Nanites!

I am a moderate Star Trek fan.  I have never dressed up like Uhura and gone to Comicon or anything, but I’ve seen all the Star Trek movies (most of them since Star Trek V in the theatre) and have watched many of the original TV reruns.  This is mainly because my dad was a huge fan, not able to go on dates on Fridays in the 60’s because he had to be home to watch the show (life was so hard before DVRs).  I never got into any of the TV spin-offs though.  So, when my husband watches The Next Generation (TNG), I refuse to watch it.  It’s not the original.  Cheesy sci-fi in the late-80’s and 90’s just isn’t the same, especially without Shatner.  However, it’s sometimes hard to avoid hearing or seeing some of it in our one bedroom loft.

You might have to squint really hard to see the nanites.

So when my friend Kari sent me an article about how nanoparticles can control blood sugar in diabetics for up to 10 days, I immediately thought of a TNG episode that accidentally seeped into my ear canals (and also guest-stars Dr. Bob Kelso from “Scrubs”).  It was an episode in which nanites, or microscopic robotic devices, could be put into humans and programmed to do medical tasks.  The actual episode storyline revolves around how the tiny computers “evolve” and start attacking the ship.  Eventually the nanites are given their own habitat to live in as autonomous creatures (reason #835 why I can’t watch this show).  But I digress.

Are “nanites” for medical use becoming a reality?

Yes and no.  Actual molecular nanorobots that can perform work inside cells are not a reality yet, but nanoparticles are.  Most nanoparticles used in the medical field utilize coatings that allow drugs or other useful molecules to be transported in the blood stream, targeted to a specific site within the body, or shielded from the immune system to avoid degradation.   Cancer drugs such as Abraxane and Doxil are two examples already in use.  Abraxane is a common cancer drug (paclitaxel) bound to a naturally-occuring blood protein (albumin).  The nanoparticle exploits the feeding system of the tumor, which takes in nutrients normally bound to albumin that are circulating in the bloodstream.  Tumors basically eat themselves to death when Abraxane is present, because they “eat” the albumin…and the drug that is bound to it.  Doxil is another cancer drug (doxorubicin) that is enveloped in a polyethylene glycol-coated liposome (similar to a cell membrane) and is used to treat Kaposi sarcoma, which causes skin tumors.  The coating targets the drug to the skin and the liposome reduces cardiotoxic effects (heart problems) of the drug.  There are many more nanoparticles currently in use, and if you want to read further, Wikipedia has a pretty good article on nanomedicine.

Using nanoparticles for long-lasting blood glucose regulation is a real breakthrough in the treatment of diabetes.  In a normal pancreas, the beta cells transport glucose from the bloodstream into the cell and metabolize it.  The energy and metabolites from glucose metabolism cause a series of events in the cell to release the hormone insulin into the bloodstream.  This mechanism allows the beta cell to sense the blood glucose levels and secrete the correct concentration of insulin in response.  People with type 1 diabetes have lost their beta cells (due to an autoimmune reaction) and can no longer produce insulin.  What makes this new nanoparticle exciting, is that it creates a closed-loop system that releases insulin by “sensing” circulating blood glucose levels, similar to a beta cell.  I have previously posted about an external “bionic” pancreas, which is an open-loop system that consists of an external continuous glucose sensor, an insulin pump, and a glucagon pump.  This type of system relies on electronic automation and accuracy.  Nanoparticles rely on chemistry for glucose sensing and insulin release.

WARNING: this paragraph contains chemistry, read at your own risk.  The nanoparticle that the Anderson lab created consists of insulin, glucose oxidase, and catalase inside an m-dextran matrix surrounded by a chitosan or alginate coating.  Insulin is usually released by the pancreas in response to increased blood glucose levels and the nanoparticle is able to “sense” blood glucose levels with glucose oxidase, an enzyme that converts glucose into gluconic acid.  Gluconic acid decreases the pH of the nanoparticle to degrade the m-dextran sphere and release the insulin.  The chemical reaction of glucose + oxygen + water catalyzed by glucose oxidase not only produces gluconic acid, but also hydrogen peroxide (which is toxic at high levels).  Therefore, catalase is the other enzyme in the particle that converts the hydrogen peroxide back into water and oxygen (to keep the glucose oxidase reaction continuing).  The spheres are coated with positively-charged chitosan or negatively-charged alginate to form an electrostatic network of nanoparticles, or nano-network.  Creating this three-dimensional, porous structure of tiny spheres increases the surface area-to-volume ratio to make the “sensor”, or the interaction between glucose in the blood and glucose oxidase in the nanoparticle, more efficient.

Upper panel: The nanoparticle. Lower left panel: The nano-network. Lower right panel: Insulin release response of the nano-network in a test tube with glucose concentration changes (100 or 400 mg/dL) every 2 hours.
From: Gu, et al. (2013) ACS Nano, 7(5): 4194-4201.

In case you skipped the previous paragraph, what makes this nanoparticle so great, is that it uses chemistry (which is usually infallible) to work.  The nanoparticle is engineered with many layers to encapsulate everything necessary for glucose concentration to be sensed, insulin to be released, and no cytotoxic (cell-killing) byproducts to be created.  And it works pretty well in mice.

Usually people with type 1 diabetes have to inject themselves multiple times a day with insulin.  They must also calculate how much insulin they should inject based on multiple factors: food intake, blood glucose measurements, and physical activity.  In this study, after injecting the 150 microliters of the nano-network into a diabetic mouse, it took 10 days for the nanoparticles to deplete.  Some mice maintained normal blood glucose levels for 15 days.  Two weeks after administration, the glycated albumin ratio (a measure of diabetic control over a few weeks) in mice treated with nanoparticles decreased from 10% to 6% (from a diabetic to a normal range).  If this type of system can be used in humans, it would increase the quality of life for diabetic patients considerably.

The problem with this nano-network system is that it is injected under the skin and sits in a visible lump until the nanoparticles break down and get cleared from the area.  Even though all the materials in the nanoparticle are biocompatible (not harmful to the body), there is local inflammation at the injection site while the lump of nanoparticles are physically there.  This system has yet to be tested in humans, who are much larger than the mice used in this study and may pose different problems.  The authors also don’t mention any experiments with a second injection after 10 days.  Insulin-dependent diabetic patients need to continue their insulin treatment for the rest of their life, so if the nanoparticles or certain components never get completely cleared from the bloodstream or begin building up after multiple injections (the authors do not mention blood pH measurements), then this treatment is not as feasible.

For now, nanoparticles are very promising in many different medical fields.  However, as electronic technology becomes smaller and smaller, nanorobots are not completely out of the question.  There is some really cool science going on in the John Rogers lab at the University of Illinois.  They have created dissolving electronics, stretchable lithium ion batteries, and malleable circuits that could be integrated into the body in the future.  Scientists just need to create electronics that are as reliable as biology and chemistry – and make sure they don’t evolve and take over the ship.

Marshmallow Fluff

I got an email forward from my mother-in-law a few months ago that had several little tricks or tidbits of knowledge that can be useful, such as “Reynolds Wrap has lock-in tabs to hold the roll in place.”  I can’t believe that I never noticed that before.  Some of the tips I had heard of previously, but some others seemed just too good to be true.

One of the tricks was, “Marshmallows can cure a sore throat. Perfect for kids who don’t like medicine.”  First of all, there is no over-the-counter medicine that can cure a sore throat.  The antibiotics that kill the Group A streptococcal bacteria causing your sore throat would do it though (and only if you have strep throat in the first place).  I’m sure they were talking about soothing a sore throat.  Even so, I would love a new trick to soothe a sore throat, especially if it involves marshmallows.  I considered how marshmallows could do such a thing.  I have heard of gargling with warm salt water, but never sugar water.  Maybe the powder on the outside of the marshmallow helps to coat the throat?  I wasn’t sure.

I didn’t really think about it until this week, when I got a cold.  My sore throat isn’t as bad as it usually is, so I thought, maybe I should stop by the store pick up some marshmallows.  That is, until my common sense came back to me and I decided to look into this a little further.  Further, as in, I Googled it.

With a simple search, I found the answer I was looking for.  Although some top hits were websites touting the wonderous marshmallow cure, the real answer was glaringly obvious.  The root of the marshmallow plant, Althaea officinalis, has been used for centuries to soothe a sore throat.  I decided this misinformation was a result of Telephone.  You know, the kids’ game when you whisper something into someone’s ear, then the sentence gets passed from person-to-person, and the words become distorted each time it gets whispered until the last person announces a sentence that makes absolutely no sense?  The problem now is, emails like this get passed around, and the Legend of the Marshmallow grows.  Other people put it on their websites and blogs as fact and eventually doctors will start prescribing marshmallows to children (I hope not).

Public domain image from Franz Eugen Köhler’s “Köhler’s Medizinal-Pflanzen”

Now that I know I can’t make a S’more and cure my sore throat, although I bet it would do wonders on my mental health, I decided to see what this marshmallow plant can do.  The root of A. officinalis contains polysaccharides (long chains of sugars) that are sticky and viscous.  There are many types of polysaccharides present in the plant, including mucilage, pectin, and starch.  Aqueous extracts of the root contain polysaccharides that can coat the throat and stomach to protect it from irritation, which, in turn, may reduce dry coughs or gastric ulcers.  A specific pectic polysaccharide, rhamnogalacturonan, has been shown to suppress coughing in guinea pigs at high concentrations.  There is some evidence that methanol extracts from the root of the marshmallow plant contain antimicrobial activities as well.  A. officinalis inhibited growth of certain strains of bacteria that cause periodontal disease and stressed E. coli bacteria (although did not kill it).  Extracts from the flower may also increase good (HDL) cholesterol, reduce inflammation, alleviate gastric ulcers, and inhibit platelet aggregation.  Although these studies hint at reducing various ills, there are very few published studies (at least in America) that concern the marshmallow plant.

So, there you have it.  If you have some polysaccharide extract from the root of Althaea officinalis, it may reduce throat irritation and help suppress a dry cough.  If you don’t happen to have this on hand, then I recommend sucking on a lozenge.  This example just goes to show, don’t believe everything you read, even when it is intermixed with other useful information.  “Telephone” seems to have turned into “Internet”.  Instead of old wives tales or home remedies being passed orally, we have now turned to internet-doctoring ourselves for the same type of advice.  Mothers everywhere love sending forwards to their children (The perfume is ether!  Driving with no headlights on is a gang initiation!  Car-jackers put paper on your back window!) in an attempt to protect them from afar, even though most all of those scenarios have been proven untrue by Snopes.  My mother-in-law prefaced her email with, “I’ve heard of some of these, but others are a revelation, if they really work!”  If they really work, indeed.

Juicing the Most out of Your Medication

Many of your medications may have warnings of TAKE WITH FOOD or DO NOT EAT 30 MINUTES BEFORE OR AFTER THIS MEDICATION because oral drugs may upset the stomach or not be absorbed as well depending on food intake.  Some foods, like the grapefruit, can act like a drug themselves.

Grapefruit juice contains a chemical called  bergamottin (and 6’,7’-dihydroxybergamottin, which were first found in bergamot oranges).  This chemical is a specific inhibitor of an enzyme in your liver and small intestine called cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) that usually metabolizes macromolecules (lipids, proteins), but also drugs and toxins.  Depending on the drug, CYP enzymes can either increase or decrease the amount of active drug in your circulation (called bioavailability).  There are warnings not to drink grapefruit juice with some statin medications because that would increase the bioavailability of the statin and could cause side effects and organ damage.

Creative Commons Copyright John Steven Fernandez

Some researchers are actually using the power of the grapefruit to benefit patients.  They are investigating whether grapefruit juice could be used as a ‘drug booster’ –  the drug dosage could be lowered, but the resulting bioavailability would be the same.  Using less drug would translate to a lower cost to the consumer.  During Phase I trials in humans, researchers determined that an 8-oz. daily glass of grapefruit juice increased the bioavailability of 25 mg of sirolimus (a possible anti-cancer drug that is currently used as an immunosuppressant) to that of 90 mg of sirolimus alone.  That translates into taking 25% of the usual drug dose but seeing the same effects of the drug on cancer cells.

There are a couple of drawbacks to using grapefruit as a prescription.  The concentration of bergamottin can vary between grapefruit juice batches.  The authors of the Phase I study contacted the Florida Department of Citrus to obtain a frozen concentrate that was tested for bergamottin levels before they used it.  The other inconsistency is the variation between individuals.  Some people have higher levels of CYP3A4 enzyme in their small intestine (as much as 40-fold), and those people see the greatest effect from grapefruit juice.

Grapefruit could be a powerful medical tool because it is a natural, easily available, low-cost food that has a specific and well-known molecular mechanism.  Who said money doesn’t grow on trees?

Shape-ups Ship Out

News broke yesterday about Sketchers settling charges against them from the Federal Trade Commission (FTC) for $40 million.  The FTC claims the company “deceived consumers  by making unfounded claims that Shape-ups would help people lose weight, and strengthen and tone their buttocks, legs and abdominal muscles”.

Now, if you’ve ever seen Shape-ups shoes, you might think they would look good with a nice pair of slacks (I’m using slacks as an out-dated term from the 80’s).  I personally would never buy shoes that look like that even if the company claimed it would tone 100 different muscles, and I wear athletic-looking shoes (I even have a different pair of Sketchers!) almost every day.  I apologize to any of my friends or family who bought these shoes (Amy) but they just didn’t do it for me.

Aesthetics aside, Sketchers made false claims about Shape-ups, Resistance Runner, Toners, and Tone-ups shoes.  Just the names are enough to get a person excited (good marketing!), but telling consumers they will perform miracles such as losing weight (without changing your lifestyle) and falsifying clinical study data is just stupid.  Great marketing always puts a shine on products, but you still “can’t polish a turd”.  (No matter what the Mythbusters say).

There will never be a miracle pill (or shoe) that will make you lose weight, get in shape, and tone your muscles without any effort from you.  The human body is an amazing organism and if you treat yours right, it will reward you.  There are so many complicated systems at work inside your body that scientists working on a ‘miracle weight loss pill’ are discovering that there may not be such a thing.  I think the best story about finding an ‘obesity cure’ begins back in the 1950’s.  A company that breeds new animal strains for scientific research, Jackson Laboratories, discovered a strain of mice that was constantly feeding, lethargic, and obese.  These mice could not get enough food and would eat until they couldn’t move.  (The blob on the right is one of those mice).

Leibel, RL (2008) International Journal of Obesity, 32:S98–S108.

When molecular biology and DNA genotyping finally caught up in the mid-1990’s, Dr. Jeffrey Friedman, Dr. Rudy Leibel, and their colleagues discovered that this mouse strain, named ob/ob (due to its obesity) had a mutation in a hormone called leptin.  They gave these obese mice leptin, and amazingly they stopped constantly eating and lost weight.  The miracle drug was found!  Even the name leptin was derived from the Greek word leptós, or thin.  Clinical leptin trials began…and ended…because people were not losing weight.  The problem was, most obese people are not obese because they have low levels of leptin.  Turns out, this hormone is made by your fat cells, or adipocytes.  The adipocytes secrete leptin into the blood stream, where it travels to your brain, finds the leptin receptors, and basically says, “hey, you, stop eating.”  So what do obese people have?  Lots and lots of leptin circulating in their blood from all of their adipocytes secreting the hormone.  Many obese people have leptin resistance, which means their brain cannot use the leptin signals they are receiving to tell you to stop eating.  So giving these people more leptin makes no difference.  This research did help some people who have similar mutations to the ob/ob mice or those that actually have a deficiency in leptin production.  However, for the majority of obese people, it could not help them.

The human body is great at adapting to its environment and working to survive.  If you help it along a little, you might be surprised at what it can do.  Don’t look for a magic pill or a magic shoe.  They just don’t exist.  So instead of buying these shoes and waiting for your calves to be toned while walking a block to your car, put on real sneakers and walk a little faster and a little farther, and then you may see some results.

How do you like them apples?

Creative Commons copyright msr via Flickr

An apple a day keeps the doctor away.  Remember the good ol’ days when maxims like this were all you needed to live a healthy and long life?  Now, the public is bombarded with confusing messages about their health every day.  The latest example is 60 Minutes report on “Toxic Sugar”.  I had several people ask me about this because they wanted to know my opinion – so here it is:  just because Dr. Sanjay Gupta says something does not mean it is true…or any one scientific study for that matter.  Dr. Richard Lustig has been in the limelight recently, as his idea to tax sugar was the basis for my Boston Sugar Party post.  Let’s look at the “facts” Lustig and others presented in the report:

“Sugar is toxic.”  Sugar itself is not toxic.  You actually need sugar to live.  Your brain needs 6 grams of glucose (a type of sugar) per hour to work properly.  In addition, when your muscles and other tissues cannot take up glucose to create energy, as in the case of type 1 diabetics, you will starve to death.  Think of it this way:  you need water to live, but if you drink massive amounts of water, you will die within hours.  If you drink massive amounts of sugary drinks, your pancreas will pump out more insulin to remove the sugar from the bloodstream, and after a while you might become obese, then you may become insulin resistant, some people might become diabetic, and only then will you cause major organ damage.  Considering the time it takes to kill you after overconsumption, water is more toxic than sugar.

“There is no foodstuff on the planet that has fructose that is poisonous.”  Lustig was trying to make the point that humans WANT to eat fructose because of evolution and we instinctively know it’s safe to eat.  I’d like to see his analysis of fructose content on holly berries, sweet peas, and the other poisonous foodstuffs listed by a poison control center in Philadelphia.

“We were born this way.”  He is obviously a Lady Gaga fan, promoting her song, “Born This Way”…ok, that’s untrue, just trying to add some levity here…he just states that we are born to love fructose.  Yes, we may enjoy eating fructose (it has the highest sweetness out of all of the natural sugars), but I still don’t buy the claim that we are prone to it because of evolution and poisonous things.

“Fructose causes heart disease and stroke.”  This is new research coming out of the Dr. Kimber Stanhope lab, and any new hypothesis must be thoroughly tested before it becomes consensus.  The amount of fructose consumed is astronomically high, at 25% of daily calories.  This is not too unusual for scientific studies trying to determine effects from diets, but not many people are actually drinking this many calories every day without any type of exercise.  She states there is are increases in LDL cholesterol and “other risk factors” for cardiovascular disease.  No mention of whether these increases are statistically significant or if sugar is ACTUALLY “just as bad for their hearts as their fatty cheeseburgers.”

“[In the 1970’s] a government commission mandated that we lower fat consumption to try to reduce heart disease.”  This is true, governmental attempts to lower fatty foods did not make us healthier.  Some foods were processed down until the fat was removed, but all the sugar, salt, and calories were still there, and usually some chemicals added in to replace the fat.  However, there was no real regulation of fatty foods and many ‘low-fat’ items on the shelf were always considered ‘diet foods’ that people did not eat consistently.  People still gravitate toward high-fat foods.  Sugar alone did not increase American adult obesity to 36%.  You can order a Double Quarter Pounder with Cheese from McDonald’s which has 740 calories, more than half of those calories coming from the 42 grams of fat.  But it only has 9 grams of sugar!  It won’t make you fat!  Again, this is just not true.  (Just to be fair to other fast food chains, an Extra-Crispy Chicken Breast at KFC will set you back 510 calories, 290 of those come from the 33 grams of fat…but only 1 gram of sugar!)  You need a well-rounded diet of protein, carbohydrate, and fat for your body to function properly.  Telling people that sugar is toxic creates the next “scare” that Lustig said happened with fat 40 years ago, and obesity rates will keep increasing.

“If you limit sugar, it decreases the chances of developing cancer.”  Dr. Lewis Cantley’s example that cancer cells have insulin receptors and will therefore take up excess glucose from the bloodstream and grow into tumors was probably the most shocking to me.  Insulin receptors bind insulin (which is secreted from your pancreas and into the bloodstream after every meal) and if cells have certain glucose transporters, insulin ‘tells’ those transporters to move from inside the cell to the cell surface.  This results in increased glucose entry into the cell.  Many cells in your body have insulin receptors such as muscle, liver, fat, and brain.  Muscle (skeletal and heart) and fat cells have the glucose transporters that are ‘activated’ by insulin.  There is no data that I am aware of which claims cancer cells can take up more glucose than any of the other cells in your body.  Also, insulin signaling (what happens inside the cell after insulin binds the insulin receptor), once activated, is eventually downregulated by a negative feedback system.  Insulin cannot just sit on an insulin receptor and hang out, causing cancer cells to keep sucking up the sugar, or blue dots, as the schematic on the television show would like you to believe.

“Every cell in our body needs glucose to survive, but the problem is, these cancer cells also use it to grow.”  Once again ALL CELLS that have the insulin receptor use glucose to grow.  Period.

“Sugar is much more addictive than we thought early on.”  These scientists seem very careful with their wording.  Dr. Eric Stice showed that dopamine was released in Gupta’s brain when he drank some soda.  Activation of taste receptors on your tongue cause dopamine to be released in the brain, no matter what the food.  If a person likes spinach, the same dopamine receptors will light up in MRI brainscans, especially if the person is hungry at the time.  Dopamine regulates feeding behavior, and not just for sugar.  Maybe sugar can be addictive, but so can so many other things (including suntanning, as I mentioned in my Tanners Anonymous post).  We can’t possibly regulate every choice people make.

As a scientist, I believe the scare tactics that Lustig is using are not within the ‘unwritten rule’ of putting the science first in research.  I am all for new ideas, but a scientist cannot go on national television to state untested claims as fact and contribute positively to the field of science. You’re probably thinking, “he must be a first-hand expert to make these claims on television, right?”  During my scan of his last 27 papers published in peer-reviewed journals since 2009, I calculated only five that were original work coming directly from his lab (where he was last author and they were not review articles).  These five papers had nothing to do with ‘toxic sugar’ and its effects on the human body.  The most recent concerns growth hormone deficiency in children after radiation treatment, and the other four are about the efficacy of lifestyle intervention (behavioral) programs in obese children.  In the other 22 papers, he either contributed to another lab’s work, or they were review or opinion articles on sugar, fast food, and obesity.  Something about this seems fishy to me, and it isn’t Friday.  You can’t be an objective scientist and (what seems to me)  to be striving for fame at the same time.  He wrote an article about ‘toxic sugar’ in the journal Nature a couple months ago, and that’s when the mainstream media started to interview him and publish articles on his opinions.  There are 5 other articles in subsequent issues of Nature that refute his claims.  Here are some quotes from these articles:

Our meta-analyses of controlled feeding trials indicate a net metabolic benefit, with no harmful effects, from fructose at a level of intake obtainable from fruit (Nature. 2012 Feb 23;482(7386):470).

To describe sugar as “toxic” is extreme, as is its ludicrous comparison with alcohol…Nutritionist Jennie Brand-Miller of the University of Sydney is not alone in her disgust that you published this opinion piece (The Australian, 4 February 2012). The Dietitians Association of Australia believes that it is simplistic and unhelpful to blame sugar alone for the obesity crisis. Alan Barclay of the Australian Diabetes Council notes in the same article in The Australian that sugar consumption in Australia has dropped by 23% since 1980. But he adds that during that time, the number of overweight or obese people has doubled, while diabetes has tripled (Nature. 2012 Feb 23;482(7386):470).

Overconsumption of foods that have a high glycaemic index (that trigger a rapid and sharp increase in blood glucose), such as wheat, potatoes and certain types of rice, also contributes to obesity and diabetes. Emphasis on sugar alone is therefore too narrow a basis for devising policies to curb these problems (Nature. 2012 Feb 23;482(7386):471).

Rather than demonizing sugar, the authors would have better served public health with recommendations to manage a balanced diet with exercise (Nature. 2012 Feb 23;482(7386):471).

The Food and Agriculture Organization of the United Nations, the US Food and Nutrition Board, and the European Food Standards Authority have all considered the issues now revisited by Lustig et al. and find no reliable evidence that typical sugar consumption contributes to any disease apart from dental caries. Without evidence that reducing sugar consumption would improve public health, Lustig and colleagues’ policy proposals are irrelevant. Scientific controversies should be settled by consideration of all the available evidence, not of a seemingly biased selection (Nature. 2012 Mar 8;483(7388):158).

I appreciate the attention the ‘Western Diet’ is getting (the diet high in refined grains, sugar, fat, and red meat), as there are major problems with it that lead to obesity and diabetes, but presenting hypotheses as fact to scare the public is not the way to do it.  This is how fad diets are created and may cause people more harm than good.  Educating the public with real information and making it easier for them to make good dietary choices is the best way to battle the bulge.  I say, it probably is best if you don’t drink sugary drinks everyday, but having one every once in a while will not kill you.  And enjoy that apple.

Animal Necessities

Several ferry and airline companies in Britain have stopped transporting animals for research under pressure from animal rights groups.  There are no British airlines that will carry animals to the UK, although foreign airlines still do.  Groups that are trying to prevent laboratories from using animals seriously compromise scientific and medical research.

Using animals for medical research is a touchy subject.  I don’t usually like to take issue with people voicing their opinion about animal research because people can get very upset about this topic.  However; as a user of animals for scientific research, I believe they are indispensable for medical progress.  Banning the use of animals in scientific research is equivalent to halting all progress to study human diseases, drug discovery, and drug safety.

There is no replacement for primary tissue (tissue from an animal) or whole animals for the study of diseases.  Cell lines, which are specific cell types immortalized in a petri dish, cannot replace primary tissue.  Cells that are continually cultured in petri dishes  are basically cancer cells.  Most cell lines come from cell-type specific tumors, which are cut up and then coddled with media and growth factors to allow them to stick to the bottom of the dish and continue growing and dividing.  Cancer cells differ greatly from non-cancerous cells in their internal signaling pathways and metabolism, therefore; cannot reliably be used to understand how normal cells work or efficacy of drugs for other diseases.

Furthermore, without a whole animal, there is no way to test metabolism of new drugs.  There are many organ systems in the mammalian body.  Drugs have specific targets, yet other organs may be damaged or the body may metabolize a drug to a non-functional molecule.  Any new drug cannot immediately be tested in humans; it’s too risky.  Drugs need to be rigorously tested in animal models to determine if they are likely to harm a person or have off-target effects.  There are several phases of drug discovery and development, and without animals, the drug development process completely stops.

Copyright University of Sydney, Kassiou Lab

To those that are concerned with animal welfare, all scientific research is tightly controlled by regulatory bodies.  In the US, the Institutional Animal Care and Use Committee (IACUC) oversees all aspects of animal research to promote responsible use of animals.  Any institution supported by the Public Health Service (PHS) ensures the appropriate care and use of all animals involved in research and follows the “U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training” and implements the Health Research Extension Act of 1985.  The Office of Laboratory Animal Welfare (OLAW) also ensures that all of the PHS and IACUC policies and regulations are enforced.  In the UK, the Animals (Scientific Procedures) Act 1986 licenses and regulates institutions, projects, and staff in similar ways.  Animal research labs in both countries have to follow protocols to ensure no abuse of animals by using the minimum amount of animals with the least amount of pain, suffering, or distress.

To animal rights activists:  think about a situation where your child has a deadly disease which could be managed and be survivable with a new drug.  Would you rather push for good checks and balances within the animal research system to ensure that they are treated humanely and use the drug that allows your child to live, or not do everything possible to save your child?  The possibilities significantly dwindle without animal research.

Like Mom Always Said…

A few days ago, the CDC announced that 14,000 people die from Clostridium difficile (C. difficile) each year.  This is a bacterium that lives in your colon, causing inflammation, diarrhea, and nausea.  You might be thinking, so what?  The problem is that many of these deaths could be prevented by proper hand-washing, because guess how you transmit bacteria from your colon to other people?  The number of deaths is shocking to me when I think that half of those cases were acquired in hospitals because of improper hand-washing by the staff (and this is one of many other hospital-borne infections that can also do harm, like staph infections).

Other than what you may have thought as a child, your mother did not make up the idea that washing your hands is good for you.  The first person to recognize that hand-washing can prevent disease was Hungarian Dr. Ignaz Semmelweiss around 1847.  He worked at Vienna General Hospital, which had two maternity clinics.  One was assisted by doctors and medical students and the other by midwives.  He observed that ~13% of the mothers at the obstetrics clinic died from ‘childbed fever’, while only 2% of the mothers died while in the care of the midwives.  Semmelweiss realized that doctors and medical students were dissecting cadavers for their autopsy or study and ‘invisible cadaver particles’ were being transferred to the new mothers.  Thus began the era of germ theory of disease, even though the microorganisms that caused these diseases were unknown at the time.  He instituted the regimen of washing hands and instruments in a chlorinated lime solution and ‘childbed fever’ was nearly eradicated.

A recent Freakonomics podcast described hand-washing practices at Cedars-Sinai Medical Center and tried to relate compliance to fiscal responsibility.  I won’t get into how you can save more money here, but the story about hand washing at a major U.S. hospital can be a lesson for all.  The hospital wanted to determine if they were doing all they could to prevent spread of infection.  They asked the doctors to self-report hand-washing, and 73% claimed they were washing their hands as they should.  However, during the same period, the nurses were ‘keeping an eye’ on the doctors and reported that only 9% of the doctors were in fact washing their hands between patients.  NINE PERCENT.  The most educated, supposedly responsible people at the hospital had the worst hygienic behavior compared to 65% of all hospital workers, including the custodial staff, who were washing their hands properly.

The best part of this story is how they got these doctors to change their behavior.  Education through signs, emails, and rewards didn’t work, but showing them exactly what was on their hands did.  Each person pressed their hand into a petri dish of agar, which was cultured for a couple of days, and then they actually SAW the bacterial colonies growing in clumps in the shape of their hand.  The hospital took a picture of the worst one and made it the screensaver to every computer in the hospital.  Now people were washing their hands – 100% of the time.  Yet, it’s human nature to become desensitized to things like this over time, and people fell back into their old habits.  The best way to get doctors to wash their hands?  Announcing the names of those that failed the hand-washing tests (using the agar plates) at departmental meetings and shaming them into doing a better job.

Human behavior is hard to change, no matter who you might be.  If we want to prevent spread of diseases everywhere, not just in the hospital, the take-home message is: wash your own hands early and often – and don’t be afraid to ask your doctor to do the same.

Is That a Pancreas in Your Pocket?

When most people hear the term ‘vital organ,’ the pancreas doesn’t usually pop into their head.  However, the pancreas is vital for survival, keeping your blood sugar in check. That’s why artificial pancreas trials are so exciting.  A majority of Type 1 diabetics are diagnosed as children or teenagers, and must live the rest of their life with insulin injections or insulin pumps, which they control themselves. Having a machine to automatically adjust insulin and glucagon injections based on continuous blood glucose monitoring would make diabetic life much easier.  This is especially important in young children and during times when awareness of low blood sugar is impaired by low blood sugar itself (or during sleep), as the brain needs 6 grams of glucose per hour to function properly.  When blood sugar levels drop too low (hypoglycemia), a person can go into a coma or die because their brain and organs are not getting enough glucose as fuel to survive.

When you eat a meal, carbohydrates and other sugars get broken down or converted into glucose, which circulates through the bloodstream.  The pancreas contains clusters of endocrine cells (cells that secrete hormones into the bloodstream) called Islets of Langerhans.  The majority of cells in the islet are beta cells which secrete insulin and alpha cells which secrete glucagon.  The beta cells sense the glucose concentration in the blood and secrete insulin in response, which travels through the bloodstream to other organs.  The insulin signals to those tissues (such as muscle, liver, and fat) to take up the glucose from the blood into the cell to be used for energy or stored for energy later.  High blood sugar (hyperglycemia) results from lack of beta cells (in the case of Type 1 diabetics) and the tissues ‘starve’ because they are not getting the signal to take up and process glucose from the bloodstream.  The body then tries to remove the glucose from the blood through excess urine production.  This is why poor glycemic control over time can damage the kidney and transplants may be necessary, although hyperglycemia causes many other complications such as microvascular diseases and nerve damage.

Normally, when a person becomes hypoglycemic, glucagon is secreted from pancreatic islet alpha cells, traveling through the bloodstream to the liver.  Glucagon signals to the liver to break down glucose stores (stored in long, branching chains called glycogen) and release glucose into the bloodstream.  If both insulin and glucagon are provided in a regulated manner, blood glucose levels can be adjusted accordingly.

Copyright discoverysedge.mayo.edu

The current insulin pumps provide a basal infusion of insulin to help keep blood glucose levels steady, but they are under the control of the user and must be manually adjusted throughout the day, especially during eating (more insulin) or exercise (less insulin).  Most diabetics prick their finger several times a day to test their blood glucose levels, as continuous blood glucose sensors are not widely used and still need calibrated at least twice a day with finger pricks.  People using insulin must be aware of rapid declines in their blood glucose levels; if their blood sugar drops too low, they must eat or drink high sugar foods or injest glucagon tablets to restore normal glycemia.  It is imperative that artificial pancreas blood glucose sensors are accurate and able to sense downward trends exceedingly well.  If a person starts exercising, muscle tissue is more sensitive to insulin and can even take up glucose independently of insulin because the need for energy (glucose) is greater.  If the sensor cannot perceive the drop in glycemia quickly and accurately; confusion, coma, and death may follow.  Combining better automatic blood glucose sensing with insulin and glucagon infusion in a bionic pancreas is a major step towards creating a better life for diabetics.  Getting the technology reliable enough is the challenge.