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Genome editing (also called gene editing) is a group of technologies that give scientists the ability to change an organism’s DNA. These technologies allow genetic material to be added, removed, or altered at particular locations in the genome. Several approaches to genome editing have been developed.
CRISPR is a technology that can be used to edit genes and, as such, will likely change the world. The essence of CRISPR is simple: it’s a way of finding a specific bit of DNA inside a cell. After that, the next step in CRISPR gene editing is usually to alter that piece of DNA. However, CRISPR has also been adapted to do other things too, such as turning genes on or off without altering their sequence.
CRISPR-Cas9, which is short for clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9. The CRISPR-Cas9 system has generated a lot of excitement in the scientific community because it is faster, cheaper, more accurate, and more efficient than other existing genome editing methods.
CRISPR is an acronym for Clustered Regularly Interspaced Short Palindromic Repeat. CRISPR-Cas9 was adapted from a naturally occurring genome editing system in bacteria. The bacteria capture snippets of DNA from invading viruses and use them to create DNA segments known as CRISPR arrays. The CRISPR arrays allow the bacteria to “remember” the viruses (or closely related ones). If the viruses attack again, the bacteria produce RNA segments from the CRISPR arrays to target the viruses’ DNA. The bacteria then use Cas9 or a similar enzyme to cut the DNA apart, which disables the virus. Thus, by destroying the viral genome, the CRISPR immune system protects bacteria from ongoing viral infection.
The CRISPR-Cas9 system works similarly in the lab. Researchers create a small piece of RNA with a short “guide” sequence that attaches (binds) to a specific target sequence of DNA in a genome. The RNA also binds to the Cas9 enzyme. As in bacteria, the modified RNA is used to recognize the DNA sequence, and the Cas9 enzyme cuts the DNA at the targeted location. Although Cas9 is the enzyme that is used most often, other enzymes (for example Cpf1) can also be used. Once the DNA is cut, researchers use the cell’s own DNA repair machinery to add or delete pieces of genetic material, or to make changes to the DNA by replacing an existing segment with a customized DNA sequence.
CRISPRs are specialized stretches of DNA. Crispr-Cas9 is best thought of as two technologies that make gene editing possible: The protein Cas9 (or “CRISPR-associated”) is an enzyme that acts like a pair of molecular scissors, capable of cutting strands of DNA, removing faulty genetic material and creating space for functioning genes to be inserted. Crispr is a kind of genetic GPS that guides those scissors to the precise location.
Genome editing is of great interest in the prevention and treatment of human diseases. Currently, most research on genome editing is done to understand diseases using cells and animal models. Scientists are still working to determine whether this approach is safe and effective for use in people. It is being explored in research on a wide variety of diseases, including single-gene disorders such as cystic fibrosis, hemophilia, and sickle cell disease. It also holds promise for the treatment and prevention of more complex diseases, such as cancer, heart disease, mental illness, and human immunodeficiency virus (HIV) infection.
CRISPER Applications
There were ways to edit the genomes of some plants and animals before the CRISPR method was unveiled in 2012 but it took years and cost hundreds of thousands of dollars. Compared to previous techniques for modifying DNA, this new approach is much faster, easier and cheaper. This has to its wide adoption among research labs worldwide within only a few years, for making specific changes in the DNA of humans, other animals, and plants. CRISPR allows removing a single (defective) gene from a genome and replacing it with another one, to prevent genetic diseases. Scientists have learned how to harness CRISPR technology in the lab to make precise changes in the genes of organisms as diverse as fruit flies, fish, mice, plants and even human cells.
Today, CRISPR Cas9 is widely used to knock out genes in animal models to study their function, give crops new agronomic traits including pesticide-resistance , synthesize microbes that produce drugs, create gene therapies to treat disease, and to genetically correct heritable diseases in human embryos. Jennifer Doudna, one of the pioneers of the gene-editing technique known as CRISPR, thinks the biotech tool could be an essential one for combating COVID-19 and future pandemics. Due to its capacity to be “reprogrammed” like software, CRISPR could eventually be integral to countless tests and treatments. In an interview at Disrupt 2020, Doudna was all optimism for the technique, which has already proven to be extremely useful in less immediately applicable situations.
CRISPR “has transformed labs around the world,” says Jing-Ruey Joanna Yeh, a chemical biologist at Massachusetts General Hospital’s Cardiovascular Research Center, in Charlestown, who contributed to the development of the technology. “Because this system is so simple and efficient, any lab can do it.” Editing with CRISPR is like placing a cursor between two letters in a word processing document and hitting “delete” or clicking “paste.” And the tool can cost less than US $50 to assemble.
Genome editing Race
In 2016, a Chinese group has become the first to inject a person with cells that contain genes edited using the revolutionary CRISPR–Cas9 technique. Earlier Scientists of Chinese Kunming Biomedical International and its affiliated Yunnan Key Laboratory of Primate Biomedical Research used CRISPR to create a pair of macaque monkeys with precise genetic mutations. Chinese scientists say they were among the first in using Crispr to make wheat resistant to a common fungal disease, dogs more muscular and pigs with leaner meat.
On 28 October, a team led by oncologist Lu You at Sichuan University in Chengdu delivered the modified cells into a patient with aggressive lung cancer as part of a clinical trial at the West China Hospital, also in Chengdu. Lu’s team extracted immune cells called T cells from the blood of the enrolled patients, and then disabled a gene in them using CRISPR–Cas9, which combines a DNA-cutting enzyme with a molecular guide that can be programmed to tell the enzyme precisely where to cut.
The disabled gene codes for the protein PD-1, which normally puts the brakes on a cell’s immune response: cancers take advantage of that function to proliferate. Lu’s team then cultured the edited cells, increasing their number, and injected them back into the patient, who has metastatic non-small-cell lung cancer. The hope is that, without PD-1, the edited cells will attack and defeat the cancer.
Normally, a parent organism with a given trait passes that genetic code to offspring about half the time. Recent advances combining the gene-editing tool CRISPR–Cas9 are now making it easier for scientists to modify a genome such that nearly all offspring inherit the desired trait.
China announced it was genetically engineering hyper-muscular SUPER-DOGS.The dogs, which are test tube bred in a lab, have twice the muscle mass of their natural counterparts and are considerably stronger and faster. An army of super-humans has been a staple of science fiction and superhero comics for decades – but the super-dog technology brings it closer to reality. The beagle puppy, one of 27, was genetically engineered by ‘deleting’ a gene called myostatin, giving it double the muscle mass of a normal beagle.
The advance genetic editing technology has been touted as a breakthrough which could herald the dawn of ‘superbreeds’, which could be stronger, faster, better at running and hunting. The Chinese official line is that the dogs could potentially be deployed to frontline service to assist police officers. Dr Lai Liangxue, researcher at Guangzhou institute of biological medicine and health, said: “This is a breakthrough, marking China as only the second country in the world to independently master dog-somatic clone technology, after South Korea.”
In 2020, Scientists in China reported to have successfully used a genome editing technique based on CRISPR-Cas9 to knock down genes relevant to fear memory in the brains of lab rats. The system, developed by a research team from the Neuroscience Research Institute of Peking University, can modify genes found in various cell types, including brain neurons, according to the research published in Science Advances magazine. Yi Ming, one of the paper’s co-authors, told local state media that success could mean new ways to treat pathological memories and the conditions it causes like PTSD, chronic pain, drug addiction and chronic stress. Negative emotions such as fear are essential for human survival, but when such memories can’t be forgotten they can cause pathological diseases, Yi said.
China has had a reputation for moving fast — sometimes too fast — with CRISPR, says Tetsuya Ishii, a bioethicist at Hokkaido University in Sapporo, Japan. Ishii notes that if the clinical trial begins as planned, it would be the latest in a series of firsts for China in the field of CRISPR gene editing, including the first CRISPR-edited human embryos, and the first CRISPR-edited monkeys. “When it comes to gene editing, China goes first,” says Ishii.
The introduction of CRISPR, which is simpler and more efficient than other techniques, will probably accelerate the race to get gene-edited cells into the clinic across the world, says Carl June, who specializes in immunotherapy at the University of Pennsylvania in Philadelphia and led one of the earlier studies. “I think this is going to trigger ‘Sputnik 2.0’, a biomedical duel on progress between China and the United States, which is important since competition usually improves the end product,” he says.
Human Gene Manipulation using CRISPR
The Chinese team, led by He Jiankui of the Southern University of Science and Technology in Shenzhen, claimed it used CRISPR to delete CCR5 from human embryos, some of which were later used to create pregnancies. HIV requires the CCR5 gene to enter human blood cells. Now, new research shows that the same alteration introduced into the girls’ DNA, deletion of a gene called CCR5, not only makes mice smarter but also improves human brain recovery after stroke, and could be linked to greater success in school. News of the first gene-edited babies also inflamed speculation about whether CRISPR technology could one day be used to create super-intelligent humans, perhaps as part of a biotechnology race between the US and China.
Alcino J. Silva, a neurobiologist at the University of California, Los Angeles, uncovered a major new role for the CCR5 gene in memory and the brain’s ability to form new connections. Silva and a large team from the US and Israel say they have new proof that CCR5 acts as a suppressor of memories and synaptic connections. According to their new report, appearing in the journal Cell, people who naturally lack CCR5 recover more quickly from strokes. What’s more, people missing at least one copy of the gene seem to go further in school, suggesting a possible role in everyday intelligence.
Three researchers involved in creating gene-edited babies were sentenced on Monday as China confirmed a third gene-edited child was also born, according to its state news agency. Xinhua reported that researchers He Jiankui, Zhang Renli and Qin Jinzhou were all sentenced for their roles in creating the babies that caused an ethical and international outrage last year. The existence of the first two children, Lulu and Nana, were announced by He in November 2018 at the International Human Genome Editing Summit, but there was no mention of a third child, until recently.
CRISPR has been used to edit animal embryos and adult stem cells, but until Chinese trial, no one has reported using the technique to edit the genome of human embryos due to ethical issues. In UK CRISPR is considered a controversial topic, with doubts that it could result in ‘designer babies’ if exploited.The rise of genetic screenings of human embryos allow scientists to create organisms by design, rather than leave it up to chance. This has also been made simpler by genetic sequencing technology that has expanded humanity’s genetic toolbox dramatically.
While in US an advisory panel of the US National Institutes of Health (NIH) has approved a planned US trial that would also use CRISPR–Cas9-modified cells for the treatment of cancer. The US researchers have said they could start their clinical trial by the end of this year. Chinese team also reported that out of 71 of the embryos used in the CRISPR experiment the technique worked properly on just a fraction of the total, and only small percentage of those managed to relay the new gene properly when they split. They also found that sometimes the procedure wound up splicing the wrong gene segment, which led to inserting new genes in the wrong places—which in normal embryos could lead to a new disease.
The most dramatic possibility raised by the primate work, of course, would be using CRISPR to change the genetic makeup of human embryos during in vitro fertilization. Using Crispr to cure disease “is probably ethical,” said Eric Hendrickson, a professor at the University of Minnesota Medical School, whose research uses Crispr techniques for DNA repair. “To use that technology to make your child run faster or jump higher is uniformly frowned upon. The technology to do that, however, will soon be in place.”
Could it be conceivable that at one point in the future we could increase the average IQ of the population? I would not be a scientist if I said no. The work in mice demonstrates the answer may be yes,” Silva says. “But mice are not people. We simply don’t know what the consequences will be in mucking around. We are not ready for it yet.”
Countries race to develop military applications of gene-editing technology
Gene editing has also potential to be misused by state and non state actors in developing deadlier pathogens. States may revive their old biological weapons programs or start new ones. Gene-editing techniques such as CRISPR could make biological weapons more deadly. Nations could develop novel or modified pathogens that would spread more quickly, infect more people, cause more severe sickness, or resist treatment more fully. Another concern is that gene editing may make it easier to carry out targeted assassinations. Conceivably, a government might edit the genes of a deadly virus so that it would affect only a single target based on his or her genetic code.
CRISPER is also being used in military applications. During the second biennial Department of Defense Lab Day May 18, 2017, One AFRL exhibit, called Military Applications of Gene Editing Technology, highlighted research into how geneticists and medical researchers edit parts of the genome by removing, adding or altering sections of the DNA sequence in order to remove a virus or disease caused by harmful chemical, biological or environmental agents a warfighter may have contact with.
In 2019, Darpa announced that it wishes to explore genetically editing soldiers. The Pentagon’s research agency wants to explore the possibility of editing a soldier’s genetic makeup to protect against chemical and biological attacks. Defense Advanced Research Projects Agency director Steven Walker said in Sep 2019 that he believes gene editing has the potential to be one of the most consequential technological advances for the U.S. military. [To] protect a soldier on the battlefield from chemical weapons and biological weapons by controlling their genome — having the genome produce proteins that would automatically protect the soldier from the inside out,” Walker said during a panel at the Center for Strategic and International Studies. Pentagon scientists are researching gene manipulation to build the soldiers of tomorrow that will be able to run at Olympic speed, and won’t need food or sleep. It will also be possible to trigger the cells of injured soldiers’ bodies to rebuild lost limbs.
A US military agency DARPA is investing $100m in genetic extinction technologies that could wipe out malarial mosquitoes, invasive rodents or other species, emails released under freedom of information rules show. Cutting-edge gene editing tools such as Crispr-Cas9 work by using a synthetic ribonucleic acid (RNA) to cut into DNA strands and then insert, alter or remove targeted traits. These might, for example, distort the sex-ratio of mosquitoes to effectively wipe out malarial populations.
The US is not alone in its military pursuit of genome technology. Russia and China have either stated or been accused of using genomic technology to enhance military capabilities.
US and China are leaders in applications of CRISPER technology. In 2018, using the new editing tool CRISPR Chinese researcher He Jiankui used CRISPR-Cas9 gene editing to alter the DNA of embryos for seven couples in 2018. The Chinese scientific team in 2018 had reportedly altered the genes of two twins Lulu and Nana before birth with the goal to make the girls immune to infection by HIV, the virus that causes AIDS. US Director of National Intelligence John Ratcliffe penned an op-ed in The Wall Street Journal that claims the Chinese government is attempting to enhance the capabilities of soldiers through genetic engineering. It’s not the first time such a claim has been made.
China’s national strategy of military-civil fusion (军民融合, junmin ronghe) has highlighted biology as a priority. It is hardly surprising that the People’s Republic of China (PRC) is looking to leverage synergies among defense, scientific, and commercial developments in biological interdisciplinary (生物交叉, shengwu jiaocha) technologies. Chinese military scientists and strategists have consistently emphasized that biotechnology could become a “new strategic commanding heights of the future Revolution in Military Affairs”
PRC research in CRISPR has rapidly progressed into clinical trials that involve the application of these gene editing techniques to animals and to humans, including because some of the regulatory requirements for medical research in China have been less strict and demanding. Strikingly, PLA medical institutions, particularly the PLA General Hospital and also the Academy of Military Medical Sciences, are involved in five of the trials known to be underway at present.
The UK government recently announced an £800 million, taxpayer-funded Advanced Research and Invention Agency (Aria). The brainchild of the British prime minister’s former chief adviser, Dominic Cummings, and modelled on the US Defense Advanced Research Projects Agency, Darpa, the organisation will focus partly on genomic research.
In Russia, the military is looking to implement genetic passports for its personnel, allowing it to assess genetic predispositions and biomarkers, for example, for stress tolerance. This could help place soldiers in suitable military lines, such as navy, air force and so forth. The genetic project also aims to understand how soldiers respond to stressful situations both physically and mentally.
CRISPR Threats
However, CRISPR is also known to cause gene edits at the wrong place in the genome, which could potentially cause some harmful effects. A notable bioethical problem is the off-target mutations that can cause many undesirable changes in the genome or even lead to fatal diseases. Current information obtained from studies on off-target mutations caused by CRISPR on the genome is very limited. Therefore, the benefit/risk relationship needs to be evaluated carefully.
A suite of experiments that use the gene-editing tool CRISPR–Cas9 to modify human embryos have revealed how the process can make large, unwanted changes to the genome at or near the target site. Previous experiments have revealed that the tool can make ‘off target’ gene mutations far from the target site, but the nearby changes identified in the latest studies can be missed by standard assessment methods. “The on-target effects are more important and would be much more difficult to eliminate,” says Gaétan Burgio, a geneticist at the Australian National University in Canberra.
There is also threat of potential harm to environment. “The dual use nature of altering and eradicating entire populations is as much a threat to peace and food security as it is a threat to ecosystems,” Jim Thomas, a co-director of the ETC group said. “Militarisation of gene drive funding may even contravene the Enmod convention against hostile uses of environmental modification technologies.”
The steep fall in the costs of gene-editing toolkits has created a greater opportunity for hostile or rogue actors to experiment with the technology. This has led to growth of Global Biohackers, a term for biologists who work outside of traditional labs and sell genetic engineering kits. In addition, the possibility that this technology can be used for the production of new biological weapons is frightening. Terrorists could employ them to make Bio weapons or lethal viruses.
DARPA has also invested over US$65 million (£45 million) to improve the safety and accuracy of genome-editing technologies. These include the famous Nobel prize-winning Crispr-Cas molecular scissor – a tool that can edit DNA by cutting and pasting sections of it.
Gene editing to develop new killer Pathogens: the Coming Bioweapons Threat
One of the gene editing risks is the resurgence of state biological weapons programs. Between 1942 and 1969, the United States developed a highly advanced biological weapons program, which was capable of large-scale lethality. American researchers also came to value the flexibility of biological weapons, which could temporarily sicken or disable people rather than kill them. During the Cold War, the Soviets also conceived of a range of strategic and operational uses for biological weapons. In addition to lethal uses, for example, they explored targeting agriculture to damage an enemy’s food stocks, economy, and morale.
Currently, you can buy a DIY CRISPR kit for $165. For the cost of Apple’s new Mac Pro package, 72 people could learn genetic editing at home. The materials needed to develop biological weapons are easy to access and relatively cheap. Many pathogens, such as the one that causes anthrax, don’t need to be developed in a lab; they can be found in nature. And states pursuing biological weapons can readily obtain the necessary equipment, which is the same as what is needed for medical or defense research. Biological weapons also offer deniability: attacks can look like natural outbreaks, and they are difficult to attribute.
But in practice, biological weapons also pose tactical and technical challenges. One is the time lag between exposure and symptoms that allow target populations to protect themselves with vaccines and other countermeasures . Launching a successful large-scale attack is also difficult limiting their utility on a battlefield. And . Unpredictable winds, changing terrain, or incorrect dosage could all lead to failure. According to Carus, the United States and the Soviet Union are the only two countries believed to have overcome such challenges enough to be capable of using aerosol releases to reliably disseminate biological weapons over a large area.
Gene-editing techniques such as CRISPR could make biological weapons more deadly. Nations could develop novel or modified pathogens that would spread more quickly, infect more people, cause more severe sickness, or resist treatment more fully. Equipment needed for wide-area dispersal may become less necessary, for example, if a pathogen can be engineered to spread faster on its own.
In 2016, Bill Gates remarked that “the next epidemic could originate on the computer screen of a terrorist intent on using genetic engineering to create a synthetic version of the smallpox virus”. More recently, in July 2017, John Sotos, of Intel Health & Life Sciences, stated that gene editing research could “open up the potential for bioweapons of unimaginable destructive potential”. An annual worldwide threat assessment report of the US intelligence community in February 2016 argued that the broad availability and low cost of the basic ingredients of technologies like CRISPR makes it particularly concerning.
Another concern is that gene editing may make it easier to carry out targeted assassinations. Conceivably, a government might edit the genes of a deadly virus so that it would affect only a single target based on his or her genetic code. This capability does not yet exist, but it might become possible with time and effort. Nonetheless, as the biosecurity expert Gigi Gronvall has noted, given the prevalence of far easier methods of assassination, states may decide that developing and testing such a weapon is not worth the time, effort, and cost.
Genetic warfare
Vladimir Putin addressed the supposed threat of gene weapons in 2018 during his speech at the annual Valdai Discussion Forum, saying that experiments on rats and dogs in the Republic of Georgia were already underway. Researchers, the president warned, were developing ways to target people in specific ethnic groups, which could trigger a new arms race. “We ought to sit down and work out some common rules in this extremely sensitive area,” he said.
In April 2019, the Russian government approved a federal research-engineering program (FNTP) to advance the country’s study of genetics, allocating 127 billion rubles ($1.7 billion) over the next eight years (111 billion in federal money plus resources from regional governments and extrabudgetary sources). In 2019 and 2020, the program received 19.2 billion rubles ($250.4 million) in federal funding, most of which came from the budgets for existing state programs. This sum represents about 2.7 percent of all federal funding for Russia’s non-military scientific research.
Mikhail Kovalchuk, president of the Kurchatov Institute (Russia’s leading research and development center in the field of nuclear energy) told members of Russia’s Federation Council in 2015. “Let’s say we create something like an artificial cell. This artificial cell, on the one hand, is medically important for diagnostics and targeted drug delivery, but it could also become something harmful. One cell with a genetic code that self-develops is actually a weapon of mass destruction.” Continuing the dark premonition, he warned that “this cell could be configured to destroy” a specific ethnic group.
Experts say Kovalchuk doesn’t understand the science here. “It’s an undeniably elegant concept: you take some unique genome feature (a so-called ‘marker’ found in members of a specific ethnic group but not in other people), and you use it as a target. Then you make a virus that infects only the people carrying this target. It’s a futile idea, however, because these markers simply don’t exist,” insists Oleg Balanovsky, the head of the Genogeography Group at the Vavilov Institute of General Genetics. “Specialists in population genetics once theoretically predicted [ethnic genome markers], but now, having fully mapped the genomes of people from different ethnicities, we’ve confirmed in practice that none of the three billion letters of our genome has the properties of any genetic target,” Balanovsky explained in an essay three years ago.
Biologist Valery Ilyinsky, the founder of the DNA testing company “Genotek,” calls gene weapons “utter absurdity” and “the stuff of science fiction movies.” “It’s impossible to tailor it for one ethnicity — it would be a ‘gun’ that fires at the planet’s entire population,” he explained to Meduza. “A weapon as expensive to develop as it would be pointless to use,” agrees Sergey Musienko, the CEO of “Atlas Biomed Group,” another DNA testing firm.
A related fear is that advances in gene editing could allow scientists to develop biological weapons capable of discriminating among target populations based on ethnic, racial, or other genetically defined characteristics. According to Gronvall, these so-called ethnic weapons would be tricky to design and test, and any target population would likely have considerable overlap with nontarget populations.
The vast majority of states—180 of them—are parties to the 1972 Biological Weapons Convention, which bans the development, stockpiling, acquisition, retention, and production of biological agents for nonpeaceful purposes. Of course, individual terrorists and groups such as the Islamic State, or ISIS, do not feel bound by international norms. Indeed, gene-editing advancements do increase the risk that such actors could use biological weapons. However, apart from CRISPR terrorists would also require biological terrorists to develop techniques for growing and disseminating biological weapons agents, for it to become an effective weapon. This would require additional skills and places CRISPR-based biological weapons beyond the reach of most terrorist groups. At least for the time being, writes James Revill, The Conversation.
Therefore nations require advance biosurveilance programs that can speedily detect and respond to biological attacks. The countermeasures or antidotes should be created faster and delay their spread. New techniques for determining their origin are needed. Such improved capabilities would act as a deterrent by denying perpetrators the devastation they might hope to achieve.
References and resources also include:
https://meduza.io/en/feature/2021/04/14/from-gene-bombs-to-classroom-curriculum
