- Prime editing devised by researchers at the Broad Institute led by David Liu is a significant advance of the original CRISPR gene editing tool discovered in 2012
- CRISPR can cut and edit your DNA to correct defects inside your body’s cells to prevent and heal a range of incurable diseases and has revolutionized biomedicine
- The original CRISPR is fraught with inaccuracies referred to as off target effects
- Prime editing substantially reduces CRISPR’s off target effects and has the potential to correct up to 89% of known disease-causing genetic variations
- CRISPR also has the capacity to edit genes in an embryo in such a way that the change is heritable
- In 2018 Chinese researcher He Jiankui “created” the world’s first CRISPR babies
- This triggered international criticism from scientists and bioethicists
- A principal concern is that CRISPR is easy-to-use, cheap, regularly used in thousands of laboratories throughout the world and there is no internationally agreed and enforceable regulatory framework for its use
In 2012 the world of biomedicine changed when a revolutionary gene editing technology known as CRISPR-Cas9 (an acronym for Clustered Regularly Interspaced Short Palindromic Repeats) was discovered. The technology harnesses your body’s naturally occurring immune system that bacteria use to fight-off viruses and has the potential to forever change the fundamental nature of humanity. Since its discovery CRISPR has been developing at lightning speed primarily because it is simple and affordable and today is used in thousands of laboratories throughout the world.
We also review a case where an ambitious scientist “created” the first CRISPR babies. This immediately triggered international criticism and a call for tighter regulatory control of the technology. Scientists and bioethicists are concerned that CRISPR can easily be used to create heritable DNA changes, which ultimately could lead to ‘designer babies’.
These two accounts of CRISPR might seem “opposites” and not sit well together in a single Commentary. Notwithstanding, what prompted putting them together was John Travis, the News Managing Editor of the well-known scientific journal Science, who soon after CRISPR’s discovery in 2012 said, “For better or worse we all now live in CRISPR’s world”.
CRISPR and your DNA
CRISPR is different to traditional gene therapy, which uses viruses to insert new genes into cells to try and treat diseases and has caused some safety challenges. CRISPR, which avoids the use of viruses, was conceived in 2007 when a yogurt company identified an unexpected defence mechanism that its bacteria used to fight off viruses. Subsequent research made a surprising observation that bacteria could remember viruses. CRISPR has been likened to a pair of microscopic scissors that can cut and edit your DNA to correct defects inside your body’s cells to prevent and heal a range of intractable diseases. The standard picture of DNA is a double helix, which looks similar to a ladder that has been twisted. The steps in this twisted ladder are DNA base pairs. The fundamental building blocks of DNA are the four bases adenine (A), cytosine (C), guanine (G) and thymine (T). They are commonly known by their respective letters, A, C, G and T. Three billion of these letters form the complete manual for building and maintaining your body, but tiny errors can cause disease. For example, a mutation that turned one specific A into a T results in the most common form of sickle cell disease.
The original CRISPR
Subsequently however, the paper was retracted, and an error correction was posted on a scientific website. Contrary to their original findings, the authors of the Nature Biotechnology paper restated that the CRISPR-Cas9 gene editing approach, "can precisely edit the genome at the organismal level and may not introduce numerous, unintended, off-target mutations".
Notwithstanding, researchers remained concerned about CRISPR’s off target effects and several devised a technique, referred to as base editing, to reduce these. Base editing is described in three research papers published in 2017: one in the November edition of the journal ‘Protein and Cell’, another in the October edition of ‘Science’ the and a third by researchers from the Broad Institute, in the October edition of the journal ‘Nature’. Base editing takes the original CRISPR-Cas9 and fuses it to proteins that can make four precise DNA changes: it can change the letters C-to-T, T-to-C, A-to-G and G-to-A. The technique genetically transforms base pairs at a target position in the genome of living cells with more than 50% efficiency and virtually no detectable off-target effects. Despite its success, there remained other types of point mutations that scientists wanted to target for diseases.
- Diabetic foot ulcers (DFUs) are a result of diabetes complications and can lead to amputations and death
- Scientists and clinicians struggle to reduce the vast and escalating burden of DFUs
- In wealthy countries like the UK there are specialist multidisciplinary diabetic foot clinics
- New and innovative therapies are beginning to emerge, which accelerates the rate of complete wound closure for DFUs
- Notwithstanding new products coming to market, the best therapy is prevention
This Commentary discusses diabetic foot ulcers (DFUs) within the context of chronic wounds. Although chronic wounds tend to be an overlooked area of medicine and do not feature prominently in the popular media; NHS England, spends £5bn a year treating 2m patients with chronic wounds. The incidence rates of people affected with wounds are rising fast and some experts suggest that nearly 60% of all wounds become chronic. According to Una Adderley, a wound expert and Director of NHS England’s National Wound Care Strategy Programme, therapy in England for chronic wounds is patchy and suboptimal, “leading to non-healing or delayed healing (which) increases the number of people living with chronic wounds. Too many people are receiving care for which there is little evidence that it works and too few are receiving care for which there is strong evidence that it works”.
According to a 2019 report by the consulting firm MarketsandMarkets the global wound care market in 2019 is estimated to be US$20bn and projected to reach US$25bn by 2024. Market drivers include the vast and fast-growing incidence rates of hard-to-heal chronic wounds, a large proportion of which are associated with diabetes, increasing R&D spending, technological developments, the growing use of regenerative medicine in wound care, recent advances in molecular data that have contributed to genome sequencing, and the increasing use of AI in the management of wound care solutions. The chronic wound care markets of North America and Europe are expected to grow at a CAGR of ~4.5% for the next 5 years, but the highest CAGR is expected in Asia where the vast pool of patients is increasing significantly, and favourable reimbursement policies are expected to persist in the region for the next decade.
When accompanied by an underlying condition such as diabetes, chronic wounds in the form of DFUs, are challenging to heal and have a deleterious effect on your quality of life: you experience pain, suffering, disfigurement, anxiety impaired mobility, malodour and social isolation. Because the prevalence of diabetes is increasing worldwide, DFUs have become a large, severe and growing public health issue as described in two research papers published in 2019.
One, published in the May 2019 edition of Diabetic Medicine, reports findings of an 18 year study of DFUs, and suggests that although current therapies in the UK result in better than previously reported survival in persons < 65 years (10 year survival is 85%), treatments fail to, “reduce recurrent incidence (of DFUs and) cumulative prevalence of all ulcers continues to increase”; from 20.7 to 33.1 per 1,000 persons between 2003 to 2017. The second paper, published in the January-March 2019 edition of the International Journal of Applied Basic Research, report sfindings of a prospective Indian study of 63 patients >18 with DFUs and shows the increase in the severity of DFUs and the consequent increase in the rate of hospital readmissions, amputations and mortality.
Diabetes is a chronic disease that occurs either when your pancreas does not produce enough insulin or when your body cannot effectively use the insulin it produces. Insulin is a hormone that regulates your blood sugar level. High blood sugar levels (hyperglycaemia) is a common effect of uncontrolled diabetes and can lead to serious complications, which include blindness, kidney failure, heart attacks, stroke, diabetic foot ulcers (DFUs), and lower limb amputations. According to the World Health Organization, the global prevalence of diabetes among people >18 has risen from 4.7% in 1980 to 8.5% in 2014. Today, some 422m people worldwide have diabetes, which has increased from 108m in 1980. There is expected to be some 642m people >18 living with diabetes by 2040.
If you have diabetes you are prone to ulcers because your increased blood sugar levels create thick, sticky blood, which can lead to peripheral artery disease (PAD), neuropathy (a loss of sensation due to nerve damage), and/or problems with circulation due to damage to your small blood vessels, which reduce your body’s ability to heal injuries.
Signs and symptoms of DFUs include numbness in your toes and a loss of feeling in your feet, painful tingling sensations, blisters, minor abrasions and cuts without pain that do not heal, skin discoloration and temperature changes With a loss of sensation, a minor injury to your foot can go unnoticed and untreated, and quickly lead to an ulcer. If you are living with diabetes, ulceration is an ongoing challenge. Only about 66% of DFUs eventually heal without surgery. If you have had a foot ulcer you are at increased risk of further ulceration. Studies suggest that around 25% of people living with diabetes who become ulcer-free have developed new ulcers within 3 months, and 34% to 41% within 12 months. Some foot ulcers are painful, and treatment often requires that you spend a significant amount of time visiting clinics to frequently change your wound dressings. The poor prognosis of DFUs is often attributed to other complications of diabetes such as peripheral neuropathy, peripheral vascular disease and persistent hyperglycaemia. Managing diabetic foot ulcers is a major challenge for healthcare systems globally and the main cause of more than half of nontraumatic lower limb amputations: every 30 seconds in the world, a lower limb is amputated due to diabetes. Amputations have life-altering repercussions for patients and represent a significant burden for the healthcare industry as a whole. Between 0.03% and 1.5% of people with DFUs require an amputation and most amputations start with ulcers.
For major amputations, the prognosis is poor because your other limb is at risk. Research suggests that only around 50% of patients survive for two years after major diabetes related amputations. The one-year mortality rate has been estimated at 32.7% after major amputation and 18.3% after minor amputation if you have diabetes. Five-year cumulative mortality for patients with diabetes undergoing a first major amputation has been estimated at 68% to 78.7%. Thus, if you have diabetes and a DFU you have almost a 50% chance of being dead within five years, which is significantly higher than for people with either breast (18%) or prostate (8%) cancers.
In the UK some 70,000 to 90,000 people living with diabetes have DFUs at any one time. If you have diabetes you are about 23 times more likely to experience an amputation than someone without diabetes. In England, diabetes leads to more than 9,000 lower limb amputations each year. Each week in England some 169 people undergo an amputation procedure as a result of diabetes. Analysis by the charity Diabetes UK found that between 2014 and 2017, 26,378 people had lower limb amputations linked to diabetes, which represented a 19% rise from 2010 to 2013. Diabetes affects almost 3.7m people in the UK. In 2017 NHS England launched a special transformation fund aimed at improving patients with diabetes access to specialist multidiscipline foot care clinics to help avoid amputations.
In the video below Hisham Rashid, Consultant Vascular Surgeon at King’s College Hospital, London, describes a DFU and explains why they benefit from specialist multidisciplinary treatment centres. “DFUs have similar features to other ulcers, and often present in the toes and heal areas of the foot with the loss of skin and an exposed base with infection and necrosis. The significant difference is that a DFU usually comes with multiple pathologies, which, in addition to infection, include neuropathy and peripheral vascular disease. DFUs do not heal quickly and often require vascular surgeons working closely with radiologists, orthopaedic surgeons to correct any deformity and a microbiology unit to manage infection,” says Rashid.
Rashid also explains that different therapies are used to heal DFUs. “If the patient has peripheral artery disease (ischaemia) then this has to be treated first with an angioplasty or a bypass or both to improve blood circulation into the foot. Once this is achieved, the ulcer is debrided and dressed. There are different dressings, which include negative pressure dressing, which sucks the blood into the tissues and thereby promotes healing. Sometimes skin graphs are necessary to get the tissue to heal faster. This can be done as a day surgery using local anaesthetic,” says Rashid.
Prevention of DFUs
Given the severity of DFUs and their vast and rapidly increasing burden on individuals with diabetes and healthcare systems, increasing attention is being devoted to prevention, which involves adequate glycaemic control and modification of risk factors. While education is an obligation of healthcare professionals, it is crucial that people living with diabetes themselves increase their awareness and understanding of the condition and integrate regular feet examination and care into their daily lives. In the video below, Roni Sharvanu Saha, Consultant in Acute Medicine, Diabetes and Endocrinology, St George’s Hospital, London, suggests that, “We’re getting better at understanding why DFUs occur, and better at examining peoples’ feet. In England, if you have diabetes you are entitled to a clinical examination of your feet at least twice a year. Checks include whether you have any minor abrasions, or whether you can distinguish hot and cold water with your feet, and signs that you might have problems with your circulation and nervous system. Ensuring that people living with diabetes receive regular checks means that if you have reduced or poor circulation, you’re referred to the correct specialty team in order to protect you from developing DFUs. Prevention is better that cure. If we can get better at examining feet, outcomes will improve. If diabetes is not controlled complications will occur”.
With the well-being of millions of people living with diabetes at stake, there is a pressing need for therapies that bring DFUs to closure as quickly as possible. The current standard of care (SOC) regimen for DFUs involves maintaining a moist wound environment, debriding nonviable tissue, relieving pressure with an offloading boot and preventing or managing wound infection. Even with a good SOC, DFUs are notoriously slow to close, creating a demand for new and innovative medicines and techniques to enhance closure. Increasingly, there are advanced therapies to facilitate healing DFUs when traditional approaches fail.
An example of a relatively new product to help close DFUs is human amniotic membrane. Amniotic membrane has been used for wound healing purposes since the early 20th century, but it represents a relatively recent and promising advanced therapy to accelerate healing in DFUs. Amniotic membrane is derived from the human placental sac that supports the foetus by forming the inner lining of the amniotic cavity. Functions of amniotic membrane include the exchange of water-soluble molecules and the production of cytokines and growth factors to facilitate the development of the foetes. The anatomic makeup of amniotic membrane dictates its functionality, and a significant characteristic is its ability to produce a wide variety of regenerative growth factors that facilitate foetal development. These growth factors, in combination with various other cytokines, have substantial potential benefits in wound healing, which include creating a structural scaffold for tissue proliferation, modulating the immune response, reducing inflammation, stimulating angiogenesis and facilitating tissue re-modelling.
Two small but significant prospective cohort studies on the effectiveness of human amniotic tissue to treat DFUs were reported in the journal Wounds. One in the March 2016 edition and another in the November 2017 edition. The first is a prospective, randomized, multicentre, controlled study and the second a retrospective cohort study of 20 patients. In both studies amniotic membrane is used in combination with SOC, including debridement, well-controlled offloading, management of bacterial burden, and adequate perfusion.
Both studies suggested that the use of amniotic membrane is more likely to: (i) lead to complete wound closure, (ii) accelerate the rate of wound closure, and (iii) present no additional safety risks when compared to SOC alone in the treatment of DFUs. The first study demonstrated a statistically significant advantage of an amniotic membrane as compared to SOC in facilitating closure of chronic DFUs. 45% of participants achieved complete wound closure, while 0% of SOC participants alone achieved complete wound closure within 6 weeks. Further, there appears to be no increased rate of adverse events associated with the use of amniotic membrane in these wounds. The second study was a retrospective cohort study using a human amniotic membrane on 20 patients presenting with DFUs and venous leg ulcers. Patients underwent a 2-week ‘run-in’ period with good SOC; and if upon their return the ulcer had closed ≥ 30% in area, the subject was excluded from participation in the study. All wounds were effectively closed in approximately 10 weeks, DFUs in 12 weeks and venous leg ulcers in 9 weeks, and no adverse events were noted, suggesting that the therapy using human amniotic membrane is safe.
The most significant limitation of both studies is their small sample size, which decreases the generalizability of their findings. Notwithstanding, the studies suggest that amniotic tissue products are efficacious options for DFUs when used in conjunction with the current SOC, which includes aggressive sharp debridement, adequate offloading and the application of sterile dressings. Further, amniotic membrane, like most biologic tissue products, requires significant processing and therefore its cost is relatively high: on average between US$500 to US$1,000 per application. Notwithstanding, these costs are significantly less than the average annual therapy cost of US$28,000 per patient for SOC for a DFU. And therefore, using amniotic tissue in the therapy for DFUs could result in significant savings for healthcare systems. Tissue storage as well as the time and skill required to apply amniotic membranes also represent challenges inherent to these products.
Millions of people are living with diabetes, which, if not managed appropriately can lead to life-changing complications. A DFU is one such complication, which often starts with a minor abrasion on your ankle or toe that you do not feel and therefore tend not to perceive to be important, until that is, it quickly escalates into a chronic wound that does not heal and eventually leads to a lower limb amputation. In most wealthy nations, health providers are aware of the dangers of DFUs and have set up multi-disciplinary diabetic foot clinics to treat and manage the condition. However, access to such clinics is patchy and the prevalence of DFUs continues to increase, and the eye-watering costs of treating and managing DFUs continue to escalate. In recent years, the therapy for DFUs has been improved by technological advances. We describe one of these: the use of amniotic tissue in conjunction with standard of care protocols. Recent research findings suggest that the use of amniotic tissue holds out the possibility not only of significant therapeutic benefits, but also of substantial cost savings for healthcare systems. Notwithstanding, perhaps the most efficacious therapy for DFUs is prevention. This means investing in effective education and awareness programs, good glycaemic control and appropriate footwear; encouraging people living with diabetes to participate in regular foot examinations and screening for peripheral neuropathy and peripheral arterial disease, and insisting that early telltale signs of foot wounds, no matter how minor, should be immediately referred to a specialist clinic.
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- Hydrocephalus is a chronic condition that occurs when excess cerebrospinal fluid (CSF) collects in your brain’s ventricles and increases pressure inside your head
- Failure to treat the condition can lead to morbidity and death
- First line therapy is the surgical insertion of a ventriculoperitoneal shunt (VPS) to restore your CSF circulation
- A significant risk with the procedure is infection
- To reduce infection manufacturers’ impregnate standard shunts with either silver or antibiotics and market the impregnated shunts at higher prices
- Which VPS (standard, silver or antibiotic) provides patients with the most protection from infection?
- Which VPS is most cost effective for healthcare systems?
“It” is Hydrocephalus; a chronic condition that occurs when excess cerebrospinal fluid (CSF) collects in your brain’s ventricles, (fluid-filled areas). CSF disperses from your ventricles around your brain and spinal cord. Too much CSF may result in an accumulation of fluid, which can cause the pressure inside of your head to increase. In a child, this causes the bones of an immature skull to expand and separate to a larger-than-normal appearance.
There are no medical therapies to effectively treat hydrocephalus. The only viable treatment is surgical. The gold standard therapy is the insertion of a ventriculoperitoneal shunt (VPS), which is a common surgical procedure to restore your CSF circulation, regulate its flow and allow you to have a normal daily life. Notwithstanding, a significant challenge is infection at the site of the surgical wound, the shunt or in the cerebrospinal fluid itself (meningitis). This effects about 15% of hydrocephalus patients and may result in further surgeries, extended hospital stays, a reduction in your quality of life and a significant hike in healthcare costs.
To reduce potential infection manufacturers’ impregnate standard shunts with either silver (silver has benefits in reducing or preventing infection) or antibiotics and market the impregnated shunts at higher prices.
There are two principal classifications for hydrocephalus: (i) communicating and (ii) non-communicating hydrocephali. Both can be subdivided into congenital (present at birth) and acquired (occurs following birth). Communicating hydrocephalus can also be subdivided into normal pressure hydrocephalus (NPH) and hydrocephalus ex-vacuo, which occurs when there is damage to your brain caused by stroke or injury. It is generally understood that congenital hydrocephalus can be caused by genetic defects, which can be passed from one or both parents to a child, but the direct hereditary links are still being investigated. Notwithstanding, experts have found a connection between a rare genetic disorder called L1 syndrome and hydrocephalus. L1 syndrome is a group of conditions that mainly affects the nervous system and occurs almost exclusively in males.
Most babies born with hydrocephalus or who develop hydrocephalus as infants will have a normal lifespan, and approximately 40 to 50% will have normal intelligence. Seizure disorders have been diagnosed in about 10% of children with hydrocephalus and the mortality rate for infants is approximately 5%.
In the video below Sanj Bassi, a Consultant Neurosurgeon at King’s College Hospital, London and a member of the London Neurosurgery Partnership, describes hydrocephalus:
Signs and symptoms
In the video below Bassi describes how hydrocephalus is diagnosed:
A shunt consists of two thin, long flexible hollow tubes, called catheters, with a valve that keeps fluid from your brain flowing in the right direction and at the proper rate and thereby reduces brain pressure to a safe level. To install a shunt a surgeon will make a small insertion behind your ear and also drill a small borehole in your scull. One catheter is then threaded into one of your brain’s ventricles through the hole in your scull, and the other is inserted behind your ear and threaded subcutaneously down to your chest and into your abdomen where excess CSF can drain safely, and your body can reabsorb it. Your surgeon may attach a tiny pump to both catheters and place it under the skin behind your ear. The pump will automatically activate to remove fluid when the pressure in your skull increases. Shunts can be programmable (externally adjustable by a magnetic device) to activate when the fluid increases to a certain volume, or non-programmable. Most surgeons tend to choose a programmable model, despite the fact that in clinical studies both types perform comparably.
To determine the relative clinical benefits and cost-effectiveness of the three different ventriculoperitoneal shunts (standard, silver or antibiotic) following their de novo insertions, the UK’s National Institute for Health Research funded a large prospective multi-centre randomised controlled clinical study - The British Antibiotic and Silver Impregnated Catheters for Ventriculoperitoneal Shunts Study - (BASICS). Findings were published in the September 2019 edition of The Lancet. These concluded that shunts impregnated with antibiotics significantly reduce the risk of infection and also healthcare costs compared to both standard shunts and those impregnated with silver. Conor Mallucci, Consultant Paediatric Neurosurgeon at Alder Hey Children’s Hospital, Liverpool, UK, and lead author of the study, suggests that shunts impregnated with antibiotics should be, “the first choice for patients with hydrocephalus undergoing insertion of their first ventriculoperitoneal shunt”.
All shunts used in the study were CE marked medical devices intended for the condition. Participants were randomly assigned to three groups: one group of 536 received a standard shunt, another of 531 received a silver impregnated shunt, and a third group of 538 received an antibiotic impregnated shunt. The minimum patient follow-up period was six months and the maximum two years. Six per cent of evaluable patients in both the standard and silver groups presented with infections and required a shunt revision. This compared to only 2% in the antibiotic impregnated shunt group that became infected and needed revising. The difference is significant.
The Study’s economic findings
The research has a further significance because, despite the high medical costs of treating hydrocephalus, the annual spend on hydrocephalus research is relatively low. For example, the US National Institutes of Health (NIH) invests less than US$8m per year in hydrocephalus research. This means that there is a dearth of clinical studies associated with the condition and no long-term follow-up research over the lifetime of patients.
Although BASICS is a significant study it should be mentioned that it is restricted by the relatively low proportion of patient-reported outcomes: 32, 31 and 12 reported infections after insertion of the standard, silver and antibiotic VPS’s respectively.
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- CanRisk is a new online gene-based health-risk evaluation algorithm for detecting breast cancer
- It identifies people with different levels of risk of breast cancer, not just those at high risk
- As the infotech and biotech revolutions merge expect authority in medicine to be transferred to algorithms
- CanRisk has the potential to provide a cheap, rapid, non-invasive, highly sensitive and accurate diagnosis before symptoms present
- Breast cancer is the most common cancer in women worldwide and is the 5th most common cause of death from cancer in women
- Currently mammography screening, which has a sensitivity between 72% and 87%, is the gold standard for preventing and controlling breast cancer
- For every death from breast cancer that is prevented by screening, it is estimated there will be three false-positive cases that are detected and treated unnecessarily
- Lack of resources do not support breast cancer screening in many regions of the world where the incidence rates of the disease are rapidly increasing
- In the near-term expect interest in the CanRisk algorithm to increase
Although over the past two decades there have been significant improvements in the detection and treatment of breast cancer, the disease remains the most common cancer in women worldwide, with some 1.7m new cases diagnosed each year, which account for about 25% of all cancers in women and it is the fifth most common cause of death from cancer in women, with over 0.52m deaths each year.
When fully developed and approved, CanRisk will be well positioned to provide a cheap, rapid, non-invasive, highly sensitive and accurate diagnostic test to detect breast cancer early in people with diverse levels of risk. This might be expected to provide an alternative to the current gold standard population-based mammography screening and assist in making a significant dent in the vast and escalating global burden of the disease.