from organized criminal gangs. It is not yet clear exactly which duties the military will take on.
"The wave of violence is unprecedented in Sweden, but it is also unprecedented in Europe, no other country has a situation like the one we have," Kristersson commented in a televised speech.
"The police cannot do all the work themselves."
According to the Swedish Police Authority's annual reports, last year a total of 62 people were killed by gunfire, marking the deadliest year for shootings since the authorities started publishing data in late 2016.
You will find more infographics at Statista
A total of 11 people were fatally shot last month alone, in addition to one person who died in a bomb blast. These 11 bring the death toll by firearms to 42 in 2023, a figure that may rise further yet with three months left until the end of the year.
September marks the second deadliest month on record for gun crime in Sweden, following only after December 2019 when 12 people were shot and killed.
Which New World Order Are We Talking About?
Which New World Order Are We Talking About?
Authored by Jeff Thomas via InternationalMan.com,
Those of us who are libertarians have a tendency…
Those of us who are libertarians have a tendency to speak frequently of “the New World Order.”
When doing so, we tend to be a bit unclear as to what the New World Order is.
Is it a cabal of the heads of the world’s governments, or just the heads of Western governments?
Certainly bankers are included somewhere in the mix, but is it just the heads of the Federal Reserve and the IMF, or does it also include the heads of JPMorgan, Goldman Sachs, etc.?
And how about the Rothschilds? And the Bundesbank—surely, they’re in there, too?
And the list goes on, without apparent end.
Certainly, all of the above entities have objectives to increase their own power and profit in the world, but to what degree do they act in concert? Although many prominent individuals, world leaders included, have proclaimed that a New World Order is their ultimate objective, the details of who’s in and who’s out are fuzzy. Just as fuzzy is a list of details as to the collective objectives of these disparate individuals and groups.
So, whilst most libertarians acknowledge “the New World Order,” it’s rare that any two libertarians can agree on exactly what it is or who it’s comprised of. We allow ourselves the luxury of referring to it without being certain of its details, because, “It’s a secret society,” as evidenced by the Bilderberg Group, which meets annually but has no formal agenda and publishes no minutes. We excuse ourselves for having only a vague perception of it, although we readily accept that it’s the most powerful group in the world.
This is particularly true of Americans, as Americans often imagine that the New World Order is an American construct, created by a fascist elite of US bankers and political leaders. The New World Order may be better understood by Europeans, as, actually, it’s very much a European concept—one that’s been around for quite a long time.
It may be said to have had its beginnings in ancient Rome. As Rome became an empire, its various emperors found that conquered lands did not automatically remain conquered. They needed to be managed—a costly and tedious undertaking. Management was far from uniform, as the Gauls could not be managed in the same manner as the Egyptians, who in turn, could not be managed like the Mesopotamians.
After the fall of Rome, Europe was in many ways a shambles for centuries, but the idea of “managing” Europe was revived with the Peace of Westphalia in 1648. The peace brought an end to the Thirty Years’ War (1618-1648) in the Holy Roman Empire and the Eighty Years’ War (1568-1648) between Spain and the Dutch Republic. It brought together the Holy Roman Empire, The House of Habsburg, the Kingdoms of Spain and France, the Dutch Republic, and the Swedish Empire.
Boundaries were set, treaties were signed, and a general set of assumptions as to the autonomy within one’s borders were agreed, to the partial satisfaction of all and to the complete satisfaction of no one… Sound familiar?
Later, Mayer Rothschild made his name (and his fortune) by becoming the financier to the military adventures of the German Government. He then sent his sons out to England, Austria, France, and Italy to do the same—to create a New World Order of sorts, under the control of his family through national debt to his banks. (Deep Throat was right when he said, “Follow the Money.”)
So, the concept of a New World Order has long existed in Europe in various guises, but what does this tell us about the present and, more important, the future?
In our own time, we have seen presidents and prime ministers come and go, whilst their most prominent advisors, such as Henry Kissinger and Zbigniew Brzezinski, continue from one administration to the next, remaining advisors for decades. Such men are often seen as the voices of reason that may be the guiding force that brings about a New World Order once and for all.
Mister Brzezinski has written in his books that order in Europe depends upon a balance with Russia, which must be created through the control of Ukraine by the West. He has stated repeatedly that it’s critical for this to be done through diplomacy, that warfare would be a disaster. Yet, he has also supported the US in creating a coup in Ukraine. When Russia became angered at the takeover, he openly supported American aggression in Ukraine, whilst warning that Russian retaliation must not be tolerated.
Henry Kissinger, who has literally written volumes on his “pursuit of world peace” has, when down in the trenches, also displayed a far more aggressive personality, such as his angry recommendation to US President Gerald Ford to “smash Cuba” when Fidel Castro’s military aid to Angola threatened to ruin Mr. Kissinger’s plans to control Africa.
Whilst the most “enlightened” New World Order advisors may believe that they are working on the “Big Picture,” when it comes down to brass tacks, they clearly demonstrate the same tendency as the more aggressive world leaders, and reveal that, ultimately, they seek to dominate. They may initially recommend diplomacy but resort to force if the other side does not cave to “reason” quickly.
If we stand back and observe this drama from a distance, what we see is a theory of balance between the nations of Europe (and, by extension, the whole world)—a balance based upon intergovernmental agreements, allowing for centralised power and control.
This theory might actually be possible if all the countries of the world were identical in every way, and the goals of all concerned were also identical. But this never has been and can never be the case. Every world leader and every country will differ in its needs and objectives. Therefore, each may tentatively agree to common conditions, as they have going back to the Peace of Westphalia, yet, even before the ink has dried, each state will already be planning to gain an edge on the others.
In 1914, Europe had (once again) become a tangle of aspirations of the various powers—a time bomb, awaiting only a minor incident to set it off. That minor incident occurred when a Serbian national assassinated an Austrian crown prince. Within a month, Europe exploded into World War. As Kissinger himself has observed in his writings, “[T]hey all contributed to it, oblivious to the fact that they were dismantling an international order.”
Since 1648, for every Richelieu that has sought to create a New World Order through diplomacy, there has been a Napoleon who has taken a militaristic approach, assuring that the New World Order applecart will repeatedly be upset by those who are prone to aggression.
Further, even those who seek to operate through diplomacy ultimately will seek aggressive means when diplomatic means are not succeeding.
A true world order is unlikely.
What may occur in its stead would be repeated attempts by sovereign states to form alliances for their mutual benefit, followed by treachery, one- upmanship, and ultimately, aggression. And very possibly a new World War.
But of one thing we can be certain: Tension at present is as great as it was in 1914. We are awaiting only a minor incident to set off dramatically increased international aggression. With all the talk that’s presently about as to a New World Order, what I believe will occur instead will be a repeat of history.
If this belief is correct, much of the world will decline into not only external warfare, but internal control. Those nations that are now ramping up into police states are most at risk, as the intent is already clearly present. All that’s needed is a greater excuse to increase internal controls. Each of us, unless we favour being engulfed by such controls, might be advised to internationalise ourselves—to diversify ourselves so that, if push comes to shove, we’re able to get ourselves and our families out of harm’s way.
* * *
Unfortunately, there’s little any individual can practically do to change the course of these trends in motion. The best you can and should do is to stay informed so that you can protect yourself in the best way possible, and even profit from the situation. That’s precisely why bestselling author Doug Casey just released Surviving and Thriving During an Economic Collapse an urgent new PDF report. It explains what could come next and what you can do about it so you don’t become a victim. Click here to download it now.
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