Happy Localized Temporal Flux!

Which is briefer – Planck time divided by infinity or its inverse?

As I write this soon-to-be-anachronistic piece, it is already the “new year” in various places around the world. For instance, in Hong Kong it is 12:04 A.M on Sunday while it is only 11:04 AM Saturday here (east coast U.S. time).

The truth is far more complicated and far more interesting to consider.

First of all, there is the notion of sidereal time—time relative to a fixed star‘s position. It is used by astronomers, who cannot rely on our own sun’s position as our positional relationship to it is not fixed. As a matter of fact, starting in the 19th century it was noticed that the “fixed stars” are not fixed either. They are just distant enough that they are far more fixed than our local star seems to be. All sorts of calculations can be sorted out to use a non-fixed distant star or bright astronomical object as relatively fixed, but I neither understand these calculations nor would you (I suspect) find them particularly interesting. So, the bottom line is sidereal time is in constant change here on earth. If I am standing shoulder-to-shoulder with you, we are in different sidereal times. Sidereal time has no respect for time zones. Time zones are useful in that it would be a nightmare to discuss the time it actually is if we were not to bunch time together in chunks like we do.

Second, time is not really measured in chunks like hours, minutes, and seconds. One really has to consider the fastest event in the universe to consider time more accurately, if not more usefully. The shortest time is the calculated Planck time, which is 5.39×10-44 seconds (in other words there are 1.9×1043 tP in one second—roughly 2 followed by 43 “zeros”—an incomprehensibly large number of events on the “standard human time scale (SHTS).” It is the amount of time it takes for a photon in a vacuum to pass through a Planck length, which is also very brief, distance-wise.

planck-time-equation
I’ll just let you go to other sources for more information, m’kay?

The thing about Planck time is that it is a time derived from a physical standard calculated by Planck, so although useful for physicists, there’s something a little incestuous about the whole business. Various elements have layers of electrons probabilistically scooting around their nuclei at mind-bending rates of speed, while also changing their quantum energy levels from their lowest energy levels (aka ground states) to a variety of higher energy levels. These electronic transitions have been studied and are variously known to behave themselves in very dutiful ways. As they are in constant motion between energy levels and motion takes time, even on the atomic scale, the distances and times are very tiny. Cesium atoms, for instance, experiences 9,192,631,770(±some variation) transitions between energy levels per second. The atomic clocks based on this cesium transition are so accurate that they are calculated to lose only 1 second in 100,000,000 years (one hundred million years!) or so.

Part of the work that scientists do is involved in never being satisfied with a “good enough” answer; they are always looking for increased, accuracy, precision, measurement stability, always looking for a more refined “truth” than that which has been understood before. If you were a professional runner, for instance, and you just achieved a personal best, you would not go home, pop open a bucket of ice cream and settle in for the rest of your life. The next time you ran, you would try to better your personal best. Same with scientists, except the standards are set by nature and the tools we have to achieve better outcomes are constantly in the process of improvement.

Cesium has been the standard for measuring seconds for some years now but has just been displaced from its throne by an ytterbium-based atomic clock that “ticks” 518,000,000,000,000 (518 trillion) atomic events per human second. This allows a crazy level of stability that makes the mere 9 billion mark previously set by the cesium atomic clocks seem like sundials. The following video is a National Institute of Standards and Technology scientist discussing this improvement on video, along with explanatory text.

https://www.nist.gov/news-events/news/2016/11/nist-debuts-dual-atomic-clock-and-new-stability-record

If all of this weren’t disconcerting enough for you, these atomic clock scientists have found that time varies with altitude as well. In experiments using aluminum atom atomic clocks, they have been able to demonstrate that these variations in time have an effect with each foot of elevation, meaning that our feet are in a different time zone that our heads (does this explain clumsiness? it’s at least a better excuse than “I can’t walk and chew gum at the same time!”). Over a 79-year lifespan, the difference would only amount to about 90 billionths of a second, but it is there all the same.

https://www.nist.gov/news-events/news/2010/09/nist-pair-aluminum-atomic-clocks-reveal-einsteins-relativity-personal-scale

The whole point is that while we usher in the new year, we might give pause to remember that what we are celebrating is a not entirely accurate astronomical event. The earth has orbited around our sun for the past 365 days and will start that process again. In the meantime, sidereal time and atomic time—and Planck time for that matter—are all moving at rates that we can’t even comprehend unless we’re practicing the science of measuring—and improving—on atomic clocks and the electronic quantum transitions that are involved. From a practical standpoint, the next time you look at a second hand on a clock or watch a minute pass, consider the atom and all the changes it has gone through in that time. Consider that, as the earth rotates and precesses on its axis each day, we are each in our very own time zone. In fact, various parts of our bodies are in various time zones, particularly if you’re measuring our relatively enormous selves in Planck lengths.

So, Happy New Year! We have orbited our sun at the rate of 67,000 miles per hour—or if that seems too fast to you, let’s just say 19 miles per second—over the past roughly 365.256 days and yet, knowing these underlying facts, we will all count down to midnight in the enormously large seconds increments “ten-nine-eight-seven-six-five-four-three-two-one-happy-new-year!” and 6.144 hours later, the new orbit of the earth around the sun will start.

Not to be a party-pooper, but…

Renewal

Hopeful

Featured image

P.S. My introductory excerpt is not a serious question, it’s just a bit of good-natured trolling…

Fire! I Bid You To Burn!!!

When did fire become a thing? Poor old Prometheus… Probably not his fault at all….

When did fire become a thing? No one knows the answer to that question. Fusion certainly occurred before fire—it happens in suns, along with nuclear fission (radioisotopes exist in the sun)—but this is not fire. It appears flamey. It is hot. It radiates through varying segments of the electromagnetic spectrum. But I am going to limit the definition of “fire” to “combustion,” if you don’t mind.

The simplest combustion reaction occurs when pure hydrogen (H2(g)) and oxygen (O2(g)) gasses are combined in a 2-to-1 ratio and given a little energetic push called activation energy (i.e. hydrogen and oxygen will hang out with each other unless they are provided this energy). Diagrammatically, the activation energy looks like this:

activation_energy-svg
Activation energies Ea(X->Y) or ‘Ea(Y->X)’ need to be supplied to initiate the reactions X-> or Y-X, respectively.

The reactants (hydrogen and oxygen in our example) start on the left side of the hump, an appropriate (or excess) amount of energy is provided, and products result on the right side of the hump. The “ΔH” thing on the right side is beyond the scope here but represents a positive, negative, or neutral amount of energy released in the reaction.

The amount of activation energy varies widely from very small (e.g. some explosives) to “no reaction will ever happen regardless of energy input.” Here is what the most basic combustion reaction looks like in chemical reaction shorthand called “stoichiometry:”

2H2(g) + O2(g) → 2H2O(g)

And now, an entertainment of limited scientific value:

Combustion is generally thought to involve hydrocarbons (e.g. octane in the “gasoline” or “petrol” you use in automobiles) or their oxygenated friends the carbohydrates (e.g. cellulose, a polymeric carbohydrate used in paper and present in wood). The simplest combustion reaction is between methane (CH4(g)) and oxygen (2(g)), again resulting water but also resulting in carbon dioxide (CO2(g)) when the reaction occurs efficiently. When it does not occur efficiently or when it occurs in the presence of other substances (e.g. most of the time) it produces by-products including carbon (elemental symbol “C” aka “soot”). Here is the stoichiometry of that simple reaction:

combustion_reaction_of_methane
Combustion of methane in oxygen(with appropriate activation energy added) results in carbon dioxide and water

Methane is commonly known as natural gas, although natural gas is not pure methane when used as a fuel. What the stoichiometry tells us about this reaction is that each molecule of methane uses two molecules of oxygen and produces one molecule of carbon dioxide and two molecules of water, along with an amount of energy released in the process. The energy is used to heat various processes, including home furnaces and water heaters, and used to drive steam and gas turbines to produce electricity.

When octane is used as the hydrocarbon, the balanced equation is as follows:

2C8H18(g) + 25O2(g) → 16CO2(g) + 18H2O(g)

In common English, this means that each molecule of octane requires 25 molecules of oxygen (and that activation energy thing, typically supplied by spark plugs) and results in 16 molecules of carbon dioxide and 18 molecules of water, along with a good burst of energy that drives the pistons, drive shaft, and wheels; the wheels have tires that turn and exert a force against driveways, roads, dirt, mud, water, etc. and the automobile moves forward—or backward—at various speeds as allowed by the transmission.

transverse_engine_layout
A transverse internal combustion engine with the drivetrain for a manual transmission

Candles (if you were wondering where all this leads) are made from paraffin wax, which is a varying mixture of hydrocarbons typically with between twenty (C20) and forty (C40) carbons in their structures. A C20 hydrocarbon like eicosane can have up to 366,319 isomers (isomers all have the same chemical formula of a chemical compound but differ in physical and some chemical properties), while tetracontane (C40H82) has 62,491,178,805,831 (that’s sixty-two trillion four hundred ninety-one billion one hundred seventy-eight million eight hundred five thousand eight hundred thirty-one) isomers (somehow, it seems like more isomers if you spell the number out). The C(xy) compounds between C20 and C40 have numerous possible isomers as well and they increase logarithmically (see chart below) as the number of carbons increase. Not all of these hydrocarbons are in paraffin but these numbers should give you an idea of how chemically complicated a simple candle may be.

log-carbon-no-vs-isomer-no
This website represents output from one method of addressing the number of isomers per number of carbons but it provided a nice Excel-friendly list for my charting purposes. The reference at the bottom of the referenced web page is in German; additional approaches can be found at the link provided at the “discussion” link provided below.

While this already seems like a brain-damaging subclause to our proceedings, the estimates for number of isomers for each number of carbon is actually more complicated than I am representing here. If you have further interest, you can take a look at this discussion. If not, let’s proceed.

There is a standard equation for calculating how much product results from combustion in oxygen of any hydrocarbon; it is:

where z = x + y/4.

This means that in cases where there are 20 carbons as for eicosane, the carbon dioxide and water molecules result in the following way:

2 C20H42(s) + 61 O2(g) → 40 CO2(g) + 42 H2O(g)

or… for each two molecules of n-eicosane (one of about 366 thousand isomers of eicosane) are consumed by combustion, sixty-one molecules of oxygen are consumed, thus producing 40 molecules of carbon dioxide and forty-two molecules of water.

The thing is that it is rare that anyone burns a candle or anything else in pure oxygen. When hydrocarbons are consumed in air, a messier equation obtains to the problem:

Note that carbon monoxide is produced, along with hydrogen gas and the more familiar carbon dioxide and water. This version of the equation is why it is critical to ensure adequate air supply when using a kerosene (or other hydrocarbon-based) space heater in a closed space; the amount of carbon monoxide goes up as the amount of oxygen available goes down. Carbon monoxide, a colorless and odorless gas, causes humans to fall asleep and die due to a special kind of asphyxiation caused by very strong binding of carbon monoxide to the iron atoms in your hemoglobin and myoglobin. Once that happens, those proteins cannot carry oxygen through your arteries and your body is “starved” of oxygen.

carboxyhemoglobin_from_1aj9
Carboxyhemoglobin is formed when carbon monoxide is present; when this happens no more oxygen can be carried by hemoglobin (or myoglobin, a related protein)

Okay, so hydrocarbons burn in air (n.b. there is also lots of nitrogen in air and that produces problematic by-products as well) and that means carbon monoxide, carbon dioxide, water, and hydrogen are produced, along with a substantial amount of particulate matter (e.g. particulate carbon and other solid carbon by-products), which ends up in our shared atmosphere (n.b. there is no “U.S.A. atmosphere” or “China atmosphere,” there is one planetary atmosphere). The most common liquid fuel currently consumed is octane but that is not consumed as pure octane, so there are other hydrocarbons and “stuff” consumed at the same time… in air… which produces problematic by-products.

Here’s a chart of how much world liquid fuel has been consumed and is projected for consumption PER DAY over the listed time period:

world-liquid-fuels-consumption-and-production-balance
Source: U.S. Energy Information Administration

Yes, the chart does indicate that we consume between 94 and 96 million barrels of liquid fuel per day. One barrel of liquid fuel is equivalent to 0.1172 metric tons and a metric ton is 2,200 pounds (for the non-metricized readers). One barrel is 257.4 pounds of liquid fuel. If we are consuming (let’s be modest) 94 million barrels of liquid fuel per day (and let’s be factual) there are 365 days in a year, we are consuming 8,846,490,400,000 pounds of fuel per year. If we were to pretend that all of this were octane (which it isn’t) and all of that octane followed the simplest hydrocarbon-to-carbon dioxide equation provided above (which it doesn’t), we say that every two units of octane produces sixteen units of carbon dioxide. These don’t have the same mass, of course.

To make this simple, a gallon of gasoline weighs about 6 pounds. Each gallon of gasoline produces about 18 pounds of carbon dioxide (idealized as stated above). If we divide the number of pounds of liquid fuel consumed annually by 6, we will have an estimate of the number of pounds of carbon dioxide produced. Well, the number is:

(8,846,490,400,000 pounds of fuel per year)/(1 gallon/6 pounds) =
1,474,415,066,666.67 pounds of carbon dioxide/year

To do our numbers-into-language thing, that is one trillion four hundred seventy-four billion four hundred fifteen million sixty-six thousand six hundred sixty-seven (let’s round up, given the decimal figure) pounds of carbon dioxide produced from the aforementioned pounds of liquid fuel. Pretty incredible, right?

The bottom lines are these:

  1. we can’t breathe carbon dioxide (it chokes us)
  2. actual combustion produces lots of other by-products that are also not useful for human respiration and cause various respiratory illnesses (cancer, emphysema, asthma for starters)
  3. these numbers don’t include gaseous fuel like methane, ethane, propane, or butane (starting with pentane and going up to heptadecane (C17), the compounds are liquid at 25°C), which are also used as fuels.
  4. these numbers don’t include non-petroleum fuels such as ethanol, which is an oxygenated hydrocarbon but also produces all the by-products listed for hydrocarbons
  5. Our global economy is heavily dependent on consuming something that
    1. is finite in quantity and
    2. produces harmful by-products
    3. is going to go up in price as the amount available nears complete consumption
  6. We have not solved the equation for producing less carbon dioxide and less harmful by-products while maintaining our current lifestyles.

Okay, end of lesson. Talk amongst yourselves. This all needs to be solved.

Burn a candle while you’re at it. Couldn’t hurt (much).

Featured image: Catano Oil Refinery Fire

Something is Going Well Around Here!

The 1,000 “like” road marker disappearing in the rear view mirror…

The WP auto-post function just told me that I have accumulated 1,000 “likes,” which are all because the imaginary “you” have been appreciating what I’ve been pouring forth since June 22nd. It hasn’t been four months yet and I have so many “likes!” Who knew?!?

I’ve logged 87 posts (one was a repeat, so doesn’t really count and one was a reblog in respect for a new WordPress-induced friend) in 111 days, meaning that I’ve hit about 78% of the days between start and present. Not bad. Could be better. Let’s see if I can pick up the slack.

Thank you, everyone!

MSOC

“Cures What Ails You!”

Step up! Step up! Are you suffering from an endless variety of maladies? Just take one swig of this and you’ll be free of all worries!

We are all getting older every day. Even the young get old (please don’t repeat this widely; some of your friends will think you’re losing it). As this happens, many of us try to hold on to youth through various means. Increased visits to our physicians, more time doing exercise, watching what and how much we eat all are efforts to maintain health for as long as possible. Many of us, young and old but particularly as the sun gently sets over the horizon, take a variety of health supplements. Whether various of these substances do any good is a hotly debated matter by, on the one hand, the medical research community and on the other, the supplement industry and advocates for less drug-and-surgery-based interventions.

While this is completely understandable from a purely human point of view, there are various important factors that consumers should understand about the way the supplement and pharmaceutical industries are regulated.

In 2013, a market analysis reported that the global market for vitamins, minerals, and nutritional and herbal supplements (VMHS) was around $82 billion annually and was predicted to grow to $107 billion by 2017. Consumers in the U.S. represent about 28% of that market. Of course, the pharmaceutical industry revenues were around $1.2 trillion in 2014 and are expected to grow to $1.6 trillion by 2018-that makes the pharmaceutical industry about 20 times as large in terms of revenue. On the other hand, costs for the pharmaceutical industry are huge. It takes about $2.9 billion to develop a drug through to full approval by regulatory agencies and takes roughly ten years—often more—to develop any successful drug candidate from identification of a molecule with activity to post-marketing study completion. This does not include sales and marketing costs (advertising, pharmaceutical sales) that are often expensive and consistently are under pressure from regulators to behave more ethically. From identification of a possible chemical structure to successfully obtaining marketing permission from a regulatory agency, only about 5 in 5,000 possible drug candidates make it through the entire process; this is only 0.1% of the drug candidates that start out. This percent is likely to go down as (1) more biological drugs are developed for (2) increasingly rare diseases.

As most VMHS products are naturally-occurring substances that are inexpensive to manufacture in bulk quantities,  as no pre-clinical or clinical studies of any kind are required to place them on market, and as little testing is required at any point in the manufacture-to-consumer supply chain, the cost vs. revenue math for supplements is significantly different.

At the end of the day, we all need to make our own decisions about what we are going to do with our personal health. The following material may help you decide whether supplements are appropriate for your desired outcomes.

VMHS market size: https://www.mckinseyonmarketingandsales.com/sites/default/files/pdf/CSI_VMHS_FNL_0.pdf

Pharmaceutical market size: https://www2.deloitte.com/content/dam/Deloitte/global/Documents/Life-Sciences-Health-Care/gx-lshc-2015-life-sciences-report.pdf

Cost of drug development: http://csdd.tufts.edu/news/complete_story/tufts_csdd_rd_cost_study_now_published

Identity:

The chemical formula or herbal source of any pharmaceutical or supplement is the at the core of the issue. If you have Type I diabetes mellitus, you will be prescribed insulin, which is a specific protein with a specific chemical structure and formula depending on its source (e.g. human, bovine, porcine, genetically engineered). While it is injected in an aqueous buffer with some stabilizers, every component of the injection is checked numerous times during the manufacturing process to make sure that nothing but insulin, water, the buffering salts (which hold the water within a specific human pH range), and the stabilizers all have to be present in very specific amounts and nothing else must be in the injection above a certain very low tolerance. If insulin is not present, patients may suffer and may die. If contaminants are present, either carried through from improperly sourced raw materials (e.g. water, salts) or introduced through inadequately cleaned equipment, patients may suffer or die. These outcomes could have an enormous reputational and financial impact on the manufacturing company. Additionally, worldwide regulatory agencies are required to audit manufacturers and determine if they are following best practices for material sourcing, checking material quality, equipment cleaning, and checking the final product, all the way through packaging and storage pre-shipment. It is a complex and meticulous business that requires a large team working together to ensure that patients get the appropriate product.

insulinhexamerSo, the identity of the product—the insulin in the above example—is very important but every component that enters the diabetic’s body is checked almost as much at various stages in the process.

In general, identity in supplements splits into two categories: (1) items that are distinct chemical entities, whether inorganic (calcium, trace metals such as copper, selenium, molybdenum, other minerals) or organic (vitamin C, vitamin B12, riboflavin, vitamin A, niacin, vitamin E, etc.) and (2) herbal supplements (echinacea, ginseng, saw palmetto, St. John’s wort, yohimbine, black cohosh, ginkgo biloba, etc.), which start life as plants, are harvested and preserved in some manner.

I take a multivitamin every morning, in spite of numerous research studies that indicate this is probably not necessary if my diet is relatively healthy (it is but I am a recent convert to a vegetarian diet). My particular multivitamin contains the following chemical items: vitamin A, C, D, E, K, thiamin, riboflavin, niacin, B6, folic acid, b12, biotin, pantothenic acid, calcium, phosphorus, iodine, magnesium, zinc, selenium, copper, manganese, chromium, molybdenum, chloride, potassium, silicon, lycopene, lutein, boron, vanadium, nickel. Each one of these has a weight or international unit (IU; this has to do with the biological activity or potency of the dose provided) associated with it. Along with some of these vitamins, there is a counterion, which makes the mineral (in particular) a salt form. These are not typically considered to have any important supplementary properties (e.g. magnesium oxide; the oxide does not have any claimed importance in the supplement), although in some cases the counterion is specifically used to impart some supplementary material (e.g. calcium phosphate; both ions are used by our physiology). In addition to these vitamins and minerals, there are excipients, which are the materials that help all of the “active” ingredients hang together, remain stable on the shelf for some specific time, and form easily into a pill. In the case of this multivitamin, the excipients include: cellulose gel, starch (corn & tapioca), hypromellose, croscarmellose sodium, silicon dioxide, gelatin (porcine), and polyethylene glycol. These do not have weights or IUs associated with them but the overall formulation of the pill is an exact science called pharmaceutics. Once a formulation is determined, it is best for the manufacturer to hold to the formulation as the quality of the pills will remain within specified ranges. This means that they will not turn to dust in the bottle or spoil early or break too often during shipping, thus leading to return customers.

There is a new category of supplement known as “USP Verified (uspverified.org). The United States Pharmacopeia Convention is a reputable organization that has assisted the U.S. regulatory authority in assuring the identity and purity of pharmaceuticals for decades. They have recently expanded their scope to assist some supplement companies in verifying the identity, purity, and amounts of vitamins and other supplements available on the market. A very limited number of supplement companies have signed up to participate in this service (you can go to the above website to see what products are covered).

While it is not certain that other supplement manufacturers do not follow appropriate controls, the only “good” reason that some don’t is because it is costly and therefore consumes a bit of profit.

In the pharmaceutical arena (which has many detractors, but not for this reason), the company must submit documentation that the medicine they have researched, developed and are selling has the unique chemical structure of that medicine. For instance (and to make this simple), aspirin (acetylsalicylic acid) must have the following structure as proven by several common, validated analytical tests:
aspirin-skeletal-svgAnother way of saying this is that for each compound, it must have the exact number of carbons, hydrogens, oxygens, nitrogens, sulfurs, etc. in the exact interrelated positions as are unique to that chemical compound.

There is some evidence that some supplement products do not include the chemical compounds (vitamins and minerals) listed on their label or that the substances are present but not in the specified weights listed. The consumer is consuming something pill-shaped but what is it? It may be that the consumer is enjoying a pill-shaped item that is mostly substances that have been tested extensively over the years and are “generally regarded as safe” (GRAS) materials. There are many categories of these materials, which are lumped together under the term “excipients.”

There are ongoing studies being performed by the Center for Biodiversity Genomics at the University of Guelph and at other academic centers around the world which attempts to identify the contents of herbal supplements. These supplements should simply be a preserved form of leaf, root, bark, etc. from some plant for which some ancient beneficial property has been observed. Many cultures from around the planet have used these types of materials, usually directly from the plant in question, for centuries, if not millennia. In some cases, benefits have been seen in some patients (the dead ones aren’t around for a discussion). In many cases, an herbal supplement may fit the old “snake oil” profile: “Good for What Ails You!”

Willow bark, for instance, has some pain, inflammation, and fever relief efficacy (it contains the raw material salicin, which is metabolized to become salicylic acid). If we were to purchase a substance called “willow bark” for the purposes described above, we would have a reasonable expectation that the willow bark would (1) be willow bark and (2) contain salicin. A lot of the studies being performed using DNA sequencing have demonstrated that the herbal supplement industry sometimes sells products labeled very specifically to contain a plant substance that does not contain the plant’s DNA (and is, therefore, not the plant) and does not contain the substance known to provide the desired medicinal effects. This is a type of fraud. It will only disappear if consumers demand more from their supplement providers.

Here are some references for further reading:

http://www.theatlantic.com/health/archive/2015/02/how-supplements-work/385119/

http://www.biomedcentral.com/content/pdf/1741-7015-11-222.pdf

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3216529/pdf/srep00042.pdf

http://www.ncbi.nlm.nih.gov/pubmed/22970567?dopt=Abstract&holding=f1000,f1000m,isrctn

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882080/

https://bmccomplementalternmed.biomedcentral.com/articles/10.1186/s12906-016-1086-0

http://www.sciencedirect.com/science/article/pii/S096399691200292X

http://bsh.ahpa.org/SampleHerb1.aspx

http://www.consumerreports.org/cro/2012/05/multivitamins/index.htm

http://apps.who.int/prequal/trainingresources/pq_pres/workshop_China2010/english/22/002-Excipients.pdf

Purity:

For each medicine or excipient, testing has to be performed to ensure that it is reasonably pure. Well, that sounds like an odd thing to say – “reasonably pure.” What does that mean? The FDA has established criteria that require a medicine to be pure from synthesis by-products (solvents, starting materials used in the synthesis, side products that are not the medicine, impurities that may be introduced during the manufacturing process from equipment used). If the drug is dosed at < 2 g/day, the threshold for reporting any impurity is 0.05%. The impurities must be chemically identified if any one of them is above 0.10%. This adds cost to development and is a significant driver for why quality control procedures are in place throughout manufacturing to ensure purity. They must be qualified (i.e. understood for toxicological and/or pharmacological purposes) if they rise above 0.15% or 1.0 mg/day, whichever is LOWER). When it gets to doing toxicological and/or pharmacological tests, the expense goes up really dramatically! If these are the criteria for drugs, shouldn’t they apply to supplements? I believe so. If you take something labelled “vitamin A,” you should have a reasonable expectation that 99.95% or more of that supplement product is vitamin A, as characterized by its chemical structure:
The excipients used should all be pure as well.

all-trans-retinol-svg

Obviously, material with lower purity profiles are less costly. If a manufacturer were to purchase bulk CMC to formulate in with the vitamin A, it should be reasonably free from impurities as characterized above. If a manufacturer were to use 95% pure carboxymethylcellulose (CMC), it would probably cost less than 99.5% or 99.95% CMC. In several of my previous jobs, I had to purchase gases for analytical purposes (hydrogen and nitrogen most commonly). If I purchased 99.9% pure nitrogen it would cost a bunch more than 99% pure nitrogen. Same applies to GRAS excipients. Is this testing done? It may or may not be. The supplement manufacturers do not fall within the purview of the FDA, so they do not need to prove their purity during an initial application for approval for marketing, nor do they need to prove this on a batch-by-batch basis during manufacturing.

One very important aspect of good manufacturing practices (cGMP) is something called cleaning validation. For medicines, all equipment that touches a drug or excipient must be cleaned between batches. The manufacturer must test the equipment after a validated cleaning procedure has been completed. The equipment must be tested for residual cleaning products (soaps, bleach), bacteria, fungi/molds, solvents, drug, excipients, etc. Is this done in the supplement arena? I don’t know and they don’t have to prove they do this. Their only limitations are consumer-driven, e.g. do consumer’s health see a negative effect after taking their supplements or not?

For further reading: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073385.pdf

Stability:

Another factor is how long the supplement (or drug) retains its optimal purity after it has been manufactured. All chemical compounds, including the salt forms of minerals (calcium chloride), interact with other materials in the environment, principally water (humidity), oxygen (it’s all around us) and light (various wavelengths of light, particularly ultraviolet light from sun can change the structure of chemicals) through various chemical mechanisms. Drug companies test stability properties of drug substance (the active ingredient) and drug product (the pill or injectable, etc.) for months and years during research and development and create strategies to optimize the drug stability (for instance, store insulin in a refrigerator). Supplement manufacturers are not required to do this testing, although some may. When products degrade over time, they create a different kind of impurity called a degradant. These are chemical substances that are related to the drug, supplement or excipients that no longer have the properties for which the product was purchased. There are limits to how long a product should be used (usually it is months, sometimes years) after purchase. The consumer has significant responsibility here. How often does a household keep a partially used medication or supplement for over a year or more and then use some? While it is “probably” not going to do significant harm, it is no longer the product that the manufacturer has tested and provided as approved by the FDA.

So, if you are in the habit of sometimes using supplements, then not using them and so on, keep an eye on the expiration date. If you have been keeping them in the dark at normal household temperatures (between 20⁰C and 25⁰C), you’re probably okay to keep using them for a couple of months or so after the expiry date as this date is probably set for an average case scenario. This does NOT apply if you are taking a biological like insulin. If you are taking an herbal supplement, it is difficult to know if (1) the marketed herb is in the bottle, (2) any stability testing was done on how long the herb will remain effective, and/or (3) whether what’s in the bottle will have the desired effect in the first place. Figure out what you need to do to increase the probability that the marketed herb is in the bottle and follow the expiration date advice, if it exists.

Amount:

I touched on this in the “Identity” section above, but it may bear repeating. On any medicine or supplement, there are markings that indicate how much of the active material is contained in a dose (ibuprofen=200 mg/tablet; vitamin C=500 mg/tablet; etc.). Drug companies are held to high standards, above and beyond the purity and stability criteria listed above. Do supplements actually contain the amount of substance that is indicated? We do not always know. Some testing indicated above in the references indicate that in some cases, there is little to none of the labelled substance in the product sold.

Batch-to-batch equivalence and product-to-product equivalence:

Once one batch of medicines is completed, it must be tested to ensure that it meets all the manufacturing criteria as listed above, but each additional batch manufactured must also meet those criteria.

Additionally, when a generic drug manufacturer creates their product, they must prove it is equivalent through extensive in vivo testing (testing in “normal healthy volunteers” or clinical trial participants) to the product made by the company that initially patented the drug. Do supplement companies do either of these kinds of testing? Does one supplement manufacturer prove that their vitamin C is identical to all other vitamin C products available? No. The upshot of this is that while all of the products are labelled “vitamin C,” one product may deliver more or significantly more than the labelled amount, while another delivers less or significantly less. There is a bit of a rocky comparison here: the innovator drug company has created a unique chemical product for the first time, while the supplement company is taking a compound that is found in nature and creating a product. The bottom line remains the same though – any supplement user would probably like to know that the product they are taking is delivering something reasonably close to the labelled amount of the substance and that this is true for each bottle of supplement they purchase from the manufacturer, regardless of batch or time of manufacture.

Pharmacological Effect:

When a medicine is developed it must show a target pharmacological effect within a statistically significant range above placebo or in the range of similar medicinal therapies; developing drugs with a statistical response below similar medicinal therapies is increasingly seen as not worthy of the enormous expense and time involved in drug development. The studies are done following a variety of complicated and statistically robust clinical trials in (1) normal healthy volunteers when the drug is considered sufficiently safe to allow this (many cancer drugs have toxicity profiles that do not allow dosing in anyone but patients) and/or (2) patients who have been diagnosed with the target illness so that the efficacy of the therapy can be evaluated. Often, the trials are doubly blinded so that the physician and the subject/patient are unaware whether they are receiving a medication or not until after the trial is completed and the results are unblinded. By the time a medication is approved by a regulatory agency it has been dosed in thousands of subjects and patients. All effects, positive and negative (adverse events) are tabulated and are provided to the public (e.g. the horrifying list of often minor potential effects heard on TV ads). Supplements rarely, if ever, go through this kind of rigorous testing. If they are tested in this manner, it is usually by academic centers that want to determine if there is anything to the efficacy claims often cited on various supplement-promoting websites.

There is a particular kind of correlation that is studied. It is called the dose-response curve. A single dose or multiple dose regimen is followed – the dose amount (milligrams, for instance) is the known portion of the experiment. The peak concentration in blood and other fluids is studied over many subjects and patients. In the case of multiple doses over many days, the steady-state concentration is determined. The follow-up pharmacological and physiological data is studied; what effect has the drug had on desired and undesirable outcomes? Is blood pressure lowered (if that is desired) or elevated (usually undesirable)? Are liver enzymes constant (usually desired) or do they change (usually undesirable)? Is mood altered, in the case of psychiatric medicines, in a manner that is desirable or not? Is a tumor reduced in size, and if so, are any side-effects minimal in comparison to the improved health of the subject?

In the case of supplements, the same relationships are often claimed (e.g. reduces free radicals in the bloodstream and tissue (vitamin C), improves prostate health (saw palmetto), improves energy (whatever that means), etc.). These are measurable “endpoints” or results in some way, so why aren’t they measured? The primary reason is that it is costly to do so with the same rigor as the pharmaceutical companies must demonstrate. The secondary reason is that very few of the supplement companies actually own the substance they are selling (e.g. vitamin C or saw palmetto), so they cannot patent the substance itself (pharmaceutical companies have a 20-year patent from the time they list the patent with that agency – and that is YEARS before it is approved or marketed). One way supplement companies get around this is they come up with combinations that are “unique” to their firm, but even in these cases, the substances in the product are not unique and another company could come up with a copy of that product if they have sufficient information. Or they could make up a similar product; as there is no requirement for the supplement company to prove pharmacological effect, there is no real reason for any company to copy another manufacturer’s blend.

Cases where the supplement companies get in trouble:

Probably the biggest example of this is with the ephedrine (e.g. ma huang or ephedra) situation a decade back.

http://www.mayoclinic.org/drugs-supplements/ephedra–ma-huang/background/hrb-20059270

Another is colloidal silver as a homeopathic therapy.

https://nccih.nih.gov/health/silver

Cases where pharmaceutical companies get in trouble in spite of regulations:

Johnson and Johnson had one of their manufacturing plants sidelined because of inadequate quality control (i.e. testing of the drug substances and products they were manufacturing).

http://www.washingtonpost.com/wp-dyn/content/article/2010/07/22/AR2010072206169.html

Several Indian manufacturing plants that export generic drugs to the U.S. have been sidelined.

http://www.raps.org/Regulatory-Focus/News/2015/11/09/23562/FDA-Form-483s-From-India-A-Deep-Dive-Into-the-Problems/

While not an actual pharmaceutical company, this pharmacy compounding company made a product contaminated with a fungus that caused numerous deaths:

http://www.cdc.gov/hai/outbreaks/meningitis.html

https://www.washingtonpost.com/national/health-science/compounding-pharmacy-linked-to-meningitis-outbreak-knew-of-mold-bacteria-contamination/2012/10/26/6e3344ee-1fa0-11e2-afca-58c2f5789c5d_story.html

Compounding pharmacies are not held to the same manufacturing standards as manufacturers (although these (as above) can do the wrong thing as well). The FDA is trying to establish a uniform set of regulations to ensure that this does not continue to be a problem: http://www.fda.gov/NewsEvents/Testimony/ucm327667.htm

Conclusion

The bottom line is that it is all about money. If a company does all the types of testing I’ve alluded to their  costs are higher than if they do only some or no testing. Supplements aren’t cheap. If you go to your pharmacy or grocery store (or supplement store for that matter), all the products of a particular type cost roughly the same, although the ones in supplement stores are almost always more expensive. Who made these pricing decisions? Are you paying for the same type of testing for all the products or not? Honestly, no one except the companies themselves know. It’s even difficult to tell whether they ask themselves these kinds of questions.

So how, you might ask, does the supplement industry get around being more diligently regulated? They are putatively healthcare-related products, aren’t they? The consumers are going to place them inside their bodies and hope for results, aren’t they? Yes and yes. The answer is that the supplement industry has a very powerful lobby and this lobby makes sure that the U.S. Congress does not pass legislation to regulate it. Congress gets paid, in some clandestine way, to ensure that consumers are not protected in the same way they are with pharmaceuticals. That is just wrong.

http://www.theatlantic.com/entertainment/archive/2014/06/john-oliver-explores-the-real-reason-for-americas-problem-with-magic-supplements/373228/

http://time.com/3741142/gnc-vitamin-shoppe-supplements/

http://www.nytimes.com/2015/02/06/opinion/the-politics-of-fraudulent-dietary-supplements.html?_r=0

http://www.cbsnews.com/news/dietary-supplements-latest-government-uproar-no-match-for-industry-lobbying-money/

As a consumer, should we be more interested in what profit our supplement companies are banking or should we be concerned about what we are putting in our bodies and why. I’ll vote for the second criteria. I wish more people understood the applicable criteria so that they would demand appropriate testing and quality control standards as well.

Here is peer-reviewed articles on the dubious benefits of supplements, although there are important reasons to follow your doctor’s recommendations if (1) your diet is not normal for some reason or (2) you are pregnant.

http://annals.org/article.aspx?articleid=728199

The bottom line?

caveat-emptor

Test

I Was Nominated (and Accept)

Confabler nominated me for a Sunshine Blogger Award!

My distant, yet close friend Confabler has nominated me for the Shiny Shiny Sunshine Award. I love her imagination and sense of whimsy; she lets her muse du jour lead and she follows. There’s a wonderful freedom to that which is (1) difficult to allow in the rational process of “writing” and (2) enjoyable to find.

1. If you were to choose an insect that would take over the world after human extinction, who would that be?

It sort of depends on our route to extinction. If it involved an epidemic, the population of flies might see a giant uptick. This would be a good one:

mydas_sp
Gauromydas heros

If it is a slow process, then I nominate the Japanese Rhinoceros beetle because it would be awesome if creatures  with such improbably fashioned protuberances were to be the alpha species (Megasoma and Titan beetles would be acceptable alternatives):

800px-kabutomushi-japanesebeetle-july2004
Allomyrina dichotoma

 If our extinction took all other terrestrial life along for the ride, I would like to see this enormous isopod (a relative of our terrestrial roly-polies) rule the seas (note inclusion of actual human hands for sense of scale):

Giant_isopod.jpg
The underside of a male Bathynomus giganteus, a species of giant isopod captured in the Gulf of Mexico in October 2002.

2. How old were you when you first read Harry Potter? And your favorite author of course?

I was pretty old when I read my only Harry Potter book (the first one). I didn’t enjoy it enough to complete the series, although I’ve seen all the films and enjoyed them well enough. In the period I read that first one, I was typically reading a lot of history and didn’t find that it was a good use of my time. When I was really young, I read the Classics Illustrated versions of novels, which were quite good at introducing a curious young mind to the wonders of literature without having to do the work (sort of illustrated CliffsNotes (I didn’t use these in school though), if you will). When I was a little older, I read Robert E. Howard, Sax Rohmer, John Carter of Mars, H. Rider Haggard, Stanley Weinbaum, George McDonald fantasies, etc.

My favorite author is Gabriel Garcia Marquez for One Hundred Years of Solitude and Love in the Time of Cholera. His writing is so rich, amusing, full of simple wisdom and abundant humanity it is hard to believe he was just a human being writing about the lives he saw playing out around him. I literally would read some passages and have to put the book down as if I had just sipped the richest chocolate elixir in the world and needed to savor it until I sipped again. His Spanish-to-English translators did a good job in getting it right; Gregory Rabassa (OHYoS translator) was even praised by Garcia Marques himself!

3. If you were invisible what is the craziest thing that you would do?

Here’s an odd one: Go and hang around bigots, transcribe their conversations, and publish them for the world to see how terrible people speak when they think no one is listening (but, oh yeah, we have the internet so this already happens). If I could walk through things, which seems fair since I’m invisible, I would go around seeing what it felt like to do that—see if there were different textures to different things on the inside than on their surface.

4.what food makes you feel like a hungry hyena?

This has changed so much over time! These days, I don’t get this kind of urge anymore. In my early adult (late teen?) years… ICE CREAM!!!!

5. A song that makes you dream?

Gymnopedie #1 by Erik Satie


6. Have you ever planted a tree?

Yes. Unasked but answered: quite a few!

7. Choose your man: superman/ Spiderman/ iron man and if he was your best friend one thing that you would make him do?

Can I choose Supergirl? If I can, I would have her take me around to various places in the world, build shelters so I could stay there and visit free, then whisk me off to the next place on “our” list (she would be enjoying the sight-seeing with me, of course! What kind of boor do you think I am?!?!).

8.How much time do you spend in front of the mirror everyday?

As little as possible, which involves shaving and brushing my teeth. I find that shaving my teeth first helps with the brushing.

9.why you started blogging and tell us about the post enjoyed the most making.

I was having a bunch of conversations with people who did not seem to understand the wonderful humility of learning and doing science and wanted to see how well I could write about how science is a discipline that can assist us all in not leaning out too far over our skis (getting ahead of ourselves and pretending we know stuff we don’t). Blogging has become so much more than that since my first post on June 22, 2016, and I have had so much fun writing fiction and revisiting some poetry I wrote several decades ago (and finding them easier to “fix” than I remembered).

I’m not sure which of my posts I enjoyed the most. They’re all my children so I like them all? I probably like the odd bits of fiction that I had no idea were inside me when I woke up and then found them on the page looking up at me. I like The Big Day of these. Of the science posts, I like The Mess: Parts 1 & 2 and the Appendix 1 items best (maybe). Of the historical pieces, I like Risk Management. Of the life pieces, I like Building Blocks the best. Anyone who reads this is encouraged to make up their own mind; I am hopelessly biased.

10. Which social media platform are you addicted to (including WordPress)?

I don’t do much social media except WordPress. I don’t like Facebook at all and deleted my account. WordPress is addicting but in a very healthy way! You get to create something and share it with new friends from all over the world. That’s a great addiction have.

Now the rules:

1.thank the person that nominated you.

Thank you, Confabler. You are a true virtual friend, and I don’t mean that in any Pokemon way either!

2. Answer the questions from your nominator.

Done.

3. Nominate fellow bloggers you follow.

Hereinafter lie the following nominees in no particular order (order, of course, being an illusion):

Confabler – it would be completely wrong not to boomerang this thing back at her; how could I like what she writes and like that she nominated me but ignore why we share interests at all?

November_child –  in her poetry, every word is judiciously considered for its various meanings and the images they stir and she makes great short stories that are deep and playful and serious all at the same time

anonymouslyautistic – for doing an AMAZING job of writing about this misunderstood spectrum of living – and for inviting others who share her interest to contribute

English Lit Geek – because she searches the web and her library for poems that communicate her inner soul to us all out here in the ‘sphere and I appreciate this!

Wiser Daily – because this guy writes REALLY well about every single subject he wraps his mind around, because he is not a scientist but writes extremely clearly about science, because he is just a damned good writer!

Breathmath – because they are doing an astonishingly serious job of trying to get the world to see the beauty in mathematics

Sheryl – because she’s written a book, is working on others, has great tips for doing the same, and kindly visits my offerings fairly often

The Nexus – because he writes REALLY well about physics and does a great job of doing what I set out to do, whether I’m doing it on any given day or not

The Biology Yak – because she is passionate about biology and shares her passion in every word on every topic she chooses

afternoonifiedlady – even though I have no idea what it is to be an afternoonifiedlady, I love her rants about living with and without her ex and trying to wrestle with notions of romance – she is very witty and amusingly pissed off!

Yaskhan – for her lovely, succinct way with words

urbanagscientist – because she is at least as worried about the misunderstanding of science as I am

Luke Atkins – because he writes really well about difficult subjects and he writes like the stuff matters a lot, which it absolutely does!

And there are more in my list of 119 writers that I am following but this is enough for now.

4. Give them 10 questions to answer.

If you wish (and I clearly cannot impose this on any of you, please respond to confabler’s funny questions. I enjoyed them, maybe you will too!

Kind regards, MSOC

https://confabler.wordpress.com/2016/09/20/shiny-shiny-sunshine-award/

It was Generous of confabler to choose me. Now I have to Jump off and do other stuff!

Today is Brought to You by the Letter “Tzett”

Z – The Sequel

There are loads of naturally occurring and synthetically created organic molecules (usually compounds composed of carbon and hydrogen but often containing other elements as well). As chemists got busy discovering these substances, they also started coming up with ways to name them in increasingly systematic ways. Very early in an organic chemistry course (or very late in a general chemistry course), students learn that organic chemistry is as much a language course as a science course. Bright students with good language skills figure this out and apply the grammar and syntax accordingly; bright math students sometimes wonder what the heck happened? The way chemical compounds are named is called nomenclature, which means (oddly enough) “name calling” from Latin roots. Before the end of any organic course, some portion of the class usually gets quite busy calling names, although not those of the organic compounds they’ve come to despise (silly students! Succumb! Breathe in that fresh and unusual knowledge!). The professors bear the brunt of the name calling, although teaching assistants and anyone else nearby will do nicely. I probably fell in love with organic chemistry when I realized the nomenclature was systematic and could be applied logically rather than learned by rote memorization. And then there is the rich, rich symbolic language that goes along with the words! So spare and simple! So full of endless possibilities!

Anyway, among the structural idiosyncracies posed by increasingly insightful physical and chemical tests chemists developed was that some organic compounds contained single carbon-to-carbon bonds, some contained shorter double carbon-to-carbon bonds, and some others contained triple bonds between carbons, which were shorter than either of the other two types. Typically, carbon requires four bonds to other elements (carbon, hydrogen, oxygen, nitrogen, sulfur, etc.). When there was a double bond between carbons, the two carbons with the double bond between them only needed another two bonds—a total of three bonds instead of four. When the two carbons had a double bond, the other elements on either side of the double bond were sort of locked in place by the relative rigidity of that double bond (triple bonds are even more rigid). If there were only two carbons in the molecule and each of the carbons were bonded to two hydrogens as well as each other, there was no problem in naming that little nugget. It was called “ethene.” Just to give you something to relate this to, if you take off one of those hydrogen “H” atoms and put on an hydroxyl “OH” bit, this little guy magically becomes ethanol, fuel of dreams, liver-pillager, starter of fights and trips to the ER.

320px-ethylene-crc-mw-dimensions-2d
Ethene (also known as ethylene)

When the chemical moieties are something other than hydrogens, the naming game gets a touch more difficult. For instance, if we are presented with a four-carbon compound that has a double bond between the second and third carbons, it would generally go by the name “but-2-ene” or the arguably simpler 2-butene (there is a global chemistry naming organization called the International Union for Pure and Applied Chemistry (IUPAC) that gets together and sorts this stuff out; but-2-ene is their preference and they have a really colorful website, so let’s go with their approach, which I also adopted with “ethene,” although “ethanol” is the IUPAC name for ethyl alcohol). Here’s but-2-ene:

cis-2-buten-svg
cis-but-2-ene
trans-2-buten-svg
trans-but-2-ene

Oops! But that’s TWO molecules. Yes it is. The thing with that rigid double bond is that once a molecule has one, and there are a sufficient number of carbons or other sufficiently complicated moieties hanging off one end of the double bond or the other, there are two possibilities. The top symbol represents the cis- form, by which it is meant that the two methyl groups (each CH3– group is known as a “methyl” group) are on the same “side” of the double bond as each other (by the way, the double bond makes all of four of the carbons lie in the same plane as each other, so it is essentially a “flat” molecule, although the hydrogens on the methyl groups sort of spoil that by spreading out in their typical tetrahedral patterns). The bottom symbol represents the trans– form, by which it is meant that the two methyl groups are on different “sides” of the double bond. They are two different molecules with different physical properties: cis-but-2-ene boils at 3.7°C, while trans-but-2-ene boils at 1°C (they melt at -138.9°C and -105°C, respectively—a pretty huge difference in melting points for two molecules with exactly the same chemical formula (C4H8)).

For a more three-dimensional look at the difference between cis– and trans-but-2-ene, take a look at the following pages, which allow you to rotate molecular models of these distinct chemicals and shows their “flatness” better than the structures shown above:

CIS: https://chemapps.stolaf.edu/jmol/jmol.php?model=C%2FC%3DC%5CC
TRANS: https://chemapps.stolaf.edu/jmol/jmol.php?model=C%2FC%3DC%2FC
(Just click on each with your left mouse button and wiggle them around)

That naming convention worked just fine… until more complicated substituents were inevitably discovered mucking up the nice cis- and trans- simplicity. As an example, let’s look at 1-bromo-2-chloro-2-fluoro-1-iodoethene:

1-bromo-2-chloro-2-fluoro-1-iodoethene-pair
Two conformers (configurational isomers) of 1-bromo-2-chloro-2-fluoro-1-iodoethene

The way this new rule works is that we must take into account the atomic masses of the ethene substituents (ethene (we’ve met before) being that two-carbon-double-bonded bit in the middle of all these halogens (e.g. F, Cl, Br, and I)). Let’s rank these halogens in decreasing atomic mass: iodine (~127 daltons or amu), bromine (~80 amu), chlorine (~35.5 amu), and fluorine (19 amu); (in science, the tilde (~) is used to mean “approximately). The rule is this: if the moieties with the highest atomic masses are on the same side (not the same end, mind you!) of the double bond, then they are “together” or “zusammen,” the German word for “together.” If the highest amu moieties are on different sides of the double bond, they are opposite or “entgegen.” It would be sort of laborious and annoying to spell out “zusammen” and “entgegen” prefixed to every molecule for which this naming convention applies, so instead the letters “Z” and “E” are used. This means compound 9 (above) is named (E)-1-bromo-2-chloro-2-fluoro-1-iodoethene, while compound 10 is named (Z)-1-bromo-2-chloro-2-fluoro-1-iodoethene.

If you’d like to know who to thank for this naming convention, make sure you give credit to R.S. Cahn, C.K. Ingold, and V. Prelog, without whom the Cahn-Ingold-Prelog Rule would not exist. It can be applied in an equivalent manner to any compound in which conformational isomers around a double bond raises some ambiguity about nomenclature. Here is one last picture that shows you how it might apply to other substituents around a double bond:

cip_priority_diagram
Attribution

And, by the way, the Germans (responsible for the words zusammen and entgegen) call the letter “Z” “tzett,” which is close to how those English-speakers on the other side of the pond (i.e. the British, but also Australians, Kiwis, and for that matter, Canadians, who are just across the Great Lake ponds) say it – “Zed.”

If you want to know a bit more, listen to the dulcet tones of Sal Khan as he goes through a few more examples.

and

Special thanks to my German tutor November Child, who writes excellent poetry and had no idea I was writing about this today.

Featured image: ©2009 Martin Fisch (Some rights reserved).

Together

Science and Elegance

When is something sufficiently elegant?

I can’t remember the first time I saw the word “elegant” used to describe a scientific (probably chemical)  process but it was probably one of the numerous inflection points at which I realized that I had finally pivoted in an inexhaustibly rewarding direction. Not that an undergraduate literature degree wasn’t fulfilling and beautiful on its own but science generally and chemistry in particular was all about discovering the way in which the universe behaved (and didn’t) and where notions, conjectures, hypotheses could transmogrify into fact. And not only single facts but clusters of facts. Not only clusters but polished jewels of truth that became more radiant and absolute with each refinement of an observation, a finding, an irrefutable nugget of wisdom gleaned from disciplined, diligent iteration through ever-expanding data sets!

Wherever I saw the word initially, it was not a rare event. I did a search on our word solely in (1) the American Chemical Society (25-year member) publication database in (2) publications that were free for me to browse and download in their entirety as many journal articles require purchase even if you area Society member. The search returned 389 articles that included the word “elegant” somewhere, either in the title, the abstract, or the body of the article. These articles ranged (for me) from the comprehensible (organic syntheses and improved synthetic techniques):

Macromolecules, 2015, 48 (3), pp 520–529
Publication Date (Web): January 27, 2015 (Article)
DOI: 10.1021/ma502460t

through more mathematically complex (various spectroscopic data analysis improvements):

J. Am. Chem. Soc., 2007, 129 (42), pp 12746–12755
Publication Date (Web): September 27, 2007 (Article)
DOI: 10.1021/ja0722574

to work I would have to study for days to understand (a lot of pure physical chemistry or computational chemistry work):

, , and J. Chem. Theory Comput., 2010, 6 (9), pp 2866–2871
Publication Date (Web): August 24, 2010 (Article)
DOI: 10.1021/ct1003077
Okay, so none of this probably seems in the least bit elegant to the general reader. In some cases, the word might be greeted with a bit of cynicism by the semi-professionally cynical self-assembling organism to which I belong (“elegant?!? Why that’s simply a slight improvement over the work my colleagues and I completed 20 years ago!” said the outraged professor while reading over the latest J. Phys. Chem. volume). Perhaps the word has fallen into over-use, like the word “awesome” among the lumpenproletariat, another group to which I belong, although not in the strict sense of the word.

I did a search in PubMed, an astonishingly useful and free database of all (or at least major) scientific and medical journal articles from around the world established and maintained by the National Institutes of Health (NIH; while searches are free (thank you, NIH), many articles can only be read by purchasing the individual article or heading down to your local university’s medical library, where it still might cost something). I did not filter for articles available for free; the search returned 4,059 items containing the word “elegant.” Here’s an example:

An elegant new test of corticospinal tract function during surgery: More work to be done.
Skinner S.
Clin Neurophysiol. 2016 Aug 24. pii: S1388-2457(16)30506-5.
doi: 10.1016/j.clinph.2016.08.014.
[Epub ahead of print] No abstract available.
PMID: 27590207

Sounds painful! If less painful than the previous procedure? Elegant!

I’m not really sure why the chemical compound cubane appeals to me so much. Maybe my underlying, subconscious interest is similar to whatever triggered Plato into thinking about Platonic solids (a very rich area of study in themselves), three-dimensional objects formed by “congruent regular polygonal faces” that he believed were the building blocks of the universe in some way (they aren’t; the building blocks are simpler and more complex than he imagined). I think the real reason is that cubane is an object conceived of as a chemist’s goal and was achieved through thinking about reagents, starting products, solvents, conditions, etc. that could be brought to bear on the problem.

The compound was first synthesized in 1964 by Philip Eaton and Thomas Cole. Initially, the synthesis scheme was as follows:

cubane-eaton
Attribution

“What does this even mean?” you might say if you were not familiar with the beautiful molecular short-hand of organic chemistry. Well, in brief, it means that you start your reaction series with some 2-cyclopentenone and react it with N-bromosuccinimide in carbon tetrachloride (CCl4) under specific temperature and reaction time parameters in glass lab ware perfectly suited to such reactions, and you end up with the second compound in the series (on the right of the arrow in the upper left of the diagram). A whole bunch more chemistry is performed until, in the end and if you’ve been very diligent all the while, you end up with a compound with the molecular formula C8H8, probably with relatively poor yield, meaning that from starting material to cubane, you have lost various percents of the original mass of carbon, hydrogen, and oxygen to by-products of varying shapes and descriptions (including some of the organic chemists least best friend – insoluble tar).

I would argue that elegance had been achieved in this first synthesis. Cubane had never been existed before 1963 (paper published in 1964) and had never been created by (1) the human mind (as an idea of something to be created) or (2) by human hands (as something to be fashioned out of dissimilar materials).

Elegance in science doesn’t stop with the first synthesis, though. It continues through the work of others who have seen that first instance of success and gotten busy attempting to make the same compound in fewer steps and with less of the starting material being diverted into by-products.

Within a couple of years, an improved synthesis was achieved by N.B. Chapman and colleagues, who whittled the initial synthetic route down to:

n-b-chapman-improved-cubane-synthesis
http://www.ch.ic.ac.uk/local/projects/b_muir/Cubane/Cubanepro/Synthesis.html

 

This version of the synthesis netted 25% cubane from the starting material – and did so in only six steps! Elegant x 1010.

And that is how elegance evolves in science. An initial idea is refined until it is really beautiful. It doesn’t make the first discovery less beautiful. It’s not really a contest. These are intellectual puzzles and scientists love to get busy solving them. Sometimes, there are ramifications to their investigations that lead to places we all probably wish had not been inevitable answers to the questions asked (think nuclear weapons, an inevitability presaged by Ernest Rutherford’s definition of the atom, and onward). Can that be helped? Not if answers are what we seek.

In the meantime, there is much beauty to be found in these processes. I know I’ve gotten a little rich with the chemistry, but just look at the pictures and appreciate that we have minds that (1) created this language, (2) can create laboratory conditions that lead from one chemical compound to another, and (3) are not satisfied with the initial answers they receive and want better solutions. That’s something that we can all understand, right?

While digging around in the literature, I came across a blog post by Dr. Anthony Melvin Crasto. His writing on cubane synthesis and other related matters made completion of this post easier than it would have been.