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New study suggests CRISPR-Cas9 may not work in many people
Our bodies may fight Cas9 proteins.
The story began in 1987 when Yoshimumi Ishino of Osaka University discovered that clusters of short sequences in certain bacterial DNA could target DNA within viruses. These palindromic clusters clusters were held together by spacer materials, and eventually came to be known as “Clustered Regularly Interspaced Short Palindromic Repeats,” abbreviated as “CRISPR.” Researchers found that protein families — “CRISPR-associated,” or “cas” genes — occurred alongside these clusters, and that the most workable and promising pairing was with the Cas9 protein. When researchers Jennifer Doudna and Emmanuelle Charpentier discovered a way to target, snip out and replace DNA using CRISPR-Cas9, "It was kind of a like a lightning bolt," according to Doudna. "It was definitely an 'aha' moment." When they published their work in 2012, the excitement was palpable as a new era of simple, efficient gene editing began. Human trials are expected to get underway in Western countries this year, and China has been experimenting with CRISPR-Cas9 for a while. Now, however, a new study by Stanford University researchers has found that a high percentage of people may contain immune responses that could prevent CRISPR-Cas9’s from working, or even be dangerous.
Streptococcus pyogenes (NIAID)
The study analyzed blood for antibodies to two bacteria from which Cas9 is derived: Streptococcus pyogenes and Staphylococcus aureus. The researchers’ concern stemmed from the fact that these bacteria frequently cause infections in humans, and so antibodies to them may be in our blood: “The presence of pre-existing adaptive immune responses in humans to either Cas9 homolog may hinder the safe and efficacious use of the Cas9/gRNA system to treat disease, and may even result in significant toxicity to patients.”
Stanford’s initial finding was produced by testing for IgG antibodies in the serum of spinal cord blood from 22 donors and peripheral blood draws from an additional 12 healthy adults. They found that 65% of the donors had antibodies for Streptococcus pyogenes, the most common source of the protein used in CRISPR-Cas9, or “SpCas9.” 79% had antibodies for Staphylococcus aureus, the source of SaCas9. Fortunately, CRISPR-Cas9 is currently envisioned for ex vivo use, with cells in laboratory media, or in vivo via viral vectors or nanoparticles. In neither case would Cas9 bump up against the IgG antibodies.
Of more serious concern is that the researchers also found T-cells that could attack cells producing Cas9 proteins in six out of 13 donors, because “The existence of the pre-existing cellular immunity would likely both limit the effectiveness of and create safety concerns for Cas9-based genome editing.” No T-cells were found that attack SpCas9, though the researchers caution that this might reflect a limitation to their methodology rather than solid proof of their absence.
Human blood with orange T-cells (ZEISS MICROSCOPY)
What makes the presence of T-cells so serious is that in vivo treatments involve “Cas9 delivery systems that express the Cas9 protein for prolonged periods of time” and so “memory T-cells might rapidly expand in response to Cas9 being presented.” The study concludes, “Furthermore, it is possible to envision that constitutive expression of Cas9 in a large proportion of cells of an organ, for example, the liver, could elicit a cytotoxic T-cell response against Cas9 expressing cells that could result in significant toxicity.”
Stanford’s finding definitely puts a bit of a cloud over the future of CRISPR-Cas9, though just how problematic these existing immune responses will turn out to be is unclear. Certainly, they’re less worrying in regard to ex vivo gene editing, where problems can be caught before modified cells are returned to patients’ blood streams. In any event, as the study concludes, “We believe our findings will stimulate crucial discussions in the genome editing community about how to most safely and effectively apply the Cas9/gRNA genome editing system for gene therapy in humans.”
Inventions with revolutionary potential made by a mysterious aerospace engineer for the U.S. Navy come to light.
- U.S. Navy holds patents for enigmatic inventions by aerospace engineer Dr. Salvatore Pais.
- Pais came up with technology that can "engineer" reality, devising an ultrafast craft, a fusion reactor, and more.
- While mostly theoretical at this point, the inventions could transform energy, space, and military sectors.
The U.S. Navy controls patents for some futuristic and outlandish technologies, some of which, dubbed "the UFO patents," came to life recently. Of particular note are inventions by the somewhat mysterious Dr. Salvatore Cezar Pais, whose tech claims to be able to "engineer reality." His slate of highly-ambitious, borderline sci-fi designs meant for use by the U.S. government range from gravitational wave generators and compact fusion reactors to next-gen hybrid aerospace-underwater crafts with revolutionary propulsion systems, and beyond.
Of course, the existence of patents does not mean these technologies have actually been created, but there is evidence that some demonstrations of operability have been successfully carried out. As investigated and reported by The War Zone, a possible reason why some of the patents may have been taken on by the Navy is that the Chinese military may also be developing similar advanced gadgets.
Among Dr. Pais's patents are designs, approved in 2018, for an aerospace-underwater craft of incredible speed and maneuverability. This cone-shaped vehicle can potentially fly just as well anywhere it may be, whether air, water or space, without leaving any heat signatures. It can achieve this by creating a quantum vacuum around itself with a very dense polarized energy field. This vacuum would allow it to repel any molecule the craft comes in contact with, no matter the medium. Manipulating "quantum field fluctuations in the local vacuum energy state," would help reduce the craft's inertia. The polarized vacuum would dramatically decrease any elemental resistance and lead to "extreme speeds," claims the paper.
Not only that, if the vacuum-creating technology can be engineered, we'd also be able to "engineer the fabric of our reality at the most fundamental level," states the patent. This would lead to major advancements in aerospace propulsion and generating power. Not to mention other reality-changing outcomes that come to mind.
Among Pais's other patents are inventions that stem from similar thinking, outlining pieces of technology necessary to make his creations come to fruition. His paper presented in 2019, titled "Room Temperature Superconducting System for Use on a Hybrid Aerospace Undersea Craft," proposes a system that can achieve superconductivity at room temperatures. This would become "a highly disruptive technology, capable of a total paradigm change in Science and Technology," conveys Pais.
High frequency gravitational wave generator.
Credit: Dr. Salvatore Pais
Another invention devised by Pais is an electromagnetic field generator that could generate "an impenetrable defensive shield to sea and land as well as space-based military and civilian assets." This shield could protect from threats like anti-ship ballistic missiles, cruise missiles that evade radar, coronal mass ejections, military satellites, and even asteroids.
Dr. Pais's ideas center around the phenomenon he dubbed "The Pais Effect". He referred to it in his writings as the "controlled motion of electrically charged matter (from solid to plasma) via accelerated spin and/or accelerated vibration under rapid (yet smooth) acceleration-deceleration-acceleration transients." In less jargon-heavy terms, Pais claims to have figured out how to spin electromagnetic fields in order to contain a fusion reaction – an accomplishment that would lead to a tremendous change in power consumption and an abundance of energy.
According to his bio in a recently published paper on a new Plasma Compression Fusion Device, which could transform energy production, Dr. Pais is a mechanical and aerospace engineer working at the Naval Air Warfare Center Aircraft Division (NAWCAD), which is headquartered in Patuxent River, Maryland. Holding a Ph.D. from Case Western Reserve University in Cleveland, Ohio, Pais was a NASA Research Fellow and worked with Northrop Grumman Aerospace Systems. His current Department of Defense work involves his "advanced knowledge of theory, analysis, and modern experimental and computational methods in aerodynamics, along with an understanding of air-vehicle and missile design, especially in the domain of hypersonic power plant and vehicle design." He also has expert knowledge of electrooptics, emerging quantum technologies (laser power generation in particular), high-energy electromagnetic field generation, and the "breakthrough field of room temperature superconductivity, as related to advanced field propulsion."
Suffice it to say, with such a list of research credentials that would make Nikola Tesla proud, Dr. Pais seems well-positioned to carry out groundbreaking work.
A craft using an inertial mass reduction device.
Credit: Salvatore Pais
The patents won't necessarily lead to these technologies ever seeing the light of day. The research has its share of detractors and nonbelievers among other scientists, who think the amount of energy required for the fields described by Pais and his ideas on electromagnetic propulsions are well beyond the scope of current tech and are nearly impossible. Yet investigators at The War Zone found comments from Navy officials that indicate the inventions are being looked at seriously enough, and some tests are taking place.
If you'd like to read through Pais's patents yourself, check them out here.
Laser Augmented Turbojet Propulsion System
Credit: Dr. Salvatore Pais
- As the material that makes all living things what/who we are, DNA is the key to understanding and changing the world. British geneticist Bryan Sykes and Francis Collins (director of the Human Genome Project) explain how, through gene editing, scientists can better treat illnesses, eradicate diseases, and revolutionize personalized medicine.
- But existing and developing gene editing technologies are not without controversies. A major point of debate deals with the idea that gene editing is overstepping natural and ethical boundaries. Just because they can, does that mean that scientists should be edit DNA?
- Harvard professor Glenn Cohen introduces another subcategory of gene experiments: mixing human and animal DNA. "The question is which are okay, which are not okay, why can we generate some principles," Cohen says of human-animal chimeras and arguments concerning improving human life versus morality.
New studies stretch the boundaries of physics, achieving quantum entanglement in larger systems.
- New experiments with vibrating drums push the boundaries of quantum mechanics.
- Two teams of physicists create quantum entanglement in larger systems.
- Critics question whether the study gets around the famous Heisenberg uncertainty principle.
Recently published research pushes the boundaries of key concepts in quantum mechanics. Studies from two different teams used tiny drums to show that quantum entanglement, an effect generally linked to subatomic particles, can also be applied to much larger macroscopic systems. One of the teams also claims to have found a way to evade the Heisenberg uncertainty principle.
One question that the scientists were hoping to answer pertained to whether larger systems can exhibit quantum entanglement in the same way as microscopic ones. Quantum mechanics proposes that two objects can become "entangled," whereby the properties of one object, such as position or velocity, can become connected to those of the other.
An experiment performed at the U.S. National Institute of Standards and Technology in Boulder, Colorado, led by physicist Shlomi Kotler and his colleagues, showed that a pair of vibrating aluminum membranes, each about 10 micrometers long, can be made to vibrate in sync, in such a way that they can be described to be quantum entangled. Kotler's team amplified the signal from their devices to "see" the entanglement much more clearly. Measuring their position and velocities returned the same numbers, indicating that they were indeed entangled.
Tiny aluminium membranes used by Kotler's team.Credit: Florent Lecoq and Shlomi Kotler/NIST
Evading the Heisenberg uncertainty principle?
Another experiment with quantum drums — each one-fifth the width of a human hair — by a team led by Prof. Mika Sillanpää at Aalto University in Finland, attempted to find what happens in the area between quantum and non-quantum behavior. Like the other researchers, they also achieved quantum entanglement for larger objects, but they also made a fascinating inquiry into getting around the Heisenberg uncertainty principle.
The team's theoretical model was developed by Dr. Matt Woolley of the University of New South Wales. Photons in the microwave frequency were employed to create a synchronized vibrating pattern as well as to gauge the positions of the drums. The scientists managed to make the drums vibrate in opposite phases to each other, achieving "collective quantum motion."
The study's lead author, Dr. Laure Mercier de Lepinay, said: "In this situation, the quantum uncertainty of the drums' motion is canceled if the two drums are treated as one quantum-mechanical entity."
This effect allowed the team to measure both the positions and the momentum of the virtual drumheads at the same time. "One of the drums responds to all the forces of the other drum in the opposing way, kind of with a negative mass," Sillanpää explained.
Theoretically, this should not be possible under the Heisenberg uncertainty principle, one of the most well-known tenets of quantum mechanics. Proposed in the 1920s by Werner Heisenberg, the principle generally says that when dealing with the quantum world, where particles also act like waves, there's an inherent uncertainty in measuring both the position and the momentum of a particle at the same time. The more precisely you measure one variable, the more uncertainty in the measurement of the other. In other words, it is not possible to simultaneously pinpoint the exact values of the particle's position and momentum.
Heisenberg's Uncertainty Principle Explained. Credit: Veritasium / Youtube.com
Big Think contributor astrophysicist Adam Frank, known for the 13.8 podcast, called this "a really fascinating paper as it shows that it's possible to make larger entangled systems which behave like a single quantum object. But because we're looking at a single quantum object, the measurement doesn't really seem to me to be 'getting around' the uncertainty principle, as we know that in entangled systems an observation of one part constrains the behavior of other parts."
Ethan Siegel, also an astrophysicist, commented, "The main achievement of this latest work is that they have created a macroscopic system where two components are successfully quantum mechanically entangled across large length scales and with large masses. But there is no fundamental evasion of the Heisenberg uncertainty principle here; each individual component is exactly as uncertain as the rules of quantum physics predicts. While it's important to explore the relationship between quantum entanglement and the different components of the systems, including what happens when you treat both components together as a single system, nothing that's been demonstrated in this research negates Heisenberg's most important contribution to physics."The papers, published in the journal Science, could help create new generations of ultra-sensitive measuring devices and quantum computers.