Meet medicine’s smartest pair of scissors: How CRISPR is revolutionizing medicine one gene deletion at a time

dna-1903318_1280What is CRISPR-Cas9?

Imagine you’re typing up your mother’s famous lasagna recipe.  After you finish, you notice that instead of typing 3 C of marinara sauce, you typed 30 C.  You quickly realize your one keystroke error would result in a very saucy lasagna that would not make your mother proud.  So before you print, you drag your mouse to the error and delete the zero.  Your recipe is saved and there’s no need to call for delivery.  The same cutting and editing principle is behind CRISPR-Cas9, the revolutionary genetic editing tool that manyhave billed as the next Nobel Prize winner.  If we think of our genetic material as a recipe for our bodies, we know that genetic mutations (or errors in the lasagna recipe), can result in the development of deadly genetic disorders such as Huntington’s or Cystic fibrosis.  With your lasagna recipe error, you simply highlight the error with your computer mouse, right click and “cut” the error out of the recipe.  CRISPR-Cas9 works the same way, by using a guide molecule (computer mouse) and an enzyme called Cas9 that can “cut” out genetic material (cut function in Word).  This tool can quickly and efficiently remove the part of a gene that is causing a disease.


Since its explosion onto the market five years ago, CRISPR has been used in a wide range of sectors, allowing scientists to treat hearing loss in mice and grow bigger tomatoes for your summertime BLTs.  But by and large, the greatest implications of CRISPR has been in the medical sector.  The therapeutic potential of CRISPR is vast; scientists have used CRISPR to target several diseases, including several that have an underlying genetic causes like amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease with no cure.  Recently, researchers treated a mouse model of ALS using CRISPR to target motor neurons in the spinal cord.  They were specifically interested in a gene called SOD1, as mutations in this gene are responsible for 20% of all genetically-caused ALS cases.  CRISPR disabled the mutated SOD1 gene in mice with ALS, resulting in increased longevity, improved motor function, and decreased muscle atrophy.  While the genetic editing didn’t cure ALS in these mice, this study is part of the growing evidence of successful CRISPR use in treating diseases that affect the brain and spinal cord.

Genetic Editing: Coming to a clinical trial near you

With astonishing success in animal models, the race is on to move CRISPR into clinical trials.  Partnering with Vertex Pharmaceuticals, CRISPR Therapeutics announced it will begin a clinical trial in Europe testing its gene editing therapy, CTX001, for patients with β-thalassemia, a deadly blood disease.  The company also plans to submit an application to treat sickle cell disease in a U.S. clinical trial.  In the U.S., doctors at the University of Pennsylvania are planning to enroll up to 18 patients fighting various forms of cancer for their Phase 1 clinical trial using CRISPR to genetically alter immune cells to better destroy cancer cells.  In both of these clinical trials, scientists will remove blood from the patient and use CRISPR to genetically alter the blood cells, These new (and hopefully improved) cells will then be injected back into the patient and the edits will be distributed (or something like that).  This ex vivo approach is less risky than injecting CRISPR directly into the bloodstream, which could cause an immune reaction.  Using genetic editing to treat medical conditions doesn’t come without ethical and methodological concerns.  One of the biggest safety concerns is the risk of off-target effects, where CRISPR could accidentally cut the DNA in the wrong location, potentially resulting in a benign mutation, or activating a cancer-causing gene.  Nevertheless, with three CRISPR clinical trials in the works, genetic editing may one day be the key to treating these debilitating diseases.

Diagnostic robots, drug printers, and breaking habits with an app: Three trends to watch for in 2018

Keeping up with the latest trends in pharma can be overwhelming-here are three technology trends that are changing the pharmaceutical marketing landscape in 2018


1) Artificial Intelligence: An extra set of very smart eyes

The mounting pile of data crucial for making medical decisions has healthcare professionals utilizing artificial intelligence (AI) to expedite data analysis and interpretation.  AI is already helping scientists diagnose and treat deadly blood infections, which require a trained technician running a microscopic analysis of the blood.  With bloodstream infection mortality rates at nearly 40%, researchers at the Beth Israel Deaconess Medical Center turned to AI.  Scientists equipped a microscope with a convolutional neural network, a type of artificial intelligence based on the mammalian visual cortex, to identify bacteria that cause bloodstream infections with a 95% accuracy.  AI is also emerging in companies looking to reduce the costly price tag of drug commercialization.  Several pharmaceutical companies including Shionogi & Co and Seegene Inc. have recently pumped resources into developing AI systems that can quickly and accurately mine through data to better direct drug research and development efforts.

2) Ctrl + P for Drugs

The popularity of three-dimensional printing (3DP) has exploded in the past few years, with applications in producing prosthetic limbs and human tissue.  Scientists are also using 3DP to develop more personalized drugs, customized to your specific healthcare needs.  The  ZipDose 3D printer, trademarked by Aprecia Pharmaceuticals, can produce highly concentrated drug tablets that are quick to dissolve and easier to swallow.  In late 2017, Aprecia signed a partnership with Cycle Pharmaceuticals using the ZipDose printer to manufacture drugs for the treatment of rare medical conditions.  Aprecia isn’t the only company racing towards using 3DP in drug manufacturing, with Vitae Industries marketing the AutoCompounder, a 3D printer that reportedly can print pharmaceutical pills in just 10 minutes.  The technology to revolutionize precision medicine has scientists excited about a 3DP drug market that is estimated to reach $522 million by 2030.  

3) Want to stop (insert bad habit)? There’s an app for that

The future of healthcare may be in the palm of your hand.  With 64% of patients using digital devices (including mobile apps) to manage their health, mobile health app developers are racing to design technology that does more than track your steps.  Designed by Somatix, SmokeBeat is a novel mobile app designed to be used with smartwatches and wristbands to monitor smoking habits in real time.  The app can correctly identify 80% of all smoking episodes by utilizing a specific algorithm that is sensitive to the specific hand-to-mouth gestures that characterize smoking a cigarette.  Importantly, smokers using the SmokeBeat app reported a significant decline in the number of smoking episodes in a 30-day period.  Remote health monitoring has the potential to give doctors and patients a comprehensive view of health habits, allowing for personalized interventions.  With the mobile health market valued at over $23 billion, and 75% of Americans owning a smart phone, expect to see a growth in the number of healthcare apps aiming to help you lead a healthier life.

What scientific trends are you excited to follow in 2018?  Let me know over on Twitter @NeuroMegan

Breaking the (CTE) Brain Barrier: Study claims to be the first to detect CTE in a living ex-NFL player

Photo by Geoff Scott on Unsplash

Chronic traumatic encephalopathy (CTE) is a brain disease that has been observed in army veterans and hockey and football players.  This brain disease originated in the 1900’s, when a study reported about boxers who appeared to act “punch drunk” by displaying motor deficits as well as speech and memory problems.  Today, CTE is widely thought to be caused by repetitive head traumas, such as sustaining a concussion during a sporting event. These head traumas cause a protein called Tau to abnormally clump together in different brain regions and kill brain cells. As a result, symptoms of CTE include impulse control problems, motor deficits and memory loss.  Research has shown that even mild head trauma can have long term effects on the brain and can result in the development of CTE.  In perhaps the most famous finding to date, a postmortem analysis of brain tissue from 111 ex-NFL football players found that 99% of the brains examined displayed the hallmark pathology of CTE.  While these findings were the first of their kind, there was some pushback.  The biggest caveat of the findings is that many of the donated brains were studied because families suspected a CTE diagnosis.  In addition, like Alzheimer’s disease, an official diagnosis of CTE cannot be made until after an individual dies.  If researchers were able to diagnose CTE in living individuals, this would be a major step towards identifying CTE susceptible populations or possible risk factors for developing the disease.

A study published in Neurosurgery claims to be the first to diagnose CTE in a living ex-NFL football player.  Scientists used a PET scan to study the brain of a 59-year old man who had played football for 22 years (12 years in the NFL).  The study used a radioactive tracer called FDDNP which binds to Tau, and identifies the Tau clusters that are indicative of CTE.  At the time of the scan, the man exhibited memory problems, a short temper, and behaved inappropriately as if “his filter was gone”.  At the age of 61, 18 months after the PET scan, his wife noticed that he showed declining motor skills, which continued to deteriorate until his death at the age of 63.  After his death, his brain was stained for tau deposits, and the deposit levels were compared to the FDDP tracer findings.  Researchers found that the PET scan detected a high level of tau deposits in several brain regions like the frontal and temporal cortex.  The PET-detected Tau deposit values were very similar to the levels observed postmortem, suggesting that the PET scan using the FDDNP tracer may accurately identify the distinctive CTE pathology in living individuals.

Some scientists claim that the FDDNP tracer may not be specific enough to be used as a diagnostic for CTE.  For example, FDDNP also binds to a protein called amyloid, whose plaques can be seen individuals with Alzheimer’s disease.  However, the authors argue that the distribution pattern of FDDNP in a CTE brain is distinct from patients with Alzheimer’s disease.  Perhaps one of the biggest unanswered questions about CTE is the understanding the incidence of the disease.  In the Neurosurgery study, the ex-NFL player had only one reported concussion in his life, and researchers acknowledge that there is no magic number on how many concussions it takes to develop CTE.  Furthermore, not everyone with numerous concussions or head trauma goes on to develop CTE.  Addressing these problems will be difficult, as CTE symptoms can take months or even years to develop.  However, the development and utilization of the FDDNP tracer may put researchers one step closer to identifying and diagnosing CTE before it’s too late.

Article: Postmortem Autopsy-Confirmation of Antemortem [F-18]FDDNP-PET Scans in a Football Player With Chronic Traumatic Encephalopathy

Published November 10, 2017 in Neurosurgery

How a genetic mutation is helping an Amish community live longer and healthier


A genetic mutation found in an Amish community might reveal the key to living longer and healthier.  The study, published in Science Advances, found that a mutation on the SERPINE gene halves the normal level of Plasminogen Activator Inhibitor-1 (PAI-1), a protein that is necessary for blood clots.  In the 1990’s it was discovered that some Amish family members from Indiana carried a double mutation of PAI-1, which results in a rare bleeding disorder.  Interestingly, other Amish members that only had a single mutation of PA1-1 did not have the rare bleeding disorder, but lived significantly longer than those without any PAI-1 deficiency.  So how could a rare genetic mutation actually extend our lifespan?

Scientists studied 177 members of the Old Order Amish from Berne, Indiana and found that 43 of the members had a single mutation of PAI-1.  This mutation cut their PAI-1 levels to half the normal amount.  The goal of the study was to determine if this single mutation resulted in improved anti-aging outcomes.  Their results were striking; carriers of the single mutation lived, on average, 10 years longer than members without the mutation. They also appeared to be protected from type 2 diabetes, with a 0% incidence rate versus 7% in those with no mutation.  In addition, those with a single mutation had lower fasting insulin rates, a hormone that when elevated, can lead to diabetes.  They also displayed increases in telomere length, a validated biological marker of aging.  A telomere “caps” the end of a chromosome, and protects our genetic material from degrading.  Longer telomeres have been strongly linked to longevity.  

The results of the study were impressive, as they found consistent anti-aging effects from a single PAI-1 mutation across multiple body systems.  This study confirmed that PAI-1 is strongly associated with the aging process, which is crucial because PAI-1 has been a target of several anti-aging therapeutics.  Inhibition of PAI-1 in mouse models of aging extends their lifespan, and protects their lungs and vascular system from accelerated aging.  Currently, a PAI-1 inhibitor is undergoing early-phase clinical studies in Japan.  There are still several questions that scientists need to address before PAI-1 inhibition is touted as the next anti-aging fix.  First, Amish members overall live longer than the average American, even without the mutation.  This suggests that there are factors besides a PAI-1 mutation that influence the aging process.  In addition, inhibiting PAI-1 too much would be dangerous.  As previously mentioned, those with a double mutation of PAI-1 are diagnosed with a rare bleeding disorder, so it will be critical to be able to control the level of inhibition.  By identifying the genetic influences of PAI-1 on aging, scientists are one step closer to developing targeted anti-aging therapeutics that go beyond your drugstore wrinkle cream.

Paper: A null mutation in SERPINE1 protects against biological aging in humans

Published: Science Advances, November 15th, 2017

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Monitoring tumor DNA may prove pivotal for early detection of liver cancer


A new blood test that detects changes in tumor DNA may allow doctors to diagnose liver cancer earlier and better monitor disease progression.  Hepatocellular carcinoma (HCC) is the most common type of liver cancer in adults and over 40,000 people will be diagnosed in the US this year.  The five year survival rate is 31% and if the cancer spreads to other regions, that rate drops to about 11%.  This poor prognosis highlights the need for improved early detection measures.  Currently, one of the first diagnostic tests that doctors use is a blood test that measures levels of alpha-fetoprotein (AFP).  This protein is produced in the liver and can be elevated in liver cancer patients, acting as a sign of tumor growth.  However, this test is not without flaws, as 30% of individuals with liver cancer can exhibit normal APF levels. Conversely, APF levels can also be elevated in individuals without liver cancer.  Because of this, a firm diagnosis of liver cancer usually involves more invasive procedures such as a biopsy.  

While the APF blood test focuses on the level of a single protein, a new blood test examines circulating tumor DNA (cTDNA), which is genetic material that is shed by cancerous tumors.  By looking at cTDNA, researchers could look at any number of possible DNA changes in HCC patients versus normal controls.  Specifically, they were interested in examining markers of methylation.  Methylation is a process that can regulate gene expression and excessive DNA methylation can turn a specific gene off.  This is especially critical in cancer, as increased methylation of tumor suppressor genes is an early event in tumor development.  

The Nature Materials study discovered that HCC patients had a specific set of methylation markers in their blood, whereas the controls did not.  They also found that these methylation markers were very effective at predicting a diagnosis of HCC and an increase in these markers was associated with a later progression of the disease.  Strikingly, 40% of HCC patients in the study had normal APF levels, suggesting that measuring methylation patterns may be a more sensitive diagnostic test.  This improved blood test is a major step is cancer diagnostics, and provides hope for early detection and improved prognosis for a disease that kills over 700,000 people worldwide each year.

Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma

Is speeding up the key to slowing down Parkinson’s?

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A recent study found that rats treated with the antidepressant nortriptyline had reduced abnormal levels of alpha-synuclein, a protein critical to the development of Parkinson’s disease.  Alpha-synuclein is normally found throughout nerve cells, but in Parkinson’s, this protein abnormally clumps together and forms Lewy bodies.  These Lewy bodies surround and destroy nerve cells, which are responsible for coordinating movements.  As these nerve cells die, patients exhibit hand tremors, limb stiffness and coordination problems.  So what triggers alpha-synuclein to clump together and eventually form Lewy bodies?

Researchers at Michigan State University suggest that speed may be the key.  In healthy brains, alpha-nuclein naturally reconfigures and folds into clusters at a specific speed.  This process is hypothesized to be slower in Parkinson’s, resulting in a toxic buildup of alpha-nuclein.  When the antidepressant nortriptyline was given to a rat model of Parkinson’s, they observed a faster rate of alpha-nuclein reconfiguration, resulting in less abnormal levels of alpha-nuclein in the brain.

While the choice of an antidepressant to treat Parkinson’s may seem unusual, this was, in fact, intentional. The authors previously examined newly-diagnosed Parkinson’s disease patients, and studied how well they fared in clinical trials.  Surprisingly, patients taking antidepressants were less likely to need additional drug therapy.  This suggested that antidepressants could help slow the progression of Parkinson’s.   Based on their recent study in rats, antidepressants appear to slow the development of Parkinson’s by speeding up the reconfiguration of alpha-nuclein.

While the current study didn’t test motor coordination in the rats treated with nortriptyline, it will be important for future studies to examine.  In addition, nortriptyline did not affect rats with existing abnormal levels of alpha-nuclein.  This suggests that nortriptyline may be most effective when administered during the early development of the disease.  Still, nortriptyline has a long history of safety and efficacy, which makes it a promising therapeutic to test in a clinical setting.

Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form

How null green tea results and a gap in protein expression is exciting news for Down syndrome researchers

Identifying when and where a specific protein is elevated may be the key to improving the deficits observed in Down syndrome (DS), according to a review published in Molecular Genetics & Genomic Medicine.  Dual-specificity tyrosine-phosphorylated regulated kinase 1A (DYRK1A) is a gene that is triplicated in DS, and has recently been touted as a target for drug development in DS.  DYRK1A plays a critical role in the development of the central nervous system, and when its expression level is normalized, behavioral deficits are improved.  So, why haven’t researchers administered a DYRK1A inhibitor to fix the deficits in DS?  Well, that’s where things get tricky.

First, there are only a few DYRK1A inhibitors that are safe to use, and you may have already consumed one without knowing it.  Epigallocatechin-3-gallate (EGCG) is the main polyphenol found in green tea, and inhibits DYRK1A in cells.  However, studies that administer EGCG have yielded contrasting results, largely due to factors like the dose and timing of EGCG treatments.  In addition, EGCG has been shown to inhibit numerous targets besides DYRK1A , thus, more specific inhibitors need to be developed.

Second, the “When” and “Where” of DYRK1A elevation during early life development is a mystery.  The levels of DYRK1A are largely unknown between embryonic day 11.5 and 45 days of age in DS mouse models.  This large age gap represents a crucial period of early brain development, and the authors hypothesize that the elevation of DYRK1A during this age range could be causing the abnormal phenotypes observed in DS.  Understanding at what age, and in what brain regions DYRK1A is elevated will be essential for scientists to better administer DYRK1A inhibitors.  

In summary, researchers are left with green tea that may (or may not) work, and a large gap in understanding when DYRK1A is elevated.  While these findings may look dismal at first glance, scientists are currently testing improved DYRK1A inhibitors, and examining levels of DYRK1A during early development.  If future studies can combine these two avenues of research, then DYRK1A inhibition may provide a means to improve the lives of individuals with DS.

Article: Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits

Published in Molecular Genetics & Genomic Medicine on September 20th, 2017


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