Arch Dis Child Educ Pract Ed. 2016 Aug; 101(4): 213215.

1HYMS Centre for Education Development (CED), Hull, York Medical School, University of York, York, UK

2Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK

3Department of Haematology, Oxford University NHS Foundation Trust, Churchill Hospital, Oxford, UK

4Academic Unit of Child Health, Sheffield Children's Hospital, Sheffield, UK

1HYMS Centre for Education Development (CED), Hull, York Medical School, University of York, York, UK

2Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK

3Department of Haematology, Oxford University NHS Foundation Trust, Churchill Hospital, Oxford, UK

4Academic Unit of Child Health, Sheffield Children's Hospital, Sheffield, UK

Received 2016 Jan 5; Revised 2016 Feb 18; Accepted 2016 Feb 19.

Keywords: CRISPR/cas9, gene editing, children, genome engineering

Clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 is a gene-editing technology causing a major upheaval in biomedical research. It makes it possible to correct errors in the genome and turn on or off genes in cells and organisms quickly, cheaply and with relative ease. It has a number of laboratory applications including rapid generation of cellular and animal models, functional genomic screens and live imaging of the cellular genome.1 It has already been demonstrated that it can be used to repair defective DNA in mice curing them of genetic disorders,2 and it has been reported that human embryos can be similarly modified.3 Other potential clinical applications include gene therapy, treating infectious diseases such as HIV and engineering autologous patient material to treat cancer and other diseases. In this review we will give an overview of CRISPR/Cas9 with an emphasis on how it may impact on the specialty of paediatrics. Although it is likely to have a significant effect on paediatrics through its impact in the laboratory, here we will concentrate on its potential clinical applications. We will also describe some of the difficulties and ethical controversies associated with this novel technology.

CRISPR/Cas9 is a gene-editing technology which involves two essential components: a guide RNA to match a desired target gene, and Cas9 (CRISPR-associated protein 9)an endonuclease which causes a double-stranded DNA break, allowing modifications to the genome (see ).

The CRISPR/Cas9 system.1 Clustered regularly interspaced palindromic repeats (CRISPR) refers to sequences in the bacterial genome. They afford protection against invading viruses, when combined with a series of CRISPR-associated (Cas) proteins. Cas9, one of the associated proteins, is an endonuclease that cuts both strands of DNA. Cas9 is directed to its target by a section of RNA. This can be synthesised as a single strand called a synthetic single guide RNA (sgRNA); the section of RNA which binds to the genomic DNA is 1820 nucleotides. In order to cut, a specific sequence of DNA of between 2 and 5 nucleotides (the exact sequence depends upon the bacteria which produces the Cas9) must lie at the 3 end of the guide RNA: this is called the protospacer adjacent motif (PAM). Repair after the DNA cut may occur via two pathways: non-homologous end joining, typically leading to a random insertion/deletion of DNA, or homology directed repair where a homologous piece of DNA is used as a repair template. It is the latter which allows precise genome editing: the homologous section of DNA with the required sequence change may be delivered with the Cas9 nuclease and sgRNA, theoretically allowing changes as precise as a single base-pair.

One of the most exciting applications of CRISPR/Cas9 is its potential use to treat genetic disorders caused by single gene mutations. Examples of such diseases include cystic fibrosis (CF), Duchenne's muscular dystrophy (DMD) and haemoglobinopathies. The approach so far has currently only been validated in preclinical models, but there is hope it can soon be translated to clinical practice.

Schwank et al used CRISPR/Cas9 to investigate the treatment of CF. Using adult intestinal stem cells obtained from two patients with CF, they successfully corrected the most common mutation causing CF in intestinal organoids. They demonstrated that once the mutation had been corrected, the function of the CF transmembrane conductor receptor (CFTR) was restored.4

Another disease in which CRISPR/Cas9 has been investigated is DMD. Tabebordbar et al recently used adeno-associated virus (AAV) delivery of CRISPR/Cas9 endonucleases to recover dystrophin expression in a mouse model of DMD, by deletion of the exon containing the original mutation. This produces a truncated, but still functional protein. Treated mice were shown to partially recover muscle functional deficiencies.5 Significantly, it was demonstrated that the dystrophin gene was edited in muscle stem cells which replenish mature muscle tissue. This is important to ensure any therapeutic effects of CRISPR/Cas9 do not fade over time. Two similar studies have described using the CRISPR/Cas9 system in vivo to increase expression of the dystrophin gene and improve muscle function in mouse models of DMD.67 Other studies have used CRISPR/Cas9 to target duplication of exons in the human dystrophin gene in vitro and have shown that this approach can lead to production of full-length dystrophin in the myotubules of an individual with DMD.8

CRISPR/Cas9 could also be used to treat haemoglobinopathies. Canver et al9 recently showed BCL11A enhancer disruption by CRISPR/Cas9 could induce fetal haemoglobin in both mice and primary human erythroblast cells. In the future such an approach could allow fetal haemoglobin to be expressed in patients with abnormal adult haemoglobin. This would represent a novel therapeutic strategy in patients with diseases such as sickle cell disease or thalassaemias. Knock-in of a fully functional -globin gene is much more challenging, which is the reason for this somewhat unusual approach.

Another potential clinical application of CRISPR/Cas9 is to treat infectious diseases, such as HIV. Although antiretroviral therapy provides an effective treatment for HIV, no cure currently exists due to permanent integration of the virus into the host genome. Hu et al showed the CRISPR/Cas9 system could be used to target HIV-1 genome activity. This inactivated HIV gene expression and replication in a variety of cells which can be latently infected with HIV, without any toxic effects. Furthermore, cells could also be immunised against HIV-1 infection. This is a potential therapeutic advance in overcoming the current problem of how to eliminate HIV from infected individuals. After further refinement, the authors suggest their findings may enable gene therapies or transplantation of genetically altered bone marrow stem cells or inducible pluripotent stem cells to eradicate HIV infection.10

There has been increasing interest in the possibility of using CRISPR/Cas9 to modify patient-derived T-cells and stem/progenitor cells which can then be reintroduced into patients to treat disease. This approach may overcome some of the issues associated with how to efficiently deliver gene editing to the right cells.

T-cell genome engineering has already shown success in treating haematological malignancies and has the potential to treat solid cancers, primary immune deficiencies and autoimmune diseases. Genetic manipulation of T-cells has previously been inefficient. However, Schumann et al recently reported a more effective approach in human CD4+ T-cells based on the CRISPR/Cas9 system. Their technique allowed experimental and therapeutic knock-out and knock-in editing of the genome in primary human T-cells. They demonstrated T-cells could be manipulated to prevent expression of the protein PD-1, which other work has shown may allow T-cells to target solid cancers.11

There is also interest in using CRISPR/Cas9-mediated genome editing in pluripotent stem cells or primary somatic stem cells to treat disease. For example Xie et al12 showed the mutation causing -thalassaemia could be corrected in human induced pluripotent stem cells ex vivo. They suggest that in the future such an approach could provide a source of cells for bone marrow transplantation to treat -thalassaemia and other similar monogenic diseases.

A number of challenges remain before the potential of CRISPR/Cas9 can be translated to effective treatments at the bedside. A particular issue is how to deliver gene editing to the right cells, especially if the treatment is to be delivered in vivo. To safely deliver Cas9-nuclease encoding genes and guide RNAs in vivo without any associated toxicity, a suitable vector is needed. AAV has previously been a favoured option for gene delivery.1 However, this delivery system may be too small to allow efficient transduction of the Cas9 gene.1 A smaller Cas9 gene could be used, but this has additional implications on efficacy.1 A number of other non-viral delivery systems are under investigation and this process requires further optimisation.

Another significant concern is the possibility of off-target effects on parts of the genome separate from the region being targeted. Unintentional edits of the genome could have profound long-term complications for patients, including malignancy. The concentration of the Cas9 nuclease enzyme and the length of time Cas9 is expressed are both important when limiting off-target activity.1 Although recent modifications in the nuclease have increased specificity, further work is required to minimise off-target effects and to establish the long-term safety of any treatment.

The therapeutic applications of CRISPR/Cas9 considered in this article have predominantly been directed at somatic cells. A particularly controversial issue surrounding CRISPR/Cas9 is that of gene editing in embryos. It has already been shown that CRISPR/Cas9 technology can alter the genome of human embryos3 which theoretically could prove useful in the preimplantation treatment of genetic diseases. However, any genetic modification of the germline would be permanent and the long-term consequences are unclear. Many oppose germline modification under any circumstances, reasoning that an eventual consequence could be non-therapeutic genetic enhancement.13 It is clear that the ethical boundaries, within which CRISPR/Cas9 can be used, remain to be fully determined.

Clinical bottom line

CRISPR/Cas9 technology has the potential to revolutionise the treatment of many paediatric conditions.

A number of practical and ethical challenges must be overcome before this potential can be realised at the bedside.

Contributors: DK conceived the idea for this article. All authors were involved in writing and reviewing the final manuscript.

Funding: AK is supported by a Wellcome Trust Fellowship (108785/Z/15/Z).

Competing interests: None declared.

Provenance and peer review: Not commissioned; externally peer reviewed.

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What is CRISPR/Cas9? - PMC - National Center for Biotechnology Information

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"I think of it more as an ideological statement."Anti-Death Activist

Billionaire tech entrepreneur and investor Peter Thiel says he's freezing his body when he dies if only as a moment of anti-death activism.

Thiel explained his "just in case" cryonics aspirations to journalist and former Twitter Filer Bari Weiss on Weiss' podcast, Honestly, in a lengthy podcast episode published last week.

"I think of it more as an ideological statement," Thiel told Weiss, as quoted by Fortune.

"I don't necessarily expect it to work," he continued, "but I think it's the sort of thing we're supposed to try to do."

In other words: cryo might not ultimately work, but as one of the most vocal leaders on the immortality-seeking technological crusade, he's duty-bound to freeze his ol' bag o' bones nonetheless. Gotta walk the walk if you talk the talk.

As for where he's seeking to freeze himself, Thiel told Weiss that he's eyeing Alcor, the prominent cryo firm that back in 2009 was accused of both accidentally decapitating and accidentally freezing what appeared to be a can of tuna to the icy head of baseball great Ted Williams.

Thiel's cryo plans aren't all that surprising, as the billionaire's enthusiasm for immortality tech has been widely documented. Along with making some notable investments into immortality tech firms, Thiel was famously accused of seeking blood infusions from young donors. And back in 2014, the VC took anti-aging to a whole new level when he declared to the Telegraph that he was "against" the concept of mortality.

"People have a choice to accept death, deny it or fight it," Thiel told Telegraph. "I think our society is dominated by people who are into denial or acceptance, and I prefer to fight it."

Thiel reiterated a version of that 2014 argument in his recent conversation with Weiss, saying that we should at least understand whyhumans are doomed to toil away in our mortal meat suits.

"We haven't even tried," the PayPal and Palantir cofounder lamented. "We should either conquer death or at least figure out why it's impossible."

Of course, the answer to that latter point may well be answered by simple biology. And to that end, immortality-seeking cryo has been decried by some experts as something along the lines of a pseudoscientific hail mary.

Regardless, whether Thiel's anti-death investments will one day pay off remains to be seen. But even if he's ultimately unable to attain immortality, at least he'll die trying.

More on immortality tech: Elon Musk Says That Immortality Tech Would Be Very Dangerous

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Despite movies like Passengers, the science behind cryonics is still a long way from reviving people who have been frozen after theyve died.

What if you had a life-threatening disease and someone offered an ambulance ride to a hospital that may hold the cure? Youd take it, right?

What if that ambulance was actually a cryonic state that kept you preserved and that hospital existed 200 years from now? Would you still go?

Cryonics, in the simplest terms, is the act of freezing someone whos been declared legally dead. The idea is to conserve the body until science can catch up and provide treatment to whatever caused the person to die.

When that scientific breakthrough occurs, the person is then revived, given the necessary medical treatment, and goes on living.

The practice recently made headlines when a 14-year-old United Kingdom girl with cancer sought the legal right to be frozen. Her parents were divorced and her father didnt agree with her intentions. The teenager asked the court to designate that only her mother could dispose of her remains so she could get her wish. In October a judge ruled in her favor.

Im only 14 years old and I dont want to die, but I know I will. I think being cryo-preserved gives me a chance to be cured, even in a hundred years time I want to live and live longer and I think that in the future they may find a cure for my cancer and wake me up, she wrote to a judge before her recent death.

Read more: Facing death at an early age

The theory of cryonics was first broached more than 50 years ago by Robert Ettinger.

In 1964, his book, The Prospect of Immortality, first introduced the idea on a mass scale. A dozen years later, he founded the Cryonics Institute.

Over the past five decades, cryonics has held on to a small but dedicated group of supporters. Today, hundreds if not thousands of people are betting on the science.

Dozens of institutions, nonprofits, and businesses around the world offer cryonic services to anyone who can afford it. Ettingers Cryonics Institute in Michigan and Alcor Life Extension Foundation in Arizona are two of the better known cryonics providers in the United States.

Those who are in favor of it say cryonics is ultimately about scientific exploration. Those who are opposed to the say it takes advantage of people in vulnerable positions.

In order for a body to get to a preserved, frozen state, a person must first be declared legally dead. Once that is determined, the freezing process involves a complex set of protocols. Its designed to cool the body, so that everything slows down at a molecular level, according to Dennis Kowalski, chief executive officer of the Cryonics Institute.

Once the blood is pumped out of the body, its cooled even further but in a way that preserves the organs and hinders tissue damage. The body is then placed into a large thermos-type bottle of liquid nitrogen where it stays indefinitely. Or until science can provide a viable cure.

I guess its about optimism. Its also about hope, Kowalski told Healthline.

But hope is not cheap. At Cryonics Institute, cryonic services costs $28,000. That price, Kowalski said, is competitive.

Part of the funds go the groups endowment, which is used to cover the long-term expenses of keeping bodies frozen for potentially hundreds of years. Kowalski does not take a salary for his work at the institute. Instead, he works full time as an emergency medical technician.

He added that if someone is interested in cryonics and is quoted a cheaper price, hed be skeptical about that organizations ability to keep a body preserved in a proper way with all the safeguards intact.

Read more: The changing definition of what is brain dead

If cryonics sounds like the stuff of science fiction, thats because it is.

A number of well-known films such as Sleeper, Space Odyssey 2001, and the soon-to-be-released Passengers starring Chris Pratt and Jennifer Lawrence all employ some version of cryonics as the crux of their story line.

In these movies, the protagonists are put to sleep or frozen and wake up in the distant future to an entirely new world.

Usually these movies scenes unfold as if these people are waking up from a really good nights sleep. Waking up is the crucial part of a cryonics equation. But Kowalski readily admits, science has yet to figure out how that will unfold for people who are in a cryonic state.

We are not even close to being able to revive people, he said.

Modern medicine does currently employ freezing methods to treat patients. Its the preferred technique to store stem cells, embryos, and small tissues.

Kowalski added that all three examples are capable of being restored free of damage from the subzero temperatures. Even hospital emergency rooms are starting to see the benefits of a lowered body temperature, he noted. Sometimes its used in the treatment of gunshot wounds and heart attacks.

He says these examples show that its only a matter time before the human body will be able to endure similar treatment.

The trend certainly seems to be heading that way, he said. Could be 20 years from now. Could be 2,000 years.

Detractors say the science and technology needed to revive and treat people are far into the future. Encouraging people to spend thousands of dollars on a yet to-be-proven medical procedure calls into question the ethics behind the industry.

I can understand why people are interested, Ryan F. Holmes, assistant director of the Markkula Center for Applied Ethics at Santa Clara University in California, told Healthline.

His concern is that people get lost in the hope of cryonics and dont really ever consider that it isnt going to work.

It seems overly hopefully and that for me is the hardest ethics part, he said.

He doesnt advocate that people should be prevented from choosing cryonics when they die, such as the case with the United Kingdom girl. But anyone who does make this choice must understand that there are a multitude of unknown factors about the science and technology.

This wouldnt even qualify as a phase 1 trial, he said. This falls into the category of experimental treatment.

Whats more, he said potential candidates should be made aware that revival if it can even occur doesnt guarantee that quality of life will be what it once was before they were sick.

We have no evidence that theyd be who they were in a very meaningful sense, he said.

Read more: Where we die: Less in ER and more at home

Kowalski said the nonprofit does not guarantee to its clients that cryonics will work.

We make every effort to educate people about their choices and what we offered. We also understand the potential for misunderstanding and misconception about what we are doing, he said. We try very hard to explain our position and provide as ethical a service as possible.

Right now they have about 1,400 people as members and around 150 bodies are frozen.

Kowalski said that people usually come to the institute in two ways.

The first group is people who are interested in cryonics and sign up by their own free will. These clients are required to fill out extensive paperwork and are given an interview as well.

Others are the result of a person dying and family members scrambling to have them embalmed.

The nonprofit adheres to a list of rules when they get an urgent cryonics request. In these situations, if they accept the body it will be held for two weeks to ensure that cost and paperwork are completed. Anyone who has been declared dead for up to 48 hours is turned away. Kowalski said overall theyve turned down about half of the post-mortem requests.

We have returned funding many times when [a] family cannot agree on disposing remains, he said. There is a series of events that must be followed or we back out to protect both ourselves and the family from mistakes.

For Kowalski, signing up for cryonics is something he got interested in as a kid. He and his family are all on board. When asked what he thinks the future will be like should the revival process work, he said he envisions a world that will be even better than today.

Im excited to see the future, he said.

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When he was 14, Kai Micah Mills brought home a long-haired tabby cat and named it Cat. Growing up in Utah, they were inseparable. Mills, a soft-spoken, antisocial teenager, had dropped out of high school and earned an income running Minecraft servers from his basement. He didn't have many friends, but he always had Cat.

Cat is getting on in years. But if his owner's new business works out the way he hopes, Cat will never die.

These days, Mills has turned his sights to something more macabre than gaming. He is a rare entrepreneur in the field of cryonics: the process of storing humans and animal remains at deep-freeze temperatures with the hope that scientific advances can one day revive them.

The startup he founded, Cryopets, aims to establish a network of veterinary clinics that provide regular check-ups and emergency care, and upon a pet's death, owners would have the option to preserve their companions. The pets would then be shipped to a Utah facility, where they wait in metal vats for resurrection day. In doing so, Cryopets embodies a "full-stack" approach to care, encompassing life, death, and the possibility of return.

Though the idea might seem far-fetched, Peter Thiel the billionaire investor who's funded artificial intelligence, reusable rockets, life extension, and seasteading would beg to differ.

In February, Thiel's foundation announced Mills and 19 others as the next class of Thiel Fellows. Each receives $100,000 over two years to start a company, on the condition they pause their college studies. Mills is one of the few high school dropouts ever admitted.

At 24, with a slim build and hair past his shoulders, Mills has spent the better part of a decade planning for a future where there is no death. Cryopets, he said, is part one.

Someday, he hopes to expand to human preservation, as the science matures and pet owners warm to the idea. "It's a gateway drug to humans," he said of his startup.

"In the end I'm interested in keeping people from dying," he explained, "not just for a little bit, but completely."

Mills' plan is starting to come together. He's spent the last year and a half fundraising, buying equipment, and assembling a scientific advisory board. Cryopets' waitlist now includes about 500 dogs, cats, rabbits, hamsters, and one monkey. Later this year, Cryopets will kick off the search to hire its first veterinarian and begin research into organ-warming methods.

The timing feels right to Mills. The longevity sector, according to a report by the British news outlet Longevity.Technology, clinched $5.2 billion in financing last year. Sam Altman poured $180 million into Retro Biosciences, which aims to extend the healthy human lifespan up to a decade. And Laura Deming, a venture capitalist focused on longevity, is quietly working on advancing organ cryopreservation. Deming's new startup, Lorentz Bio, hasn't been previously reported.

With backing from the tech world's top transhumanist, Mills now has to convince people to take a gamble on his animal hospital for immortal pets. And here's the rub: He may be long dead by the time they can be revived.

Growing up in the Mormon church, Mills always figured he'd live forever. Even after he fell out of religion in his teens, he didn't give up on the idea of everlasting life.

On YouTube, he came across Russian millionaire Dmitry Itskov, who had sold his media empire and funded research with the goal of cheating death. "Eternal life not through faith but science," Mills said. "I really loved that approach."

For years Mills sat on the idea. He sold his server business at 16 and started another company, Branch, making virtual offices where workers moved around rooms like a video game. Branch rode pandemic trends to the tune of $1.6 million from investors like Homebrew and Naval Ravikant. But the company felt more like his cofounder's brainchild than his, and, in 2021, Mills left to dig into longevity.

He joined an incubator and spoke to many experts in aging, but his conversations left him with a sense of dread.

"We have such a long way to go to curing aging," Mill said. "It didn't seem like something that was plausible in my lifetime."

He started to think about how he could buy himself more time. Then he thought about Cat.

For any number of reasons, animals make better cryonics-guinea pigs than humans. It's cheaper to freeze pets because of their small size, Mills explained, and it avoids hairy legal battles. But their big advantage is that there's higher predictability around their deaths.

When a pet is close to death, it may be euthanized at an animal hospital, which is ideal for getting the body ready for cryopreservation. The process includes cooling the body in an ice bath, pumping out the blood, and replacing it with an antifreeze solution that prevents cold damage.

It's important, according to Alcor, a leading cryonics organization, to start the preparations shortly after death to prevent decay. "Longer delays place a greater burden on future technology to reverse injury and restore the brain to a healthy state," Alcor's website says.

"Humans don't get euthanized," Mills said. "We die in some sudden death fashion."

So, he decided to tackle cryonics for pets first.

The plan for Cryopets is to open an animal hospital for piloting this model of caring for pets in life and death, plus a storage facility. Eventually,it wants to partner with other hospitals, training them on how to prepare the bodies and then storing them at its facility.

Cryopets is not the first to market. The Cryonics Institute in Detroit, Michigan, and Alcor in Scottsdale, Arizona, will preserve the furry friends of its human members, for an additional cost that ranges up to $132,000. The price comes down if the person opts to have only the head stored. Cryopets, however, will only offer full-body cryopreservation.

Mills hasn't figured out a pricing structure yet, but says pet owners will make a payment that covers their pet's storage for as long as necessary.

Insider asked Mills what happens when a pet's owner dies too. They might have arranged for their own cryopreservation, he explained, so they can come back at a future date with their pet. If not, Mills says Cryopets will put the frozen animal up for adoption. He imagines a time-traveling critter would be quite popular.

"Can you imagine," Mills said, "the line of people who would be more willing to take care of a cat from the 1800s?"

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Ten years ago this week, Jennifer Doudna and her colleagues published the results of a test-tube experiment on bacterial genes. When the study came out in the journal Science on June 28, 2012, it did not make headline news. In fact, over the next few weeks, it did not make any news at all.

Looking back, Dr. Doudna wondered if the oversight had something to do with the wonky title she and her colleagues had chosen for the study: A Programmable Dual RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity.

I suppose if I were writing the paper today, I would have chosen a different title, Dr. Doudna, a biochemist at the University of California, Berkeley, said in an interview.

Far from an esoteric finding, the discovery pointed to a new method for editing DNA, one that might even make it possible to change human genes.

I remember thinking very clearly, when we publish this paper, its like firing the starting gun at a race, she said.

In just a decade, CRISPR has become one of the most celebrated inventions in modern biology. It is swiftly changing how medical researchers study diseases: Cancer biologists are using the method to discover hidden vulnerabilities of tumor cells. Doctors are using CRISPR to edit genes that cause hereditary diseases.

The era of human gene editing isnt coming, said David Liu, a biologist at Harvard University. Its here.

But CRISPRs influence extends far beyond medicine. Evolutionary biologists are using the technology to study Neanderthal brains and to investigate how our ape ancestors lost their tails. Plant biologists have edited seeds to produce crops with new vitamins or with the ability to withstand diseases. Some of them may reach supermarket shelves in the next few years.

CRISPR has had such a quick impact that Dr. Doudna and her collaborator, Emmanuelle Charpentier of the Max Planck Unit for the Science of Pathogens in Berlin, won the 2020 Nobel Prize for chemistry. The award committee hailed their 2012 study as an epoch-making experiment.

Dr. Doudna recognized early on that CRISPR would pose a number of thorny ethical questions, and after a decade of its development, those questions are more urgent than ever.

Will the coming wave of CRISPR-altered crops feed the world and help poor farmers or only enrich agribusiness giants that invest in the technology? Will CRISPR-based medicine improve health for vulnerable people across the world, or come with a million-dollar price tag?

The most profound ethical question about CRISPR is how future generations might use the technology to alter human embryos. This notion was simply a thought experiment until 2018, when He Jiankui, a biophysicist in China, edited a gene in human embryos to confer resistance to H.I.V. Three of the modified embryos were implanted in women in the Chinese city of Shenzhen.

In 2019, a court sentenced Dr. He to prison for illegal medical practices. MIT Technology Review reported in April that he had recently been released. Little is known about the health of the three children, who are now toddlers.

Scientists dont know of anyone else who has followed Dr. Hes example yet. But as CRISPR continues to improve, editing human embryos may eventually become a safe and effective treatment for a variety of diseases.

Will it then become acceptable, or even routine, to repair disease-causing genes in an embryo in the lab? What if parents wanted to insert traits that they found more desirable like those related to height, eye color or intelligence?

Franoise Baylis, a bioethicist at Dalhousie University in Nova Scotia, worries that the public is still not ready to grapple with such questions.

Im skeptical about the depth of understanding about whats at issue there, she said. Theres a difference between making people better and making better people.

Dr. Doudna and Dr. Charpentier did not invent their gene-editing method from scratch. They borrowed their molecular tools from bacteria.

In the 1980s, microbiologists discovered puzzling stretches of DNA in bacteria, later called Clustered Regularly Interspaced Short Palindromic Repeats. Further research revealed that bacteria used these CRISPR sequences as weapons against invading viruses.

The bacteria turned these sequences into genetic material, called RNA, that could stick precisely to a short stretch of an invading viruss genes. These RNA molecules carry proteins with them that act like molecular scissors, slicing the viral genes and halting the infection.

As Dr. Doudna and Dr. Charpentier investigated CRISPR, they realized that the system might allow them to cut a sequence of DNA of their own choosing. All they needed to do was make a matching piece of RNA.

To test this revolutionary idea, they created a batch of identical pieces of DNA. They then crafted another batch of RNA molecules, programming all of them to home in on the same spot on the DNA. Finally, they mixed the DNA, the RNA and molecular scissors together in test tubes. They discovered that many of the DNA molecules had been cut at precisely the right spot.

For months Dr. Doudna oversaw a series of round-the-clock experiments to see if CRISPR might work not only in a test tube, but also in living cells. She pushed her team hard, suspecting that many other scientists were also on the chase. That hunch soon proved correct.

In January 2013, five teams of scientists published studies in which they successfully used CRISPR in living animal or human cells. Dr. Doudna did not win that race; the first two published papers came from two labs in Cambridge, Mass. one at the Broad Institute of M.I.T. and Harvard, and the other at Harvard.

Lukas Dow, a cancer biologist at Weill Cornell Medicine, vividly remembers learning about CRISPRs potential. Reading the papers, it looked amazing, he recalled.

Dr. Dow and his colleagues soon found that the method reliably snipped out pieces of DNA in human cancer cells.

It became a verb to drop, Dr. Dow said. A lot of people would say, Did you CRISPR that?

Cancer biologists began systematically altering every gene in cancer cells to see which ones mattered to the disease. Researchers at KSQ Therapeutics, also in Cambridge, used CRISPR to discover a gene that is essential for the growth of certain tumors, for example, and last year, they began a clinical trial of a drug that blocks the gene.

Caribou Biosciences, co-founded by Dr. Doudna, and CRISPR Therapeutics, co-founded by Dr. Charpentier, are both running clinical trials for CRISPR treatments that fight cancer in another way: by editing immune cells to more aggressively attack tumors.

Those companies and several others are also using CRISPR to try to reverse hereditary diseases. On June 12, researchers from CRISPR Therapeutics and Vertex, a Boston-based biotech firm, presented at a scientific meeting new results from their clinical trial involving 75 volunteers who had sickle-cell anemia or beta thalassemia. These diseases impair hemoglobin, a protein in red blood cells that carries oxygen.

The researchers took advantage of the fact that humans have more than one hemoglobin gene. One copy, called fetal hemoglobin, is typically active only in fetuses, shutting down within a few months after birth.

The researchers extracted immature blood cells from the bone marrow of the volunteers. They then used CRISPR to snip out the switch that would typically turn off the fetal hemoglobin gene. When the edited cells were returned to patients, they could develop into red blood cells rife with hemoglobin.

Speaking at a hematology conference, the researchers reported that out of 44 treated patients with beta thalassemia, 42 no longer needed regular blood transfusions. None of the 31 sickle cell patients experienced painful drops in oxygen that would have normally sent them to the hospital.

CRISPR Therapeutics and Vertex expect to ask government regulators by the end of year to approve the treatment.

Other companies are injecting CRISPR molecules directly into the body. Intellia Therapeutics, based in Cambridge and also co-founded by Dr. Doudna, has teamed up with Regeneron, based in Westchester County, N.Y., to begin a clinical trial to treat transthyretin amyloidosis, a rare disease in which a damaged liver protein becomes lethal as it builds up in the blood.

Doctors injected CRISPR molecules into the volunteers livers to shut down the defective gene. Speaking at a scientific conference last Friday, Intellia researchers reported that a single dose of the treatment produced a significant drop in the protein level in volunteers blood for as long as a year thus far.

The same technology that allows medical researchers to tinker with human cells is letting agricultural scientists alter crop genes. When the first wave of CRISPR studies came out, Catherine Feuillet, an expert on wheat, who was then at the French National Institute for Agricultural Research, immediately saw its potential for her own work.

I said, Oh my God, we have a tool, she said. We can put breeding on steroids.

At Inari Agriculture, a company in Cambridge, Dr. Feuillet is overseeing efforts to use CRISPR to make breeds of soybeans and other crops that use less water and fertilizer. Outside of the United States, British researchers have used CRISPR to breed a tomato that can produce vitamin D.

Kevin Pixley, a plant scientist at the International Maize and Wheat Improvement Center in Mexico City, said that CRISPR is important to plant breeding not only because its powerful, but because its relatively cheap. Even small labs can create disease-resistant cassavas or drought-resistant bananas, which could benefit poor nations but would not interest companies looking for hefty financial returns.

Because of CRISPRs use for so many different industries, its patent has been the subject of a long-running dispute. Groups led by the Broad Institute and the University of California both filed patents for the original version of gene editing based on CRISPR-Cas9 in living cells. The Broad Institute won a patent in 2014, and the University of California responded with a court challenge.

In February of this year, the U.S. Patent Trial and Appeal Board issued what is most likely the final word on this dispute. They ruled in favor of the Broad Institute.

Jacob Sherkow, an expert on biotech patents at the University of Illinois College of Law, predicted that companies that have licensed the CRISPR technology from the University of California will need to honor the Broad Institute patent.

The big-ticket CRISPR companies, the ones that are farthest along in clinical trials, are almost certainly going to need to write the Broad Institute a really big check, he said.

The original CRISPR system, known as CRISPR-Cas9, leaves plenty of room for improvement. The molecules are good at snipping out DNA, but theyre not as good at inserting new pieces in their place. Sometimes CRISPR-Cas9 misses its target, cutting DNA in the wrong place. And even when the molecules do their jobs correctly, cells can make mistakes as they repair the loose ends of DNA left behind.

A number of scientists have invented new versions of CRISPR that overcome some of these shortcomings. At Harvard, for example, Dr. Liu and his colleagues have used CRISPR to make a nick in one of DNAs two strands, rather than breaking them entirely. This process, known as base editing, lets them precisely change a single genetic letter of DNA with much less risk of genetic damage.

Dr. Liu has co-founded a company called Beam Therapeutics to create base-editing drugs. Later this year, the company will test its first drug on people with sickle cell anemia.

Dr. Liu and his colleagues have also attached CRISPR molecules to a protein that viruses use to insert their genes into their hosts DNA. This new method, called prime editing, could enable CRISPR to alter longer stretches of genetic material.

Prime editors are kind of like DNA word processors, Dr. Liu said. They actually perform a search and replace function on DNA.

Rodolphe Barrangou, a CRISPR expert at North Carolina State University and a founder of Intellia Therapeutics, predicted that prime editing would eventually become a part of the standard CRISPR toolbox. But for now, he said, the technique was still too complex to become widely used. Its not quite ready for prime time, pun intended, he said.

Advances like prime editing didnt yet exist in 2018, when Dr. He set out to edit human embryos in Shenzen. He used the standard CRISPR-Cas9 system that Dr. Doudna and others had developed years before.

Dr. He hoped to endow babies with resistance to H.I.V. by snipping a piece of a gene called CCR5 from the DNA of embryos. People who naturally carry the same mutation rarely get infected by H.I.V.

In November 2018, Dr. He announced that a pair of twin girlshad been born with his gene edits. The announcement took many scientists like Dr. Doudna by surprise, and they roundly condemned him for putting the health of the babies in jeopardy with untested procedures.

Dr. Baylis of Dalhousie University criticized Dr. He for the way he reportedly presented the procedure to the parents, downplaying the radical experiment they were about to undertake. You could not get an informed consent, unless you were saying, This is pie in the sky. Nobodys ever done it, she said.

In the nearly four years since Dr. Hes announcement, scientists have continued to use CRISPR on human embryos. But they have studied embryos only when theyre tiny clumps of cells to find clues about the earliest stages of development. These studies could potentially lead to new treatments for infertility.

Bieke Bekaert, a graduate student in reproductive biology at Ghent University in Belgium, said that CRISPR remains challenging to use in human embryos. Breaking DNA in these cells can lead to drastic rearrangements in the chromosomes. Its more difficult than we thought, said Ms. Bekaert, the lead author of a recent review of the subject. We dont really know what is happening.

Still, Ms. Bekaert held out hope that prime editing and other improvements on CRISPR could allow scientists to make reliably precise changes to human embryos. Five years is way too early, but I think in my lifetime it may happen, she said.

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CRISPR, 10 Years On: Learning to Rewrite the Code of Life

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Sergeyis the founder of the Longevity Vision Fund.

getty

As founder of Longevity Vision Fund, I am often asked about the most promising life extension breakthroughs, from early cancer diagnostics to human avatars and everything in between. The simple answer is that there are many but thats probably not the kind of answer you were looking for!

Instead, lets look at the latest longevity breakthroughs working on each of the five major levels of biological organization (cell, tissue, organ, organ system and organism) and what they each aim to accomplish.

1. Cells: Reprogram

Biologists classify cells as the simplest level of organization in a living organism. Aging on a cellular level is often defined as the accumulation of destructive changes caused by changes to gene expression that gradually shift our cells to aged state.

This is why its particularly exciting that a new study demonstrated that it is possible to partially reprogram old cells, allowing them to regain youthful function. Led by a team of researchers including the legendary Dr. David Sinclair, scientists used cellular reprogramming to reinstate youthful function and successfully rejuvenate old cells in the eyes of mice successfully restoring vision in a mouse version of glaucoma.

The process used by the scientists in this study, REVIVER (which stands for "recovery of information via epigenetic reprogramming"), has shown that old tissues can "keep" a record of youthful epigenetic information that can be accessed for functional age reversal.

2. Tissue: Regenerate

Numerous cells working together toward one common goal are called tissue. Tissue and organ regeneration company LyGenesis has shown that it can regrow functioning ectopic organs in a patients lymph nodes using cellular therapy.

LyGenesis co-founder Dr. Eric Lagasse first demonstrated that allogeneic hepatocytes, injected into lymph nodes of mice with diseased livers, would regenerate and take over normal liver functions. The study was also conducted in larger mammals with equally impressive results: Liver tissue grown in pigs lymph nodes could treat genetic liver diseases. Dr. Lagasse and his team believe this method could ultimately help people with various liver diseases, including end-stage liver disease (ESLD) with clinical trials in humans set to begin later in 2021.

With almost 114,000 people in the United States on the waiting list for an organ transplant, LyGenesis could relieve suffering for many. Instead of one donor organ treating one patient, LyGenesis could allow tissue from one donor organ to treat many patients. The company, whose investors include Juvenescence and my organization, Longevity Vision Fund, also has plans for kidney, pancreas and thymus regeneration. LyGenesis achievements are a crucial step toward whole organ regeneration that could, along with other upcoming technologies, allow us to live to 200 (or at least beyond the commonly accepted maximum of 120 years).

3. Organ: Rewire

The brain is the body's most complex organ, with an impressive 86 billion neurons in the human brain (all of which are in use). Neuralink, a company founded by Elon Musk, wants to make it even more functional.

The company is developing a brain-computer interface that will potentially give us the ability to control computers and smartphones with our minds! Neuralink has already demonstrated that it can record a rats brain activity via thousands of tiny electrodes implanted in its brain. Musk has also unveiled a pig with a coin-sized computer chip, which he described kind of like a Fitbit in your skull with tiny wires."

While a Fitbit in your skull may seem fun but hardly essential, imagine what the company could do for patients with severe age-related neurological conditions, such as dementia or Parkinsons. Neuralink is preparing for human trials and, if successful, first plans to use their devices to help paraplegics with tasks such as making mouse clicks on a computer.

4. Organ System: Reverse (The Epigenetic Clock)

An organ system is a group of organs working together to perform one or more biological functions. Our bodies are made up of 11 basic organ systems that include the nervous system, cardiovascular system and more.

Dr. Greg Fahyhas shown (for the first time in humans!) that it may be possible to reverse biological age. Participants in the trial reduced their biological age by two and a half years (on average) after one year of treatment. In addition to the reduction in biological age, the participants also showed signs of immune system rejuvenation.

The reduction in the biological age was measured by world-renowned scientist Steve Hovarths epigenetic clock. This clock works by analyzing gene expression alterations (that change throughout our lifespan in a predictable manner) to estimate a persons biological age.

5. Organism: Rewrite

We are entering an era where discovery of diseases is more often conducted at the genome level and where a growing number of studies are finding overlap between "common" and "rare" human diseases, further enhancing our understanding of the ways in which they develop. So, wouldnt it be nice if we could find a "cure for all and any diseases"and be done with it already?

It looks like we are close. Prime editing (a new generation of genome editing) can, in principle, put 89% of human diseases in purview. Prime editing may allow researchers to edit more types of genetic mutations than current "state of the art" CRISPR. Since prime editing doesnt rely on the ability of cells to divide to help make the desired changes in the DNA (unlike CRISPR), it could be used to correct genetic mutations in cells that often don't divide such as those in the nervous system. This could provide a cure for a number of previously untreatable diseases, such as Parkinson's and Huntington's.

The search for a single cause and, therefore, cure for aging has been replaced with the view that it is a highly complex and multifactorial process. Therefore, the longevity breakthroughs listed above are complementary to (rather than in competition with) each other in our quest to put an end to age-related diseases.

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Will You Live To 200? Five Levels Of Breakthroughs In ...

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Best EGF Serum (Epidermal Growth Factor Serum) In 2023: Discover the Ultimate In Skin Rejuvenation  Outlook India

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Best EGF Serum (Epidermal Growth Factor Serum) In 2023: Discover the Ultimate In Skin Rejuvenation - Outlook India

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From Wikipedia, the free encyclopedia

Human and pet preservation by freezing

Cryonics Institute (CI) is an American nonprofit foundation that provides cryonics services. CI freezes deceased humans and pets in liquid nitrogen with the hope of restoring them with technology in the future.[1][2]

The Cryonics Institute was founded by the Father of Cryonics Robert Ettinger on April 4, 1976, in Detroit, Michigan, where he served as president until 2003. Ettinger introduced the concept of cryonics with the publication of his book The Prospect of Immortality published in 1962.[3][4][5] Operations moved to Clinton Township, Michigan in 1993,[6] where it is currently located.

The cryonics procedure performed by the Cryonics Institute begins with a process called vitrification where the body is perfused with cryoprotective agents to protect against damage in the freezing process. After this, the body is cooled to -196C over the course of a day or two days in a computer-controlled chamber before being placed in a long-term storage container filled with liquid nitrogen. The Cryonics Institute utilizes storage units called cryostats, and each unit contains up to eight people.[citation needed] The process can take place only once the person has been declared legally dead. Ideally, the process begins within two minutes of the heart stopping and no more than 15.[7][8][9]

The Cryonics Institute also specializes in Human Cryostasis, DNA/Tissue Freezing, Pet Cryopreservation, and Memorabilia Storage.[10][11]

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Cryonics Institute - Wikipedia

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