Rewriting the Blueprint
Gene editing for improved agriculture, healthcare, and beyond.
Healthcare
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Disease Treatment/Cure
Gene therapies, especially those involving CRISPR and TALENs have been highly regarded for their abilities to identify target genes, as well as genes that can potentially be resistant to drugs. These ground-breaking biotechnological advancements equip scientists with the tools to find solutions to the world’s ailments.
CRISPR
The exciting new genome-editing tool, CRISPR, specifically its Cas9 domain, has been widely used by many companies and has been found to potentially have the ability to cure several diseases, previously thought to be incurable! Below are just some of the many disorders and ailments that CRISPR has the potential to treat, some of which are projected to enter clinical trials soon.
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Cancer: Hangzhou Cancer Hospitals have extracted T-cells from a variety of cancer patients to be modified by CRISPR to remove genes that code for the protein PD-1, which tumor cells can attach to. This reorders the cell to not attack cancer cells. Clinical trials have proven that at least 86 cancer patients have been treated with CRISPR in China alone.
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AIDS: Scientists are looking into CRISPR to cut the infectious portions of HIV in immune cells of those afflicted with the disease. More recently, a scientist in China has been under the scrutiny of the bioethics community for using this technology to create HIV-resistant human embryos. This approach utilizes CRISPR to insert a helpful mutation in the CCR5 gene that alters a surface protein on immune cells to make individuals resistant to HIV.
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Muscular Dystrophy: Duchenne’s muscular dystrophy, a disease that causes muscle degeneration, caused by a mutation of the DMD gene has been studied in mice. CRISPR has been used to target multiple mutation “hotspots” to take care of the ~3,000 mutations that can cause the disease. Exonics Therapeutics and Editas Medicine have been working on ways to bring these treatments to humans.
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Huntington’s Disease: This disease is caused by a mutation in which a series of repeats of DNA causes a mutation in the huntingtin gene. This gene codes for the toxic huntingtin protein, and when a patient suffers from this mutation, it causes severe neurodegeneration. Since many potentially dangerous side effects can result from CRISPR activity on non-target sites, scientists at The Institute of Bioorganic Chemistry in Poland have recently been designing a new safer method of treating Huntington’s with a modified version of CRISPR that acts as a nickase--an enzyme that cuts a single DNA strand rather than creating a double-stranded break. This helps to increase precision to make the treatment safer.
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“‘We demonstrated that excision of the repeat tract with the use of a Cas9 nickase pair resulted in inactivation of the huntingtin gene and abrogation of toxic protein synthesis in cellular models of Huntington’s disease,’ says Dr. Olejniczak [at The Institute of Bioorganic Chemistry in Poland]. ‘Our strategy is safe and efficient, and no sequence-specific side effects were observed.’” (AC.2)
Huntington's Disease:
Of the many diseases that can be cured by CRISPR!
Therapeutic Drugs
CRISPR can be used to perform gene-knockouts and inactivate certain portions of the genome that code for harmful proteins such as those that form cancerous tumors. This method is known as a 'genome-wide screen.' By utilizing CRISPR in test animals, such as mice, they can deactivate all genes found in tumors to identify which are the cause. From there, researchers can use this knowledge to engineer drugs that can eliminate harmful proteins as a form of cancer treatment. However, this is only half the battle as proteins’ various domains (specific regions that serve different functions--some more crucial than others) make it difficult to determine whether or not a certain drug will be effective or not. Once more, CRISPR is used to better understand proteins and which parts are most critical for function--researchers engineer drugs to locate and target the most critical domains to effectively treat conditions such as cancer.
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Drug testing proves to be an issue: most drugs are tested on animal models, such as mice before they reach human clinical trials. As most genetic conditions are caused by multiple genes, and previous methods could only introduce single mutations into a test animal at a time, scientists have used CRISPR systems to introduce multiple mutations at a time. This has not only created animal models that more closely resemble human systems but has also lowered the cost and time it takes to modify the test animals
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CRISPR scanning is yet another method used in genetically engineered drug manufacturing: while commonly used to perform a DSB followed by insertion of a modified gene, scientists allow the cell’s natural systems to repair the break, creating a genetic mutation and DNA 'scar'. This mutation, of course, alters the protein formation. So, by introducing a variety of manipulations, scientists can study the effects on proteins and use them to understand which are the most important domains, thus increasing drug-efficacy.
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CRISPR suppressor-scanning can also be used. This is similar to the procedure above, only this time, the scanning is done when prospective drugs are present. Having these potential medicines present allows drug manufacturers to observe which domains are affected--whether that be positively or negatively. Identifying which domains the drug is advantageous in (for example, regions where it is successful in killing cancer cells) and those in which they are counter-productive in (for instance, regions where the drug helps the tumor grow; drug-resistant domains) is immensely useful in designing and determining which drug is the most efficient in treating a particular disease.
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Drug testing proves to be an issue: most drugs are tested on animal models, such as mice before they reach human clinical trials. As most genetic conditions are caused by multiple genes, and previous methods could only introduce single mutations into a test animal at a time, scientists have used CRISPR systems to introduce multiple mutations at a time. This has not only created animal models that more closely resemble human systems but has also lowered the cost and time it takes to modify the test animals.
Safe, efficient drugs for the modern world!
One day you could be treated with drugs made with gene therapy!
Revolutionary healthcare in the works!
While CRISPR receives most of the publicity in the biomedical field, TALENs is also an up-and-coming tool that holds much potential to save millions of lives. TALENs can cure many of the same diseases as CRISPR, however, sickle cell disease is of the most prominent. Diseases like cystic fibrosis are also being looked into to treat via TALENs editing.
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TALENs
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Sickle Cell Disease: TALENs effectiveness to treat SCD has been tested numerous times, notably with induced pluripotent stem cells (iPSCs) humans. These studies have not been conducted on human stem cells, and therefore, scientists can not be so quick to begin human trials. While TALENs have only been seen to correct one allele, it is still therapeutically adequate for potential patients as heterozygotes (those possessing one copy of each allele--dominant and recessive) with HbA (normal hemoglobin structure) and HbS (sickled hemoglobin structure) would express no symptoms. Additionally, trials have found few chances of off-site mutations in regions similar to the HBB locus. As of 2016, these technologies have only been tested on iPSCs, not yet on those of humans, however, it is undoubtedly on the horizon for future studies. All in all, however, after these series of different trials, scientists have proven TALENs to be an efficient tool for SCD therapy in the near future.
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Cystic Fibrosis: Cystic fibrosis is a chronic disease--caused by mutated portions of the CF transmembrane conductance regulator (CFTR) gene--in which abnormal amounts of mucus are produced in the lungs and air canals, thus causing respiratory problems. To sufficiently treat this condition, scientists must not only correct the mutation but also repair damaged tissue. Researchers hope to use iPSCs, derived from CF patients to repair the damaged epithelial cell airways. TALENs have been chosen in this study over CRISPR-Cas9 systems since TALENs function in pairs--meaning that two systems are required to perform a DSB--increases specificity and reduces the off-site side effects of the DSB. This is crucial for CF specifically since while there are more than 2,000 possible mutations of the CFTR gene, the most common one is a very specific deletion of the CTT trinucleotide. TALENs-injected iPSCs can serve as a treatment for those with CF, by correcting the CFTR gene and repairing damaged airways.
TALENs is known for having high success rates in human cells since it requires two systems (heterodimers) for a double-stranded break rather than a single one as in CRISPR, thus making TALENs more precise.
Reproductive Health
With genome editing tools quickly developing, comes the opening of several doors to revolutionize healthcare. While the above section outlines treatments for disease, these technologies can also be used to prevent them before they even occur. However, this brings up several ethical concerns: Can parents now design their babies in a science-fiction version of Build-a-Bear®? One disease may be prevented, but does it increase the susceptibility of other diseases in these infants? Nonetheless, the possibilities for genome editing for reproduction and infertility are astonishing. Read, watch, and explore to see how scientists are venturing to uncharted areas of reproductive solutions.
Disease Prevention: At the Weill Cornell's Center for Reproductive Medicine, scientists are working with CRISPR in hopes of editing and correcting mutations in the BRCA2 gene in sperm which have been known to cause ovarian, breast, and prostate cancers. Not only has ethical scrutiny posed as an inhibition to the process, so has the structure of the sperm themselves: since the DNA is concentrated in its head, it is immensely difficult to insert the CRISPR system. To combat this, scientists have been looking into electroporation to hopefully “shock” the sperm into “loosen[ing] up” momentarily to inject CRISPR.
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Infertility: Disease prevention is not the only reproductive health solution scientists have been dabbling in with CRISPR: scientists at the University of Washington have been utilizing this tool to solve the mysteries behind infertility. Many women are unable to maintain a pregnancy due to the fact that their zygotes (fertilized eggs) never embed themselves into the uterus, and thus never reach post-implantation development. Why? Well, scientists have used CRISPR to screen the possible genes responsible. They were able to find that folliculin (FLCN) is a gene that serves no direct developmental function, but, when absent, prevents the zygote’s cells from maturing past their pluripotent state and thus inhibits it from being implanted. It was found that the Wnt cell signal pathway responsible for fetal development inhibited cells with the “knocked-out” FLCN gene from reaching the post-implantation stage. By turning off this signal pathway, researchers were able to restore the zygote’s ability to progress into post-implantation development. Additionally, those with mutations in their FLCN gene can affect the TFE3 transcription factor which regulates protein formation. Researchers have concluded that
"the activation of the Wnt pathways by TFE3 in the embryonic cells missing the FLCN gene prevents the cells from leaving the preimplantation state”
Genome Editing and ARTs for Healthier Babies!
When used in combination with assisted reproductive technologies (ART), genome editing tools and methods such as CRISPR can be used to help sort for the most viable sperm so expectant parents can feel reassured knowing that their babies will be happy and healthy. Of the many ARTs include IVF (in-vitro fertilization), which is where donor sperm and egg are joined in a laboratory and safely injected into expectant mothers when either parent is infertile/incapable of natural conception. Pre-implantation genetic diagnosis (PGD) can also be performed by companies such as MicroSort ® to ensure that sperm are disease-free.
(AC.11)
Animals
Mosquitoes: Geneticists at the Imperial College of London have been experimenting with gene drives in mosquitoes to be resistant to the malaria parasite. Not limited to eradicating vector (animal or insect)-borne diseases, gene drives can also be used to revert insecticide susceptibility. As mentioned above, mutations within the organism’s genome pose as pitfalls to gene drive outcomes. There are ways to cheat this system however, as Andrea Crisanti and Tony Nolan of Target Malaria discovered after targeting the double-sex fertility gene in Anopheles gambiae mosquitoes to successfully prevent females (only females bite and transmit disease) from laying eggs within 8-12 generations. How could this gene have been spared from mutation? Well, it is one of many genes classified as “highly conserved”: any disruption of its function could yield fatal consequences for the organism. Since this reduces the likelihood of a mutation, these genes are most favorable for successful gene drives.
Rather than eliminating entire populations, scientists have also been experimenting with ways of equipping mosquitoes with disease-preventative gene drives. For instance, scientists at UCSD have been “engineer[ing] Aedes aegypti mosquitoes to express an antibody that protected the insects against all four major strains of dengue.” Additionally, the team has been working on “building an all-purpose gene drive that activates a toxin when any virus[...] infects” the mosquito. From there, whenever a mosquito is infected with a disease like dengue, yellow fever, etc. it will die before it can infect humans.
Gene Drives: Gene drives are methods of inserting or deleting genes with CRISPR to propagate through populations faster than at a typical inheritance rate. The modified “drive” is copied in its entirety onto the partner DNA in order to completely eliminate the naturally occurring gene.
“Funding most of that effort is the US Defense Advanced Research Projects Agency (DARPA), the research arm of the US Department of Defense. In 2017, DARPA’s Safe Genes programme announced it was spending $65 million across seven US research teams studying how to control, counter and reverse gene drives.”
Rodents: Mice have been used all throughout gene editing adventures, typically in the laboratory setting for animal testing, but scientists have recently been examining ways to edit the rats themselves. The Genetic Biocontrol of Invasive Rodents (GBIRd) program aims to use gene drives in rodents on various islands as an alternative to pesticides. These rats disturb the existing wildlife, and traditional pesticides can only be used on approximately 15% of islands--islands with large human populations make regular pesticide use less conducive.
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Dogs: Biomedical researcher David Ishee has been utilizing CRISPR systems to edit dogs to be free of diseases common in certain breeds. For centuries, dogs have been born as a result of selective breeding for desirable traits, however, the processes have yielded gradual evolutionary changes that can take decades to show. One disease he has tried to rid in canines is hyperuricemia, a condition in which the SLC2A9 gene is mutated causing excessive uric acid in the blood which can cause bladder stone formation and even rupture.
Although these edits come at a hefty price, “reaching 6 figures per animal,” Ishee argues that using CRISPR systems is much more efficient. Additionally, he points out that gene editing and selective breeding with CRISPR are ethically one and the same (AC.13).
With genetic diversity quickly declining, dogs are being plagued by an ever-growing disease pool. To accommodate, CRISPR and other technologies must be used to increase genetic diversity at a quicker, more immediate rate than traditional breeding.
The question lies…
Does this mean we will one day be able to design our own dogs beyond health?
Mosquitoes
Mosquitoes
Learn more about mosquito control projects here.
Rodents
Rodents
Explore more about rodent-borne disease control here.
Dogs
Dogs
See how some scientists in China are designing dogs to be extra muscular here.
Agriculture
Food of the Future
The earliest forms of genetically modified crops have been those that are selectively cross-bred to produce the tastiest and plumpest fruit. Truly the goal has remained constant throughout history, only, technologies have made monumental strides forward, making the process more precise and timely. Here are just some of the many ways genome editing has helped to feed the world through more nutritious and efficient food supplies. Refer to the chart below for further exploration!
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Rice: One major development in agricultural genome editing is Golden Rice. The boosted commodity has been engineered to provide immense health benefits for those in developing countries. The Golden Rice Project inserts two genes into traditional rice: “plant phytoene synthase (PSY) and bacterial phytoene desaturase (CRT I)” to induce beta-carotene production during photosynthesis. This is crucial for struggling nations as many of these countries suffer from a condition known as vitamin-A deficiency (VAD) which can cause blindness and other vision issues. Beta-carotene, a nutrient found in foods like carrots, is converted into this essential vitamin. With Golden Rice, not only will these nations’ children have full tummies, but they will also go on to live happy and healthy lives!
Delicious & nutritious!
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Corn: For many years, growers have needed to protect their bounties, but with many environmentally toxic insecticides and pesticides, new solutions have been imagined. One example is Bacillus thuringiensis (Bt) corn. Rather than spraying crops down with harsh chemicals that can run off and pollute the environment, many farmers have inserted a gene from the bacterium Bacillus thuringiensis to produce the protein Bt delta-endotoxin to kill feeding Lepidoptera larvae caterpillars like the European corn borer. When eaten by the pests, “the protein binds to the gut wall and the insect stops feeding,” eventually causing the intestinal walls to deteriorate, killing the caterpillar.
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Peanuts: Millions of people suffer from deadly nut allergies, specifically, peanuts. Exposure to even the nimblest trace of this nut can trigger a fatal reaction called anaphylactic shock that, when left untreated for even just a few minutes, can be deadly. So how does this correlate to gene editing? One day scientists can probably use CRISPR or TALENs to reverse this gene in humans, but recently, they have been conducting research on how they can remove the allergic-reaction inducing portion from the peanut entirely. How? Well, as with any other crop, scientists are looking to use CRISPR to knock out specific genes--in this case, those that code for the most common reaction-triggering allergens. This is a hefty task however since peanut allergies are multi-variant and have many contributing genes. Additionally, knocking out too many genes may cause these nuts' nutrient contents to deteriorate. An “allergy-free” peanut is extremely unlikely, however, it is probable that allergy-friendly peanuts may hit markets in the near future so everyone can enjoy PB & J’s safely.
