Image: Illustration of the CRISPR/Cas9 DNA complex; the RNA sequence (red) guides Cas9 enzymes (rods) to cut a specified area of the DNA chain (blue).
Developed less than four years ago, CRISPR is a fairly new technology, but excitement surrounding it has facilitated a rush toward clinical application. Scope for CRISPR is huge; theoretically we understand the process of using this efficient and highly precise method to cure relatively simple diseases that involve only single mutations in the genome. The ability to effectively ‘fix’ the ‘broken’ genes that cause diseases such as cystic fibrosis, Huntington’s disease and sickle cell anemia could have life-changing implications on human patients.
However, what we haven’t seen yet is proof that CRISPR technology can safely be used in human patients. That brings us to this week, a historical week for CRISPR.
Advances over the past 40 years have fueled the introduction of revisions to National Institutes of Health (NIH) Guidelines, this time including amending the criteria and process for how human gene transfer protocols would be selected for review by the Recombinant DNA Advisory Committee (RAC). The RAC was established to weigh the risks of studies involving gene therapy, and also investigate reports of deaths and side effects resulting from gene therapy. This amendment to their remit limited in-depth review and public discussion to exceptional cases in the hope that the RAC will be able to devote its full resources to where they are most needed. In gene therapy cases the protocols submitted for review by the RAC are progressing closer to the realm of clinical application, and with this level of scientific evolution comes ethical challenges and the prospect of unknown and dangerous side effects.
The RAC’s first exceptional case occurred this week. During the 21st and 22nd June meeting, the RAC reviewed and approved a proposal from the University of Pennsylvania, which aims to conduct the first in human use of gene editing using CRISPR/Cas9 technology.
How will CRISPR therapy in humans work?
The protocol detailed the use of an immune therapy in which a patient’s own blood cells will be removed and genetically altered to enable them to fend off cancer cells more effectively. Specifically, two genes in the patient’s T cells will be modified to express T cell receptors targeting myeloma, melanoma and sarcoma tumor cells. Currently these types of cancer require patients to undergo demanding treatment through chemotherapy, radiotherapy and surgery. Researchers are looking at methods to re-program our own immune systems to do the job for us with this protocol, avoiding grueling treatment regimens which can themselves cause huge damage to patients.
The committee will only approve an experiment if it’s certain that researchers are giving their work a high level of respect; in a statement released about the proposal Dr Francis Collins, NIH Director, reiterated the NIH’s commitment to “support innovations in biomedical research in a fashion that reflects well-established scientific and ethical principles”. This approval indicates that we, as a scientific community, are beginning to get to catch up with the ethical conundrums that surrounds the scientific advances we have the ability to make.
Are other trials planned?
The planned timing of the University of Pennsylvania’s proposed study has not been released but excitement already surrounds a biotechnology company based in Cambridge, Massachusetts. Editas Medicine have previously said they intend to begin a trial in 2017 using CRISPR to treat a rare eye disease. The disease in question is Leber congenital amaurosis, which affects light-receiving cells in the retina and results in sufferers being able to see only large, bright shapes, and can ultimately result in complete blindness. The condition affects only approximately 600 people in the US. This specific target has been praised by scientists as the exact genetic error is known and the eye is an easy to reach site for genetic treatments. Therapy will involve deleting ~1,000 DNA bases from the CEP290 gene found in the photoreceptor cells of patients. Preliminary experimental data have suggested that following therapy with CRISPR, the gene should then function correctly and relieve symptoms entirely.
It looks like the race to move CRISPR technology from the laboratory bench to the hospital bedside is well and truly on, but is this excitement justified?
Perhaps not so; the federal RAC approved the University of Pennsylvania’s study unanimously, with one member abstaining, but the experiment has further regulatory hurdles to clear – it must still be approved by the Food and Drug Administration (FDA), which regulates clinical trials conducted in the US. This in itself is a significant stage of the regulatory process.
If approved, this will be a small early-stage trial involving roughly a dozen patients. These early-stage trial data are designed to test the safety of the therapy, not the efficacy. Researchers will need to consistently demonstrate CRISPR’s safety, efficacy, and viability as a clinical intervention throughout numerous trials stages involving both healthy volunteers and volunteer participants with cancer before it ever has an impact on patients. Given that the failure rate of early-stage trials is estimated to be approximately 95%, it’s likely that this study won’t be the first to gain RAC approval before a CRISPR driven therapy is available for use for human patients in the clinic.
Whilst this approval does mark a significant landmark for the advancement of CRISPR into the clinical domain, we need to keep things in perspective; this is likely the beginning of a very long journey.
Antimicrobial resistance threatens the effective prevention and treatment of an ever-increasing range of infections caused by bacteria, parasites, viruses and fungi. The most well-documented, discussed and feared of which is bacterial resistance. The media regularly run stories of bacterial strains becoming resistant to the medications we have access to. Some may call this ‘fear-mongering’, but the prospect of a world without a method to cope with infections is a scary thing. It would impact every aspect of our lives – the food we eat, the size of our families and where our families can live, the destinations we can travel to, and what our careers look like.
Image Credit: CDC/ C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus. Scanning electron micrograph of HIV-1, colored green, budding from a cultured lymphocyte.
Human immunodeficiency virus (HIV)
A lentivirus (a subgroup of retrovirus) that causes HIV infection, and if left untreated leads to the development of acquired immunodeficiency syndrome (AIDS). HIV infects cells that are vital to the human immune system, therefore weakening the body’s ability to fight disease.
There is no cure for HIV. Current treatments focus on the use of anti-retroviral drugs, and though medical interventions can effectively suppress HIV replication it is not yet possible to entirely eliminate HIV from infected cells. With latent HIV still present in the genome of infected cells, replication resumes when therapy is stopped or interrupted, meaning that patients are reliant on drugs for their whole lives. This isn’t ideal as many patients may not always have access to the drugs they need and compliance is a real issue. This problem of life-long drug dependency is especially troublesome for developing countries where patients may be reliant on international aid.
The first X-Men movie hit our screens back in 2000 and we’ve been treated to multiple sequels and spinoffs over the last 16 years, the latest of which, ‘X-Men: Apocalypse’, will be released across cinemas globally this month. X-Men: Apocalypse focuses on ‘Apocalypse’, the first and most powerful mutant who awakens after thousands of years to be greeted by a world he’s disillusioned with. We follow Apocalypse and his team of mutants on their quest to cleanse mankind and create a new world order. Obviously things don’t go entirely to plan for Apocalypse as Raven (also known as Mystique) and Professor X work to lead the X-Men to stop their nemesis and save mankind – sounds like a pretty busy weekend for the mutants.
It seems like each time a new X-Men movie is released the world turns to science to ask if it will be possible to create a generation of X-Men in the future, and when. On the blog this week we’ve decided to answer those questions for you, so over the next few weeks or months when you’re asked if X-Men could ever be real just point your interrogators over here – you’re welcome!
noun Zi·ka virus \ˈzē-kə-\
A virus transmitted by mosquitoes which typically causes mild infection (fever, rash, joint pain) in humans. The Zika virus is a flavivirus transmitted by mosquitoes of the species Aedes aegypti.
The World Health Organisation (WHO) has declared Zika virus a global health emergency; they’ve now launched a global prevention and control strategy in order to try and provide a cohesive action plan for research, response and evidence dissemination regarding potential treatments. Anxiety surrounds the Rio Olympics beginning in August to such an extent that the Australian Olympic Committee will be providing their athletes with anti-Zika virus condoms which provide not only a physical barrier, but a lubricant laden with antivirals too.
Yesterday was Mother’s Day here in California (and the rest of the US, and in 84 other countries around the globe) – and one thing we can all be grateful for are the mitochondria that are found in most of our cells. We inherit these amazing little energy-producing organelles from our mother’s egg cell during fertilization. So be sure to thank your mother this year for the ability to synthesize ATP in your cells!
It turns out that catalytically “killing” Cas9’s endonuclease activity isn’t always a bad thing. Especially if you’re interested in doing reversible gene knockdown. Back in 2013, Stanley Qi and coworkers published their report, “Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression” in Cell, documenting the use of dCas9 for “CRISPRi” – CRISPR interference.
Data analyst Natalia Bronshtein excels in producing visualizations of complex sets of information and growing trends. Here, Natalia has produced a visualization of the global spread of CRISPR publications across the globe. From the coining of the word, “CRISPR” in 2002 by Ruud Jansen to the explosion of publications following its first reported uses in genome engineering in late 2012, see how CRISPR/Cas9 technology has spread user-friendly DNA editing the world over.
Check it out http://insightfulinteraction.com/crispr.html