The Fake Drug Problem

 

By Gesa Junge, PhD

Tablets, injections, and drops are convenient ways to administer life-saving medicine – but there is no way to tell what’s in them just by looking, and that makes drugs relatively easy to counterfeit. Counterfeit drugs are medicines that contain the wrong amount or type of active ingredient (the vast majority of cases), are sold in fraudulent packaging, or are contaminated with harmful substances. A very important distinction here: counterfeit drugs do not equal generic drugs. Generic drugs contain the same type and dose of active ingredient as a branded product and have undergone clinical trials, and they, too, can be counterfeited. In fact, counterfeiting can affect any drug, and although the main targets, particularly in Europe and North America, have historically been “lifestyle drugs” such as Viagra and weight loss products, fake versions of cancer drugs, antidepressants, anti-Malaria drugs and even medical devices are increasingly reported.

The consequences of counterfeit medicines can be fatal, for example, due to toxic contaminants in medicines, or inactive drugs used to treat life-threatening conditions. According to a BBC article, over 100,000 people die each year due to ineffective malaria medicines, and overall, Interpol puts the number of deaths due to counterfeit pharmaceuticals at up to a million per year. There are also other public health implications: Antibiotics in too low doses may not help a patient fight an infection, but they can be sufficient to induce resistance in bacteria, and counterfeit painkillers containing fentanyl, a powerful opioid, are a major contributor to the opioid crisis, according to the DEA.

It seems nearly impossible to accurately quantify the global market for counterfeit pharmaceuticals, but it may be as much as $200bn, or possibly over $400bn. The profit margin of fake drugs is huge because the expensive part of a drug is the active ingredient, which can relatively easily be replaced with cheap, innate material. These inactive pills can then be sold at a fraction of the price of the real drug while still making a profit. According to a 2011 report by the Stimson Center, the large profit margin combined with comparatively low penalties for manufacturing and selling counterfeit pharmaceuticals make counterfeiting drugs a popular revenue stream for organized crime, including global terrorist organizations.

Even though the incidence of drug counterfeiting is very hard to estimate, it is certainly a global problem. It is most prevalent in developing countries, where 10-30% of all medication sold may be fake, and less so in industrialized countries (below 1%), according to the CDC. In the summer of 2015, Interpol launched a coordinated campaign in 115 countries during which millions of counterfeit medicines with an estimated value of $81 million were seized, including everything from eye drops and tanning lotion to antidepressants and fertility drugs. The operation also shut down over 2400 websites and 550 adverts for illegal online pharmacies in an effort to combat online sales of illegal drugs.

There are several methods to help protect the integrity of pharmaceuticals, including tamper-evident packaging (e.g. blister packs) which can show customers if the packaging has been opened. However, the bigger problem lies in counterfeit pharmaceuticals making their way into the supply chain of drug companies. Tracking technology in the form of barcodes or RFID chips can establish a data trail that allows companies to follow each lot from manufacturer to pharmacy shelf, and as of 2013, tracking of pharmaceuticals throughout the supply chain is required as per the Drug Quality and Security Act. But this still does not necessarily let a customer know if the tablets they bought are fake or not.

Ingredients in a tablet or solution can fairly easily be identified by chromatography or spectroscopy. However, these methods require highly specialized, expensive equipment that most drug companies and research institutions have access to, but are not widely available in many parts of the world. To address this problem, researchers at the University Of Notre Dame have developed a very cool, low-tech method to quickly test drugs for their ingredients: A tablet is scratched across the paper, and the paper is then dipped in water. Various chemicals coated on the paper react with ingredients in the drug to form colors, resulting in a “color bar code” that can then be compared to known samples of filler materials commonly used in counterfeit drugs, as well as active pharmaceutical ingredients.

Recently, there have also been policy efforts to address the problem. The European Commission released their Falsified Medicines Directive in 2011 which established counterfeit medicines as a public health threat and called for stricter penalties for producing and selling counterfeit medicines. The directive also established a common logo to be displayed on websites, allowing customers to verify they are buying through a legitimate site. In the US, VIPPS accredits legitimate online pharmacies, and in May of this year, a bill calling for stricter penalties on the distribution and import of counterfeit medicine was introduced in Congress. In addition, there have also been various public awareness campaigns, for example, last year’s MHRA #FakeMeds campaign in the UK,  which was specifically focussed on diet pills sold online, and the FDA’s “BeSafeRx” programme, which offers resources to safely buying drugs online.

In spite of all the efforts to raise awareness and address the problem of fake drugs, a major complication remains: Generic drugs, as well as branded drugs, are often produced overseas and many are sold online, which saves cost and can bring the price of medication down, making it affordable to many people. The key will be to strike the balance between restricting access of counterfeiters to the supply chain while not restricting access to affordable, quality medication for patients who need them.

We need to talk about CRISPR

By Gesa Junge, PhD

You’ve probably heard of CRISPR, the magic new gene editing technique that will either ruin the world or save it, depending on what you read and whom you talk to? Or the Three Parent Baby, which scientists in the UK have created?

CRISPR is a technology based on a bacterial immune defense system which uses Cas9, a nuclease, to cut up foreign genetic material (e.g., viral RNA). Scientists have developed a method by which they can modify the recognition part of the system, the guide RNA, and make it specific to a site in the genome that Cas9 then cuts. This is often described as “gene editing” which allows disease-causing genes to be swapped out for healthy ones.

CRISPR is now so well known that Google finally stopped suggesting I may be looking for “crisps” instead, but the real-world applications are not so well worked out yet, and there are various issues around CRISPR, including off-target effects, and also the fact that deleting genes is much easier than replacing them with something else. But, after researchers at Oregon Health and Science University managed to change the mutated version of the MYBPC3 gene to the unmutated version in a viable human embryo last month, the predictable bioethical debate was reignited, and terms such as “Designer Babies” got thrown around a lot.

A similar thing happened with the “Three Parent Baby,” an unfortunate term coined to describe mitochondrial replacement therapy (MRT). Mitochondria, the cells’ organelles for providing energy, have their own DNA (making up about 0.2% of the total genome) which is separate from the genomic DNA in the nucleus, which is the body’s blueprint. Mitochondrial DNA can mutate just like genomic DNA, potentially leading to mitochondrial disease, which affects 1 in 5000-10000 children. Mitochondrial disease can manifest in various ways, ranging from growth defects to heart or kidney to disease to neuropsychological symptoms. Symptoms can range from very mild to very severe or fatal, and the disease is incurable.

MRT replaces the mutated mitochondrial DNA in a fertilized egg or in an embryo with the healthy version provided by a third donor, which allows the mitochondria to develop normally. The UK was the first country to allow the “cautious adaption” of this technique.

While headlines need to draw attention and engage the reader for obvious reasons, oversimplifications like “gene editing” and dramatic phrases like “three parent babies” can really get in the way of broadening the understanding of science, which is difficult enough as it is. Research is a slow and inefficient process that easily gets lost in a 24-hour news cycle, and often the context is complex and not easily summed up in 140 characters. And even when the audience can be engaged and interested, the relevant papers are probably hiding behind a paywall, making fact checking difficult.

Aside from difficulties communicating the technicalities and results of studies, there is also often a lack of context in presenting scientific studies – think for example of chocolate and red wine which may or may not protect from heart attacks. What is lost in many headlines is that scientific studies usually express their results as a change in risk of developing a disease, not a direct causation, and very few diseases are caused by one chemical or one food additive. On this topic, WNYC’s “On The Media”-team have an issue of their Breaking News Consumer Handbook that is very useful to evaluate health news.

The causation vs. correlation issue is perhaps a little easier to discuss than big ethical questions that involve changing the germline DNA of human beings because ethical questions do not usually have a scientific answer, let alone a right answer. This is a problem, not just for scientists, but for everyone, because innovation often moves out of the realm of established ethics, forcing us to re-evaluate it.

Both CRISPR and MRT are very powerful techniques that can alter a person’s DNA, and potentially the DNA of their children, which makes them both promising and scary. We are not ready to use CRISPR to cure all cancers yet, and “Three Parent Babies” are not designed by anyone, but unfortunately, it can be hard to look past Designer Babies, Killer Mutations and DNA Scissors, and have a constructive discussion about the real issues, which needs to happen! These technologies exist; they will improve and eventually, and inevitably, play a role in medicine. The question is, would we rather have this development happen in reasonably well-regulated environments where authorities are at least somewhat accountable to the public, or are we happy to let countries with more questionable human rights records and even more opaque power structures take the lead?

Scientists have a responsibility to make sure their work is used for the benefit of humanity, and part of that is taking the time to talk about what we do in terms that anyone can understand, and to clarify all potential implications (both positive and negative), so that there can be an informed public discussion, and hopefully a solution everyone can live with.

 

Further Reading:

CRISPR:

National Geographic

Washington Post

 

Mitochondrial Replacement Therapy:

A paper on clinical and ethical implications

New York Times (Op-Ed)

 

HeLa, the VIP of cell lines

By  Gesa Junge, PhD

A month ago, The Immortal Life of Henrietta Lacks was released on HBO, an adaptation of Rebecca Skloot’s 2010 book of the same title. The book, and the movie, tell the story of Henrietta Lacks, the woman behind the first cell line ever generated, the famous HeLa cell line. From a biologist’s standpoint, this is a really unique thing, as we don’t usually know who is behind the cell lines we grow in the lab. Which, incidentally, is at the centre of the controversy around HeLa cells. HeLa was the first cell line ever made over 60 years ago and today a PubMed search for “HeLa” return 93274 search results.

Cell lines are an integral part to research in many fields, and these days there are probably thousands of cell lines. Usually, they are generated from patient samples which are immortalised and then can be grown in dishes, put under the microscope, frozen down, thawed and revived, have their DNA sequenced, their protein levels measured, be genetically modified, treated with drugs, and generally make biomedical research possible. As a general rule, work with cancer cell lines is an easy and cheap way to investigate biological concepts, test drugs and validate methods, mainly because cell lines are cheap compared to animal research, readily available, easy to grow, and there are few concerns around ethics and informed consent. This is because although they originate from patients, the cell lines are not considered living beings in the sense that they have feelings and lives and rights; they are for the most part considered research tools. This is an easy argument to make, as almost all cell lines are immortalised and therefore different from the original tissues patients donated, and most importantly they are anonymous, so that any data generated cannot be related back to the person.

But this is exactly what did not happen with HeLa cells. Henrietta Lack’s cells were taken without her knowledge nor consent after she was treated for cervical cancer at Johns Hopkins in 1951. At this point, nobody had managed to grow cells outside the human body, so when Henrietta Lack’s cells started to divide and grow, the researchers were excited, and yet nobody ever told her, or her family. Henrietta Lacks died of her cancer later that year, but her cells survived. For more on this, there is a great Radiolab episode that features interviews with the scientists, as well as Rebecca Skloot and Henrietta Lack’s youngest daughter Deborah Lacks Pullum.

In the 1970s, some researchers did reach out to the Lacks family, not because of ethical concerns or gratitude, but to request blood samples. This naturally led to confusion amongst family members around how Henrietta Lack’s cells could be alive, and be used in labs everywhere, even go to space, while Henrietta herself had been dead for twenty years. Nobody had told them, let alone explained the concept of cell lines to them.

The lack of consent and information are one side, but in addition to being an invaluable research tool, cell lines are also big business: The global market for cell lines development (which includes cell lines and the media they grow in, and other reagents) is worth around 3 billion dollars, and it’s growing fast. There are companies that specialise in making cell lines of certain genotypes that are sold for hundreds of dollars, and different cell types need different growth media and additives in order to grow. This adds a dimension of financial interest, and whether the family should share in the profit derived from research involving HeLa cells.

We have a lot to be grateful for to HeLa cells, and not just biomedical advances. The history of HeLa brought up a plethora of ethical issues around privacy, information, communication and consent that arguably were overdue for discussion. Innovation usually outruns ethics, but while nowadays informed consent is standard for all research involving humans, and patient data is anonymised (or at least pseudonomised and kept confidential), there were no such rules in 1951. There was also apparently no attempt to explain scientific concept and research to non-scientists.

And clearly we still have not fully grasped the issues at hand, as in 2013 researchers sequenced the HeLa cell genome – and published it. Again, without the family’s consent. The main argument in defence of publishing the HeLa genome was that the cell line was too different from the original cells to provide any information on Henrietta Lack’s living relatives. There may some truth in that; cell lines change a lot over time, but even after all these years there will still be information about Henrietta Lack’s and her family in there, and genetic information is still personal and should be kept private.

HeLa cells have gotten around to research labs around the world and even gone to space and on deep sea dives. And they are now even contaminating other cell lines (which could perhaps be interpreted as just karma). Sadly, the spotlight on Henrietta Lack’s life has sparked arguments amongst the family members around the use and distribution of profits and benefits from the book and movie, and the portrayal of Henrietta Lack’s in the story. Johns Hopkins say they have no rights to the cell line, and have not profited from them, and they have established symposiums, scholarships and awards in Henrietta Lack’s honour.

The NIH has established the HeLa Genome Data Access Working Group, which includes members of Henrietta Lack’s family. Any researcher wanting to use the HeLa cell genome in their research has to request the data from this committee, and explain their research plans, and any potential commercialisation. The data may only be used in biomedical research, not ancestry research, and no researcher is allowed to contact the Lacks family directly.

Paperfuges and Foldscopes: The Case for Low-Tech Science

 

By Gesa Junge, PhD

 

If you have ever been inside a lab you will know that centrifuges and microscopes come in various shapes and sizes and degrees of sophistication, but in some form they are used every day in most research labs around the world. Microscopes and centrifuges are pretty basic lab equipment, although some versions can be very high-end, for example high-speed centrifuges that can cool down to fridge temperatures, or electron microscopes that can magnify structures up to 2 million times. But even basic centrifuges and microscopes cost a few thousand dollars, and they require electricity and maintenance. These are not big issues for most universities and established research institutes, but for scientists working in the field, or in developing countries, money and electricity can be hard to come by.

With this in mind, Manu Prakash from Stanford University developed a centrifuge and a microscope made of paper. Yes, you read that right. The centrifuge is basically a paper disk on two strings that you pull to make the disk spin (kind of like a whirligig Saw Mill, remember those?) – check out this video from Wired Magazine. The whole thing costs 20 cents and fits into a jacket pocket, but it can spin samples up to 12500rpm, which is fast. Fast enough, for example, to separate blood into blood cells and plasma, which is a key step in many diagnostic procedures.

And the foldscope is basically origami. It is printed on paper, you cut out the parts and fold them up and insert a lens. The microscope does need electricity, but it can run on a battery for up to 50 hours, and the sample can be mounted on a piece of tape, as opposed to a glass slide. The lens determines the magnification, and they can go up to 2000x. For reference, we can distinguish individual human cells easily at 10x, nuclei become clearly visible at 20x and bacteria at 40x. Using different color LEDs, this can even be converted into a fluorescent microscope, meaning it can be used to analyse different stains of tissues.

The paperfuge and the foldscope are the implementation of an emerging concept called “frugal science”, and aim to bring scientific advances to inaccessible and under-developed regions. And while Manu Prakash’s ideas are very low-tech approaches, the idea of making science useful to everyone also benefits from innovation and advanced technology. For example, Dr Samuel Sia at Columbia University has developed a smart phone dongle technology called mChip which can diagnose HIV from a finger prick’s worth of blood. This device contains all the necessary reagents which mix at the push of a button, and it plugs into the headphone jack of a phone as a power supply. Testing takes about 15 minutes and costs about $1 (the dongle is $100), which is a huge improvement over current methods. In a similar concept, a company called QuantumMDx in Newcastle in the UK is developing a handheld DNA testing tool, which could be used to identify strains of pathogens. And electronics company Phillips has come up with the MiniCare I-20, a handheld device that can measure troponin I levels from a single drop of blood taken from a pinprick. Troponin I is a marker of a damaged heart muscle, and is often measured in emergency departments.

All of these innovations address a really important, and sometimes overlooked, point: science and technology, in all their greatness and cool fascination, will only benefit humanity if applied in the community in a way that leads to real-life changes. As with so many resources, scientific expertise and technology, and therefore the benefit of science, are distributed incredibly unevenly among the world’s society. For example, malaria and AIDS drugs are still not reaching many of the people who need them, be it for financial, infrastructural, political, or organisational reasons. Diagnostic tests often require well-equipped labs and trained technicians. And while they are limited in their applications for research, the paperfuge and the foldscope have the potential to revolutionize diagnostics as well as education around the world. Cutting-edge research may require more sophisticated centrifuges that spin faster, microscopes that have better resolution, computers to store the images, and teams of scientists analyzing the data. But the frugal science approach is well-suited for the diagnosis of diseases, or to help a high school science class understand what cells are.

If you would like to find out more about the foldscope, check out Manu Prakash’s very cool TED talk. More information on Dr Sia’s mChip can be found here.

 

End Crisis, Bridges and Scattered Genes: Chromatin Bridges and their Role in Genomic Stability

By Gesa Junge, PhD

Each of our cells contains about two meters of DNA which needs to be stored in cells that are often less than 100uM in diameter, and to make this possible, the DNA is tightly packed into chromosomes. As the human cell prepares to divide, the 23 pairs of chromosomes neatly line up and attach to the spindle apparatus via their middle point, the centrosome. The spindle apparatus is part of the cell’s scaffolding and it pulls the chromosomes to opposite ends of the cell as the cell divides, so that every new daughter cell ends up with exactly one copy of each chromosome. This is important; cells with more or less than one copy of a chromosome are called aneuploid cells, and aneuploidy can lead to genetic disorders such as Down Syndrome (three copies of chromosome 21).

In some cancer cells, chromosomes with two centromeres (dicentric chromosomes) can be detected, which can happen when the ends of two chromosomes fuse in a process called telomere crisis. Telomeres are a sort of buffer zone at the ends of the chromosome which consist of repeats of non-coding DNA sequences, meaning there are no genes located here. As one of the DNA strands is not replicated continuously but in fragments, the telomeres get shorter over the lifespan of a cell, and short telomeres can trigger cell cycle arrest before the chromosomes get so short that genetic information is lost. But occasionally, and especially in cancer cells, chromosome ends fuse and a chromosome becomes dicentric. Then it can attach to the spindle apparatus in two points and may end up being pulled apart as the two daughter cells separate, sort of like a rope tied to two cars that drive in opposite directions. This string of chromosome is referred to as a chromatin bridge.

Researchers at Rockefeller University are studying these chromatin bridges and what their relevance is for the health of the cell. A paper by John Maciejowski and colleagues found that the chromatin bridges actually stay intact for quite a long time. Chromosomes are pretty stable, and so the chromatin bridges lasted for an average of about 9 hours (3-20h) before snapping and quickly being pulled back into the original cell (see video). Also, the nucleus of the cell was often heart-shaped as opposed to the usual round shape, which suggests that the chromatin bridge physically pulls on the membrane surrounding the nucleus, the nuclear envelope. Indeed, proteins that make up the nuclear envelope (e.g. LAP2) were seen on the chromatin bridge, suggesting that they take part of the nuclear envelope with them as they divide.  Also, cells with chromatin bridges had temporary disruptions to their nuclear envelope at some point after the bridge was resolved, more so than cells without chromatin bridges.

The chromatin bridges also stained positive for replication protein A (RPA), which binds single stranded DNA. DNA usually exists as two complementary strands bound together, and the two strands really only separate to allow for DNA to be copied or transcribed to make protein. Single-stranded DNA is very quickly bound by RPA, which stabilises it so it does not loop back on itself and get tangled up in secondary structures. The Rockefeller study showed that a nuclease, a DNA-eating enzyme, called TREX1 is responsible for generating the single-stranded DNA on chromatin bridges. And this TREX1 enzyme seems to be really important in resolving the chromatin bridges: cells that do not have TREX1 resolve their chromatin bridges later than cells that do have TREX1.

So how are chromatin bridges important for cells, the tissue and the organism (i.e. us)? The authors of this study suggest that chromatin bridges can lead to a phenomenon called chromothripsis. In chromothripsis, a region of a chromosome is shattered and then put back together in a fairly random order and with some genes facing the wrong direction. Think of a new, neatly color-sorted box of crayons that falls on the floor, and then someone hastily shoves all the crayons back in the box with no consideration for color coordination or orientation. Chromothripsis occurs in several types of cancers, but it is still not really clear how often, in what context and exactly how the genes on a chromosome end up in such a mess.

According to this study, chromothripsis may be a consequence of telomere crisis, and chromatin bridges could be part of the mechanism: A chromosome fuses ends with another chromosome and develops two centromeres. The dicentric chromosome attaches to two opposite spindles and is pulled apart during cell division, generating a chromatin bridge which is attacked by TREX that turns it into single-stranded DNA, the bridge snaps and in the process the DNA scatters, and returns to the parent cell where it is haphazardly reassembled, leaving a chromothripsis region.

The exact mechanisms of this still need to be studied and the paper mentions a few important discussion points. For example, all the experiments were performed in cell culture, and the picture may look very different in a tumor in a human being. And what exactly causes the bridge to break? Also, there are probably more than one potentially mechanism linking telomere crisis to chromothripsis. But it is a very interesting study that shines some light on the somewhat bizarre phenomenon of chromothripsis, and the importance of telomere crisis.

Reference: Maciejowski et al, Cell. 2015 Dec 17; 163(7): 1641–1654.

 

 

Goals and Habits: A Scientific Take on New Year’s Resolutions

 

By Gesa Junge, PhD

Happy New Year! Did you make any New Year’s Resolutions? Are they exactly the same ones as last year? Maybe science can help you actually keep them this year (so you can make new ones for 2018).

Giving up on New Year’s Resolutions is incredibly common. Statistics suggest that about half of us make New Year’s Resolution, but less than 10% keep them. Still, there are some ways that psychologists, behavioral scientists and even economists suggest can help you actually make some lasting changes.

Setting the right goals is an important first step. There is a whole TED article on the science behind goal-setting, but the key issues are to pick a meaningful goal, and figuring out exactly why it is so important to you to make this change in order to stay motivated. Also, goals need to strike a balance between too easy and too hard – research from the 1980s shows that more difficult goals can make you work harder. Similarly, specific goals lead to better outcomes than vague and generic goals, probably because it is easier to measure success.

But realistically, in order to make long-term changes, you need to change your habits. Neurologists distinguish between goal-oriented and habitual actions, and according to a 2006 study, almost half of our behavior is habitual. Routines allow our brains to function more efficiently. This makes sense – if we had to focus on all the little actions that are required to for everyday things like making a cup of tea or taking the subway to work, that would be incredibly exhausting.

So a lot of processes can become automated, often even without you noticing. Studies show that rodents trained to find a food reward in the left arm of a T-maze will quickly get into the habit of running straight down to the left arm even if the reward is no longer there. The basal ganglia are thought to play a key role in habit formation, although there is still some controversy around which brain regions are specifically responsible for habit formation. NIH researchers found that, on a molecular level, the endocannabinoid system plays a role. Endocannabinoids are endogenous signalling molecules that stimulate activity via cannabinoid receptors, and mutations in the CB1 cannabinoid receptor prevented mice from forming habits in a lever-press test for a sucrose reward.

As we probably all know habits can be pretty difficult to change. Researchers at MIT trained rats to turn left for chocolate or right for sugar water in a T-maze, depending on which one of two audio signals they received. If the rats are later given chocolate milk mixed with enough lithium chloride to make them nauseous, they will still follow the audio cue to the left (even if they did not always drink the milk), indicating the behavior had become habitual. However, this behavior was lost when the researchers interfered with the infralimbic cortex, and the rats soon started habitually turning right for the sugar water, regardless of the sound cue. But once this new habit was broken (again by interfering with the infralimbic cortex), the animals reverted back to the original habit of going left or right depending on the sound cue. This suggests that habits are really replaced as opposed to lost, and that they can come back, which would explain why it is a) quite hard to break a habit in the first place and b) not to fall back into old habits later.

So a good strategy might be to change or replace habits rather than trying to get rid of them completely. In order to achieve this, there are various commitment devices, that is, measures that make you do the things you would otherwise probably not feel like doing. There is a very interesting Slate article that gives more examples, but one that sounds particularly effective is a website called StikK, founded by behavioral economists from Yale. Here, you can formulate a commitment and put money on the line which, if you don’t reach your goal, is donated to a charity, person or – probably most effective – an anti-charity. An anti-charity is a cause you truly despise (think political parties, lobbying groups, sports teams…).

Another interesting tool is “temptation bundling”, essentially combining activities you like to do with activities you know you should do but don’t particularly enjoy, e.g. only binge-watching Netflix while ironing or cleaning the house. This was evaluated in a study at the University of Pennsylvania that showed that allowing people to only listen to engaging audio books at the gym (by means of a locked-away iPod) caused them to spend more time at the gym than control groups. Unfortunately, all the effects were lost after Thanksgiving break, but November is a while away, so maybe it would be worth a try.

So it may take some effort, but hopefully you can find a way to stick to your resolutions longer than last year. Or at least past Ditch New Year’s Resolutions Day which apparently is January 17th. Good luck, and all the best for 2017!

 

Scizzle’s Christmas Gift Guide 2016

By Sally Burn, Gesa Junge, and Deidre Sackett

 

Ho ho ho, science lovers! It’s that time of year again: panic buying gifts for your nearest and dearest! If your intended recipient happens to be a scientist or a fan of all things science, we have a veritable selection of gift ideas. Or perhaps you yourself are angling to receive a science-themed present and want to point the buyer in the right direction. Then look no further: behold, Scizzle’s 2016 Christmas gift guide!

 

Culinary Science

Turn any kitchen into a lab with our handpicked selection of geeky culinary gifts. Spice up your cooking with the Chemist’s Spice Rack from ThinkGeek or whip up some cosmic cookies with these 3D spaceship cookie cutters. Then put a smile on the mathematician in your life’s face by serving them festive dessert on the i eight sum pi plates. Finally, prevent your Christmas lunch leftovers from being stolen from the communal fridge by taking them to work in this human organ for transplant insulated lunch bag.

 

Technical Tipples

Bring out the crazy scientist mixologist in you this festive season with a Chemist’s Cocktail Kit, then serve up your creations in drinking glasses that are out of this world. The Planetary Glass Set contains ten gorgeous tumblers – representing all eight planets in our solar system, plus the sun and Pluto. Pair the glasses with an anatomically informative coaster set to avoid marking your table – we heart these cardiac anatomy coasters, although the more cerebral minded may prefer a set of Brain Specimen Coasters.

 

Science Bling

Wear the whole solar system around your neck with this fabulous Solar Orbit Necklace or just keep Pluto’s heart close to your own with a Pluto pendant. Like DNA? Put a ring on it with this simple DNA helix ring available on Etsy.

 

Science Apparel

Help the female neurobiologist in your life stand out from the crowd in this Neurons Glow-in-the-Dark-Dress. Or go all out science with the Nerdy Science Dress, festooned with Erlenmeyers, microscopes, formulae, and DNA helices. And for sir, may we suggest the Too Molecule for School Men’s Socks.

 

For Kids (Both Little and Big)

You’re never too young or old to cuddle up with a plush brain, spleen, rectum, or any of the thirteen adorable soft organs available from Uncommon Goods. Or how about a crochet Erlenmeyer flask?

 

SciArt

Check out the Etsy store of the ultra-talented Ella Maruschchenko, whose illustrations have been featured on the cover of many leading journals, for science-themed prints and mugs. For an even greater range of SciArt gifts, head over to the Artologica Etsy store where you will find gorgeous paintings, silk scarves, and petri dish ornaments.

 

High End Geek Gadgetry

The Smartphone Instant Photo Lab is at the higher end of the gift budget ($169.99 and $24.99 for film) but worth it for the thrill of printing your candid Christmas party shots direct from your phone to Polaroid-style paper.

 

Under $10 – for Secret Santa and Stuffing Stockings

Finally, for $3 you can be the proud gifter of an infectious disease stress ball and for under $10 you can pick up a set of five solar power toy cars, a cute Space Capsule Tea Infuser, or even this super chic chemistry lab beaker vase.

 

Have Yourself a Merry Literature Christmas

By Gesa Junge, PhD

 

Now that Halloween and Thanksgiving are over, it seems that the world is moving full-speed towards Christmas. And while TV has Christmas adverts and Christmas specials, and the frequency of Christmas songs on the radio has been steadily increasing, what does Christmas look like in the world of scientific publishing? Interestingly, a Pubmed search for “Christmas”, has over a thousand results with “Christmas” in the title.

Some of these papers focus on holiday-related injuries, such as burns or falls. For example, one study analysed burn injuries due to Christmas decorations-associated fires, and while these are fairly rare, the majority of them actually occur after the holiday, presumably due to trees and wreaths drying out and becoming more flammable. Researchers in Calgary observed that several trauma patients were injured while installing Christmas lights, and this along with statistics showing increased risk of falls during winter months, prompted them to study this correlation. Most people in this study fell off of ladders or roofs, and most patients were male and middle-aged. The study also found that several patients sustained serious injuries, with  20% of patients requiring admission to the ICU and the median duration patients stayed in hospital being just over 2 weeks (15.6 days, range 2-165). This

Another study looked into blood alcohol content after consumption of commercially available (notably not homemade) Christmas pudding for lunch, measuring ethanol content of the pudding and then calculating what the blood alcohol content would be immediately after pudding consumption and 30 minutes later. The maximum blood alcohol content did not exceed 0.05g/dL  and the authors conclude that “[h]ospital staff should feel confident that the enthusiastic consumption of Christmas pudding at work in the festive season is unlikely to affect their work performance […]”, as long as they ate less than 1kg of it.

There is also an interesting paper which addresses the question of how to win the Christmas cracker pull. This is a UK-based tradition, in which two people pull on opposite ends of a Christmas cracker until it splits into two uneven pieces, and the person who ends up holding the larger piece wins the usually completely useless plastic toy inside the cracker. The study distinguishes between three techniques: The QinetiQ strategy (two-handed pull, slightly downwards), the passive-aggressive strategy (two-handed grip, but letting the other person pull) and the control strategy (both sides pull approximately parallel to the floor). Turns out, the passive aggressive strategy is the one most likely to lead to a win (92% probability, 95% CI 0.76-1), at least with regards to Christmas crackers.

The results of the Christmas cracker and Christmas pudding studies are published in the same issue of the Medical Journal of Australia alongside a few other brilliant Christmas-related papers, one of which offers a diagnosis of “patient R”, suffering from a shiny lesion on his nose that severely affected his quality of life. The paper suggests lupus pernio may be the unifying diagnosis.

Finally, a group of researchers in Denmark set out to show that there is indeed such a thing as “the Christmas spririt”. This is not a well-defined state, but rather a generally joyful state brought about by decorations, food and smells associated with Christmas. The researchers showed people images with a Christmas theme (e.g. a street in the dark decorated with lights, or a plate of Christmas cookies decorated with a Santa figure and Christmas baubles) and similar images with nothing Christmas-associated (e.g. a regular street, or a plate of cookies on a kitchen counter with no decoration) while monitoring brain activity in a functional MRI scanner. They studied ten people who had celebrated Christmas from a young age (the Christmas group) and ten people who did not celebrate Christmas (the non-Christmas group). Both groups showed increased activity in the primary visual cortex when being shown Christmas-themed images compared to everyday images, but the Christmas group also showed greater activity in several brain regions that did not occur in the non-Christmas group, including the primary motor and premotor cortex, the right inferior/superior parietal lobule, and the bilateral primary somatosensory cortex. This suggests that people who have a strong association with Christmas traditions and celebrations respond differently to Christmas-themed images than people who have no association with Christmas. However, how exactly those brain areas bring about the mysterious Christmas spirit is not clear.

So in conclusion, please be safe when installing holiday lights and keep an eye on the candles, but do feel free to eat Christmas pudding while passive-aggressively pulling Christmas crackers, and if you still can’t seem to find the Christmas spirit, go get a functional MRI scan. Merry Christmas and Happy Holidays!

Immunotherapy: Using Your Own Cells to Fight Cancer – Part 2

 

By Gesa Junge, PhD

 

Part 1 of this post described passive immunotherapies like antibodies and cytokines, but there are also active immunotherapies, which re-target our immune system towards cancer cells, for example cancer vaccines. These can be preventative vaccines, offering protection against cancer-associated viruses such as Hepatitis B (liver cancer) or Human Papilloma Virus (HPV, cervical cancer). The link between HPV and cervical cancer was first described in 1983, and a vaccine was approved in 2006. By 2015, the incidence of HPV infections in women under 20 had decreased as much as 60% in countries that had 50% vaccination coverage, although it may still be too early to tell what the impact on HPV-associated cancer incidence is. There are also other factors to consider, for example screening programmes are also likely to have a positive impact on HPV-associated cancers.

Vaccines can also be therapeutic vaccines, which stimulate the immune system to attack cancer cells. To date, the only cancer vaccine approved in the US is Provenge, used for the treatment of metastatic prostate cancer. For this therapy, a patient’s white blood cells are extracted from the blood, incubated with prostatic acid phosphatase (PAP, a prostate-specific enzyme) and granulocyte macrophage colony stimulating factor (GM-CSF) in order to produce mature antigen presenting cells which are then returned to the patient and search and destroy tumour cells.

Many other therapeutic cancer vaccines are in development, for example OncoVax, which is an autologous vaccine made from a patient’s resected tumour cells. OncoVax has been in development since the 1990s and is currently in phase III trials. Another example is GVAX, an allogenic whole-cell tumour vaccine currently being studied in phase I and II trials or pancreatic and colorectal cancer. As an allogenic vaccine, it is not made from the patient’s own blood cells (like an autologous vaccine), and it does not target specific antigens but rather increases the production of cytokines and GM-CSF.

Another therapy which is based on re-programming the patient’s immune system is adoptive T-cell transfer. As with some cancer vaccines, a patient’s T-cells are isolated from the blood, and the cells with the greatest affinity for tumour cells are expanded in the lab and the re-infused in the patient. A recent modification of this technique is the use of chimeric antigen receptor (CAR) T-cells, where the T-cell receptors are genetically engineered to be more tumour-specific before re-infusion. This approached was especially promising in chronic lymphocytic leukaemia, where some patients experienced remissions of a year and longer. Later, CAR T-cells were also tested in acute lymphocytic leukaemia, where response rates were as high as 89%.

Finally, a new class of cancer drugs called immune checkpoint inhibitors has been making headlines recently, some of which are now approved for the treatment of cancer. Immune checkpoints are part of the mechanism by which human cells, including cancer cells, can evade the immune system. For example, the programmed cell death (PD) 1 receptor on immune cells interacts with PD1 ligand (PDL1) on cancer cells, which inhibits the killing of the cancer cell by the immune cell. Similarly, CTLA-4 is a receptor on activated T-cells which downregulates the immune response.

The first checkpoint inhibitor was an antibody to CTLA-4, ipilimumab, which was approved for the treatment of melanoma in 2011. PD1 antibodies such as pembrolizumab and nivolumab were only approved in 2014, and the only PDL1 antibody (atezolizumab) in 2016, so it is difficult to tell what the long-term effects of checkpoint inhibitor treatment will be. Numerous checkpoint inhibitors are still undergoing trials, most of the advanced (phase III) ones being targeted to PD1 or PDL1. However, there are other compounds in early trials (phase I or II) that target KIR (killer-cell immunoglobulin-like receptor) which are primarily being studied in myeloma, or LAG3 (lymphocyte activation gene 3), in trials for various solid tumours and leukaemias.

Immunotherapies all come under the umbrella of biological therapies. Biologics are produced by organisms, usually cells in a dish, unlike synthetic drugs, which are manufactured using a chemical process in the lab. This makes biologicals more expensive to manufacture. Ipilimumab therapy, for example, can cost about $100 000 per patient, with pembrolizumab and nivolumab being only slightly less expensive at $48 000 – $67 000. This puts considerable financial strain on patients and insurance companies. From a safety perspective, biologicals can cause the immune system to overreact. This sounds odd, as the whole point of immunotherapy is to activate the immune system in order to fight tumour cells, but if this response gets out of control, it can lead to potentially serious side effects as the immune system attacks the body’s organs and tissues.

All of these therapeutic approaches (antibodies, interleukins, vaccines, and checkpoint inhibitors) are usually not used alone but in combination with each other or other chemotherapy, which makes it difficult to definitively say which drug works best. But it is safe to say that collectively they have improved the lives of a lot of cancer patients. If you are interested in finding out more about the fascinating history of immunotherapy, from the discovery of the immune system to checkpoint inhibitors, check out the CRI’s timeline of progress on immunology and immunotherapy here.

 

Immunotherapy: Using Your Own Cells to Fight Cancer – Part 1

 

By Gesa Junge, PhD

 

Our immune system’s job is to recognize foreign, unfamiliar and potentially dangerous cells and molecules. On the one hand, it helps us fight infections by bacteria and viruses, while on the other hand it can leave us with annoying and potentially dangerous allergic reactions to harmless things like peanuts, pollen or pets. Tumor cells are arguably very harmful to our health, and yet the immune system does not always eliminate them. This is partially because cancer cells are our own cells, and not a foreign, unfamiliar intruder.

The immune system can recognize cancer cells; this was first postulated in 1909 by Paul Ehrlich and subsequently found by several others. However, detecting cancer cells may not be enough to prevent tumor growth. Recent research has shown that while detection can lead to elimination of cancer cells, some cells are not killed but enter an equilibrium stage, where they can exist undisturbed and undergo changes, and finally the cells can escape, if they have changed in a way that allows them to grow undetected by the immune system. This process of elimination, equilibrium and escape is referred to as “cancer immunoediting” and is one of the most active research areas in cancer, particularly in regard to cancer therapy.

Immunotherapy is a form of cancer therapy that harnesses our immune system to kill cancer cells, and there are various approaches to this. Probably the most established forms of immunotherapy are antibodies, which have been used for almost two decades. They generally target surface markers of cancer cells; for example, rituximab is an antibody to CD20, or trastuzumab, which targets HER2. CD20 and HER2 are cell surface proteins highly expressed by leukaemia and breast cancer cells, respectively, while normal, healthy cells have lower expression, making the cancer cells more susceptible. Rituximab was approved for Non-Hodgkins Lymphoma in 1997, the first of now nearly 20 antibodies to be routinely used in cancer therapy. In addition to this, there are several new antibodies undergoing clinical trials for most cancers. These are mainly antibodies to tumour-specific antigens (proteins that may only be expressed by e.g. prostate or lung cancer), and checkpoint inhibitors such as PD1 (more on that in part 2).

Initially, antibodies were usually generated in mice; however, giving murine antibodies to humans can lead to an immune response and resistance to the mouse antibodies when they are administered again later. Therefore, antibodies had to be “humanised”, i.e. made more like human antibodies, without losing the target affinity, and this was only made possible by advances in biotechnology. The first clinically used antibodies, such as rituximab, were chimeric antibodies, in which the variable region (which binds the target) is murine and the constant region is human, making them much better tolerated. Trastuzumab is an example of a humanised antibody, where only the very end of the variable region (the complementarity-determining region, CDR) is murine, and the rest of the molecule is human). And then there are fully human antibodies, such as panitumumab, an anti-EGFR antibody used to treat colorectal cancer. There is actually a system to labeling therapeutic antibodies: -ximab is chimeric, -zumab is humanised and –umab is human.

Antibodies can also be conjugated to drugs, which should make the drug more selective to its target and the antibody more effective in cell-killing. So far there are only very few antibody-drug conjugates in clinical use, but one example is Kadcyla, which consists of trastuzumab conjugated to emtansine, a cytotoxic agent.

Other examples of immunotherapy are cytokines such as interferons and interleukins. These are mediators of the immune response secreted by immune cells which can be given intravenously to help attack cancer cells, and they are used for example in the treatment of skin cancer. Interleukin 2 (IL-2) was the first interleukin to be approved, for the treatment of advanced melanoma and renal cancer, and research into new interleukins and their therapeutic potential is still going strong. Especially IL-2 and IL-12, but also several others are currently in clinical studies for both and various other indications, such as viral infections and autoimmune diseases.

In addition to passive immunotherapies like antibodies and cytokines, there are also active immunotherapies which re-target our immune system towards cancer cells, for example cancer vaccines. More on this, and on new drugs and their issues in part 2.