The new gene editing technology has triggered a huge change in the research field - the new weapon of biology is a double-edged sword
June 11, 2015 Source: Bio Valley
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];Genetics scientist Bruce Conklin of the Gladstone Institute in San Francisco has been trying to find out how DNA mutations affect different human diseases, but the tools used are somewhat cumbersome. When he studies cells from patients, it is difficult to know which sequence is important for the disease and which is just background noise. At the same time, implanting mutations into cells is an expensive and laborious task.
In 2012, he read about a newly published technology called CRISPR. It enables researchers to quickly change the DNA of virtually any organism, including humans. Shortly thereafter, Conklin abandoned the previous method of modeling the disease and switched to the new technology. Currently, his lab is frantically changing genes associated with various heart diseases. "CRISPR is bringing about earth-shaking changes," Conklin said.
This sentiment is widely shared: CRISPR is causing a dramatic change in the field of biomedical research. Unlike other methods of genetic editing, it is cheap, quick, and simple to use, and thus swept the global laboratory. Researchers hope to use it to modulate human genes to eliminate disease, create more life-threatening plants, and eliminate pathogens. “I have experienced two major developments since I started doing research.†Cornell University geneticist John Schimenti said that the gene amplification method, which was revolutionized in the field of genetic engineering after being invented in 1985, PCR Similarly, "CRISPR is affecting life sciences in so many ways."
However, despite the good future of CRISPR, some scientists are concerned that the rapid pace of development in this area has hardly set aside time to address the ethical and safety issues that may arise from similar trials. When the news of scientists using CRISPR to transform human embryos was revealed in April this year, the problem was pushed to the spotlight. Although the embryos they use do not make babies safe to give birth, this report raises heated debate about whether and how to use CRISPR to make hereditary changes in the human genome. At the same time, there are other concerns. For example, some scientists worry that organisms that have undergone genetic editing will disrupt the entire ecosystem.
Initiating a research revolution
Biologists have been using molecular tools to edit genomes for a long time. About 10 years ago, they were excited about an enzyme that was known to be a precise and efficient way to edit genes called zinc finger nucleases. However, James Haber, a molecular biologist at Brandeis University in Massachusetts, said that zinc fingers that cost more than $5,000 to order are not commonly used because they are difficult to genetically engineer and costly. The CRISPR is very different: it relies on an enzyme called Cas9 that directs it to the target DNA using a guided RNA molecule, and then edits the DNA to disrupt the gene or insert the desired sequence. Often, researchers need to order only RNA fragments, and other ingredients are readily available. All costs are only $30. “This makes the technology popular, so everyone is using it.†Haber said it was a huge revolution.
The CRISPR approach is rapidly surpassing zinc finger nucleases and other editing tools. For some researchers, this means giving up technology that has been spent years improving. “I’m depressed,†says Bill Skarnes, a geneticist at the Sanger College Institute at the Welkom Foundation in the UK. “But it’s very exciting.†Skarnes used most of his career in the 1980s. One technique: insert DNA into embryonic stem cells and use these cells to produce transgenic mice. This technology has become the mainstay of the lab, but it is time consuming and very expensive. The time required for CRISPR is small, so Skarnes adopted the technology two years ago.
Researchers have traditionally relied heavily on model organisms such as mice and fruit flies. Currently, CRISPR makes it possible to edit genes in more organisms. For example, in April of this year, researchers at the Whitehead Institute of Biomedical Research in Massachusetts reported that Candida albicans was studied using CRISPR. This is a fungus that is particularly lethal in people with weakened immune systems but has been difficult to manipulate in the laboratory. Jennifer Doudna, a pioneer in CRISPR technology from the University of California at Berkeley, is recording a list of creatures that have been altered by CRISPR. To date, she has nearly 40 entries, including the causative parasite, the trypanosomes, and the yeast used to make biofuels.
However, rapid progress has its own drawbacks. "People don't have time to describe the characteristics of some of the most basic parameters in this system," said Bo Huang, a biophysicist at the University of California, San Francisco. "There is a mentality now that we don't need to understand it as long as it works." How and why it works.†This means that researchers occasionally encounter failures. Huang and his lab struggled for two months, making CRISPR suitable for imaging research. He suspects that there will be less delays if you know more about how to optimize the design of guided RNA.
Widely used
Last year, MIT bioengineer Daniel Anderson and his colleagues used CRISPR to correct a mutation in tyrosinaemia associated with human metabolic diseases in mice. This is the first time that CRISPR has been used to correct pathogenic mutations in adult animals and is a major advancement in the use of this technology for human gene therapy.
In the science and biotechnology circles, the idea that CRISPR can accelerate the development of gene therapy is a major point of excitement. However, while highlighting the potential, Anderson's research also shows how far it is to actually apply the technology. In order to deliver the Cas9 enzyme and its guiding RNA to the target organ, the liver, the research team had to pump a large amount of fluid, which is generally considered to be unsuitable in the human body, into the blood vessels. The trial corrected the pathogenic mutations in only 0.4% of the cells, which was not sufficient to affect many diseases.
In the past two years, some companies have sprung up to develop CRISPR-based gene therapy. Anderson and others say the first clinical trial of such a therapy will take place over the next one to two years. These first trials will outline the application of CRISPR, where the CRISPR component can be directly injected into the eye and other organs, or the cells can be removed from the body and genetically engineered in the laboratory and returned to the body. For example, blood-forming stem cells may be modified for the treatment of diseases such as sickle cell anemia or beta-thalassemia. While the delivery of enzymes and guided RNA to many other organizations will be a greater challenge, researchers hope that one day this technology can be used to address a broader range of genetic diseases.
While Anderson and others are aiming to correct DNA in human cells, some people are turning their attention to crops and livestock. Prior to the advent of gene editing technology, this was often achieved by inserting genes into random locations in the genome, along with genes, sequences derived from bacteria, viruses, or other species that drive gene expression. However, this process is inefficient and always becomes a material that confuses critics who mix DNA from different species or fear that such insertion would disrupt other genes. More importantly, obtaining approval for the use of GM crops is complex and costly, so that genetic corrections are made to large commodity crops such as corn and soybeans.
With CRISPR, the situation will change: fast and low cost may make genetic editing a viable option for smaller special crops and animals. In the past few years, researchers have used this method to genetically engineer small pigs and obtain disease-resistant wheat and rice. They are also making progress in genetically transforming cattle with no horns, disease-resistant goats and vitamin-rich sweet oranges.
Ecosystem is changed
In addition to agriculture, researchers are considering how CRISPR can or should be used in wild animals. Much of the focus is on a method called gene-driven because it quickly spreads the edited gene throughout the population. This work is in its infancy, but similar techniques can be used to eradicate mosquitoes or mites that carry disease, remove invasive plants or eliminate herbicide resistance in ragweed that has afflicted some American farmers.
However, many researchers are very concerned that changing the entire population or removing it all will have unpredictable and catastrophic consequences for the ecosystem: this may mean that other pests will appear or affect predators at higher positions in the food chain. They are also concerned that guided RNA will mutate over time. Subsequently, this mutation will sweep the entire population, with unanticipated effects.
“This approach has to have a fairly high return because it has irreversible hazards and unexpected or hard-to-predict consequences for other species,†said George Church, bioengineer at Harvard Medical School. In April 2014, Church and a team of scientists and policy experts wrote a review article in Science, warning researchers about the risks of accidental leakage driven by experimental genes and suggesting ways to prevent it from happening.
At the time, gene drivers seemed to be a distant prospect. However, less than a year later, development biologist Ethan Bier of the University of California, San Diego, and his student Valentino Gantz reported that they designed a similar system in fruit flies. Bier and Gantz use a three-layer box to house fruit flies and use laboratory safety measures commonly used to study mosquitoes carrying malaria. However, they did not follow all the guidelines that the authors of the above review strongly recommend, such as designing ways to reverse the changes caused by genetic modification. Bier said they are conducting the first principle experiment and wondering if the system will work before it becomes more complex.
For Church and others, this is a clear warning that the popularity of genetic editing through CRISPR can produce unpredictable and undesired results. MIT political scientist Kenneth Oye said: "We need more action." The National Research Council has formed an expert group to explore gene drivers, and other high-level discussions are also underway. However, Oye is concerned that science is moving forward at lightning speed, and that regulatory changes may only occur after a genetically driven leak has received attention.
However, the problem is not black or white. Micky Eubanks, an insect ecologist at Texas A&M University, said that the gene-driven approach initially surprised him. "My initial instinctive reaction was 'My God, it's terrible. It's so frightening,'" Eubanks said, but when you think about it again, and it's the environment that humans have caused and will continue to cause. Changing the trade-offs will reveal that it is only a drop in the ocean.
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