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How CRISPR Is Revolutionising Drug Discovery And Medicine

The science behind CRISPR is both fascinating and controversial. A powerful biotechnology tool that gives scientists unprecedented access to the genetic makeup of all living organisms including humans, it originally evolved as an adaptive immune system in bacteria to defend against viruses. When harnessed in the laboratory, however, it allows scientists to edit genes with remarkable accuracy, almost like a pair of scissors that can cut through DNA strands. The technology has already been used to treat diabetes and muscular dystrophy in mice, and in 2020 was used on humans for the first time in a landmark clinical trial to treat a rare condition that causes blindness. It’s easy to see, then, why the medical and scientific community are fascinated by the potential that CRISPR technology has to revolutionise the drug discovery process, and herald a whole new era for human health.  How does CRISPR work? CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats. These ‘repeats’ are located within bacteria’s DNA, and are actual copies of small pieces of viruses. Bacteria use these copies to identify harmful viruses, and send out the Cas9 enzyme in response to chop them up, mitigating the threat. Having studied this process in depth, researchers in the lab are using a similar approach to turn the microbe’s virus-fighting system into a scientific tool that can quickly and efficiently tweak almost any gene in any plant or animal. Although CRISPR is not the first method available to scientists to alter DNA, it is by far the easiest to use, slashing research time as well as costs. CRISPR is also completely customisable; it can edit virtually any segment of DNA within the 3 billion letters of the human genome with a high degree of accuracy. How can CRISPR impact drug discovery and development? The route to market for any drug is long, costly, and uncertain. In the US, the testing and discovery of any new medication takes more than a decade, with an associated cost that could be upwards of $1 billion. Added to this, the chances of a new drug reaching market is only one in 5,000. This is because all new drugs need to generate satisfactory safety and efficacy data, as well as meet various criteria to be granted marketing authorisation. In the UK, this process is even more complex; drug companies need the National Institute of Health and Care Excellence to recommend that their medication should be available on the NHS, which involves yet another round of cost-benefit analyses that sees many medications rejected at the final hurdle. All of this can be very frustrating for researchers, as well as patients suffering from conditions difficult to treat with standard therapeutics. Another complication for medical researchers is that diseases which arise from genetic mutations, such as cancer and cystic fibrosis, are notoriously difficult to treat. CRISPR, however, is beginning to herald a new era in which future drugs may become safer, cheaper, and drastically more effective. Here are some of the ways this technology is making an impact. Exploring the genetic basis for poorly understood diseases  For decades, scientists considered the 98% of our DNA that does not encode for proteins to be inconsequential for drug development. However, we’re increasingly beginning to realise that this so-called ‘dark matter of the genome’ may be more important than previously thought, and actually possess regulatory functions that contribute to disease. Identifying singular, rare mutations that cause devastating genetic conditions such as muscular dystrophy has proved relatively straightforward for scientists, but when it comes to understanding diseases that merely carry a genetically inherited risk with a possible environmental trigger, the story is much more complicated – and this dark matter may hold the key to our understanding. A research team at Duke University are currently exploring this concept by utilising the CRISPR/Cas9 tool to explore the previously poorly understood 98% of the human genome to map out and understand the role it may play in disease development, thus paving the way for treatments that target parts of this genetic material. Helping to make drugs safer Establishing the safety and efficacy of any drug involves a great deal of testing. For ethical reasons, however, initial testing not performed on people. Instead, prior to clinical trials, scientists try to mimic the impact of drugs on crucial tissues, such as the liver and heart, by testing in cell lines and animal models, ensuring that only drugs that pass these tests are escalated to trials in human patients. However, sometimes drugs will show promise when tested on monkeys or mice - as well as in human clinical trials consisting of a few thousand people - yet fail to work as effectively or even cause harmful side effects when used widely. One example of this is the anti-inflammatory drug given the brand name Vioxx, which unfortunately caused thousands of heart attacks despite having previously seemed extremely safe in animal as well as human trials. CRISPR technologies eliminate this issue by enabling researchers to build much more sophisticated cellular models that will more accurately reflect how humans will respond to a new medication. For example, it’s crucial to study how cells absorb, distribute, metabolise and excrete drugs, and part of this work includes identifying the metabolic enzymes of receptors responsible for these actions. This feat can be achieved by generating ‘genetic knockouts’ of enzymes and receptors, something CRISPR technology is optimised for.  Improving existing therapies Certain treatments, such as those targeted towards certain forms of cancer, already rely on therapies involving genetic modification. One example of this is CAR-T therapy, which a complex type of immunotherapy sometimes used to treat leukaemia and lymphoma. This type of therapy genetically engineers certain cells to express a receptor that recognises, targets, and destroys cancer. Essentially, CAR-T therapy gives the body a helping hand by making T cells perform their job more effectively. However, generating the required cells using standard genome engineering technologies can be cumbersome and complicated, not to mention costly. CRISPR has enabled researchers to engineer long CAR sequences more efficiently, and has also been proven to boost safety and efficacy. It has also provided the ability to generate multiple gene edits in T cells, a feat that has historically been challenging. Aside from CAR-T, researchers believe that CRISPR could hold the key to developing other effective treatments for cancer, too. The technique is already enabling scientists to gain a deeper understanding of how the disease metastasises, currently a critical gap in knowledge that limits the treatment options available for patients at the advanced stages of the disease.  What does the future hold for CRISPR in medicine? Clinical trials are currently underway using CRISPR to treat a whole range of diseases, from rare and devastating disorders such as transthyretin amyloidosis, to more common conditions such as sickle cell anaemia, which impacts one in every 2000 live births in England. Despite its vast therapeutic potential, however, it’s important to bear in mind that the technology does have its limitations. Although it’s useful for deleting problematic genes, it's less effective at replacing them, meaning that only certain inherited conditions can be treated this way. In addition, scientists still have other issues to iron out, such as the potential for unintended consequences known as ‘off-target’ modifications; mutations that are simultaneously created elsewhere in the genome that may have unknown implications. In the summer of 2018 three papers were published raising concerns about such off-target effects, which noted that cells which had successfully been edited using CRISPR turned out to have a defective p53 gene, which may have the potential to cause cancer. Although such unforeseen consequences may be worth it for patients suffering from life-threatening conditions, the impact of such treatments for patients with less serious disorders falls within a much greyer area of medical ethics. In addition, controversies still surround other potential applications of CRISPR technology. Critics worry that the technique could one day be used to enhance normal human traits such as appearance or athletic ability, for example. In 2018, further ethical questions were raised when rogue Chinese researcher He Jianku claimed to have implanted CRISPR-Cas9 gene edited embryos into six women, resulting in at least one successful twin pregnancy, leaping precariously into an era in which science could rewrite the gene pool of future generations. It’s clear, then, that as science discovers incredible new ways to take control of its own evolution, humanity must also learn to wield such power with reason, responsibility, and restraint.   Our Pharma Partners team are experts in life science recruitment, and specialise in pharmaceutical physicians, medical affairs, R&D, and the pharmacovigilance space. You can take a look at all our roles here, or get in touch with us for a confidential discussion.