Tuesday, June 30, 2015

Atomic Tuesday: The Leptons

The Lepton Family
by Rich Feldenberg

The leptons are a family of elementary particles that have characteristic properties.  They have a value of quantum angular momentum, known as spin that is always a 1/2 integer value.  They also have an electric charge (minus for normal matter leptons and positive for anti-matter leptons).  Leptons are not effected by the strong nuclear force so are not bound to atomic nuclei in the way Up and Down quarks can be. 

The most familiar of the leptons is the electron.  The electron is common and is bound to atoms through its electromagnetic attraction to the positive charge in the nucleus.  There are two heavier versions of leptons called the muon and the tau.  The muon and tau are considered electron-like neutrinos, since they are identical to electrons in every way except for their mass.

In contrast to the electron-like leptons, there are neutral-leptons called neutrinos.  They come in different varieties and there is one variety associated with the electron, muon, and tau.  The neutrinos are very light, having such a small mass that they have been very difficult to measure until recently.  The neutrinos do not have an electric charge (hence neutral-leptons) and so interact with matter very rarely since they have no interaction through electromagnetic or strong forces, and barely register through the gravitational force.  They can interact through the weak nuclear force.  It is estimated that there are billions of neutrinos zipping through every square centimeter of your body every second of your life.  You don't notice them because there interaction with matter is so weak.

Monday, June 29, 2015

Mutation Monday (Your Mutation Station): Thymine dimers

by Rich Feldenberg

Welcome back to your mutation station.  Today we'll look at a harmful effect on your DNA due to ultraviolet light, which leads to dimerization of the nucleotide bases thymine (T).  If there are two T bases next to each other in the DNA strand and they absorb UV light they can undergo a photochemical reaction that causes them to link-up.   The double bonds in the base break and then form single bonds to their neighbor.

This blocks normal base pairing on to the other DNA strand of the double helix, and results in a mutation.  Fortunately there are cellular repair mechanisms that can find and fix these errors, but some errors escape detection and cause major harm.  Some melanomas are thought to be due to thyimine dimers caused by the effect of UV sunlight.

Thymine dimers are actually a more specific form of what is called pyrimidine dimers.  The bases thymine and cytosine (T and C) are pyrimidines.  Two pyrimidines can dimerize under the same conditions leading to the same sort of DNA mutations.  You could have T-T dimers (thymine dimers), but also T-C, and C-C leading to the same problems.   So, remember to use sunblock and be careful about exposure to the sun!!

Friday, June 26, 2015

Fossil Friday: Dickinsonia

by Rich Feldenberg

Welcome to the long forgotten Ediacaran Period (635-542 Million years ago) in the Precambrian.  An assortment of unusual and fascinating fossils have been found dating to this time period, when multicellular life was just getting large enough to make good fossil imprints.  It is sometimes known as "The Garden of Ediacaran" because it is thought that at this early stage of animal evolution most creatures were basically filter feeders, and no major predation had yet developed (including the tools used by predators such as teeth, eyes, or sophisticated brains).  In that sense it may have been a very peaceful and "innocent" chapter in the history of life, before an evolutionary arms race between predator and prey began in the Cambrian and continues on to this day.

One common fossil found in rocks of this age is that of Dickinsonia.  This little guy was round shaped with a bilateral symmetry - something that shows some level of sophistication from the even earlier radially symmetric ancestors.  It seems to have had a head-end and a tail-end and was divided into segments.  It is not clear what kind of animal Dickinsonia really was, and there is a great bit of controversy in the scientific community in regards to its proper placement on the tree of life.  It seems to have been capable of movement over the ocean floor, as there have been fossilized tracts found that are thought due to its movements.   It may have belonged to a phyla that went extinct by the end of the Ediacaran period, or alternatively it may be related to modern day creatures.  Some experts have speculated that it is related to modern day jellyfish and some even think it may be related to animals that eventually became vertebrates.  Others have even gone so far as to say that it was not an animal at all, but part of a short lived, and ultimately unsuccessful evolutionary experiment in some type of multicellular life form that went extinct half a billion years ago.  What ever Dickinsonia was it made beautiful fossils!

Wednesday, June 24, 2015

Why Brontosaurus being back challenges my ability to change my mind

Why Brontosaurus being back challenges my ability to change my mind.
by Rich Feldenberg

Ok, here’s the thing.  I grew up dino-crazy.  From the time I was in 3rd grade onward, I had a love for the prehistoric beasts we know as dinosaurs.  I’m not saying that a lot of kids don’t come down with dino-fever when they’re little (it is a common childhood illness after all), but it seems that for the vast majority of people it is a mild self-limiting disorder that is really nothing to worry about.  I didn’t fall into the category with the majority of inflicted, I was in the small percentage of patients where the condition became chronic.  There is an even smaller percentage of chronic dino-fever sufferers that go on to become paleontologists (so yes, there are some out there that have it worse than me).  I didn’t grow up to become a paleontologist, like I thought I would in 3rd grade, but I continue to have an interest in learning more about my extinct darlings (all extinct that is except for the avian variety - birds!).  Of all the dinosaurs I knew about in 3rd grade - and there are a lot more known today than there were then - brontosaurus was definitely one of my favorites.  It would certainly be amazing to be able to see what a living animal would have looked like.  Here's hoping for Jurassic Park or Jurassic World technology one day - minus the rampaging raptors and out of control T. rex, of course!

Brontosaurus was one of the long-necked dinosaurs or sauropods.  They were a varied group and some, like brontosaurus, grew gigantic.  The sauropods were the biggest land animals to ever walk the earth.  Only blue whales are larger, and those whales are cheaters (literally, the “biggest” cheaters) because they use the buoyancy of the salty ocean water to prevent their tremendous weight from crushing the life out of them.  Not good old brontosaurus, they were built to take it.  In case you haven’t noticed, whales don’t last too long on dry land.  Back in my day (you know 3rd grade) we thought that brontosaurus probably had to live in lakes and other bodies of water to support their mass, but over the last few decades it has become clear that isn’t so.  They roamed the dry land in herds.  Their legs and backs had to hold up under the unrelenting gravity of planet earth.  Their lungs had to expand to fill with air and their hearts had to pump blood through a super long neck leading to a brain (alright, so it was a tiny brain) with the weight of their own tissues constantly trying to flatten them.  A pretty impressive physiology had to be set in place by the wonder of evolution, and it is amazing to speculate on what environmental pressures lead to such crazy gigantism through natural selection.  

So what does all this have to do with brontosaurus being back, or me having a tough time changing my mind?  Well, back during my paleontological training in 3rd grade, brontosaurus was the most famous of the sauropod dinosaurs.  We did know about sauropods like diplodocus and brachiosaurus, but brontosaurus was the one most often portrayed in drawings and paintings.  Little did our young minds realize at the time, but there was a scientific controversy on the nomenclature of brontosaurus.  It seems that brontosaurus was named by the famous paleontologist Charles Marsh in 1879, but Marsh had already named a different skeleton of sauropod Apatosaurus in 1877.  Marsh, of course, thought that these two animals were different kinds, but in 1903 another scientist, named Elmer Riggs, studying the fossils, concluded that the two specimens were, in fact, one and the same species.  Even though Marsh was the discoverer of both specimens, the rules of dinosaur nomenclature state that the first named is the true name.  In other words, there was no brontosaurus, just apatosaurus.  

Scientists had known, and basically accepted this since 1903, but it didn’t seem to trickle down to the general public until a long time later.  I’m not really sure when it became generally well known that brontosaurus was out and apatosaurus was in.  It may have been the 90s or early 2000s.  All I remember was being devastated that brontosaurus was no longer a thing!  The name was already well engrained in my mind, and it seemed annoying to have to now call brontosaurus, apatosaurus, but I was already scientifically trained by that time and was willing to do the right thing.  I began using the name apatosaurus when talking or thinking about the great beast.  

Now new research has revealed that the bones of brontosaurus and apatosaurus really are two different kinds of animals.  So, just this year, brontosaurus is back after 112 years of mistaken identity.  When I saw the reports of the research teams conclusions I was overjoyed.  Yay, brontosaurus is back!  I love you brontosaurus!  Then the joy I felt at going back to a well engrained fact made me think about the difficulty humans have changing their minds.  The cognitive strain caused by having to accept new facts as true, and our emotional need for a stable, unchanging view of the world.  Darn, there are no free lunches after all!

Changing gears just a bit from the bones of the Thunder lizard to the frontal cortex of the “wise man” (Homo sapiens), research in cognitive psychology by nobel laureate Daniel Kahneman reveals that we rely on two systems to construct our view of reality, and to update that view as new information is processed.  These systems are called system 1 and system 2.  So much for creative naming.  System 1 is our quick thinking system.  It is similar to intuition or a gut feeling.  You don’t really have to think about the situation, the answer just comes to you.  Some of it is just evolutionary programming that is triggered by certain stimuli, like face recognition for example.  It allows us to rely on certain heuristics that may be right a lot of the time, so we can make snap decisions.

System 2 on the other hand is our slow thinking system.  It is dependent on more careful thinking and consideration to detail.  Applying statistical analysis or the scientific method to a problem would draw on system 2.  Unfortunately, system 2 is slow, expends a lot of mental energy, and is therefor expensive from a survival point of view.  In reality we use both systems everyday.

I think that since I learned about brontosaurus from such an early age, I formed a sort of heuristic of recognition when I saw or read something about apatosaurus.  There was a cognitive strain associated with placing apatosaurus in the memory location where brontosaurus was supposed to live.  The article that validated the uniqueness of brontosaurus as it’s own species gave me a sort of permission to use my old tried and true heuristic for recognizing the creature - much like recognizing a familiar face of a friend or celebrity.  A relief of the cognitive strain meant that I didn’t have to rely on system 2 each time to draw upon the fact that there is no brontosaurus, only apatosaurus.

This seemed a bit disappointing to me, since I consider myself someone who values system 2 type thinking a lot.  And this was only about the name of the brontosaurus.  Think of all the many beliefs deeply embedded in our minds due to having been placed there from an early age.  It makes it difficult, though fortunately not impossible, for us to self-examine facts that we take for granted.  But science teaches us that individual facts are updated, revised, and sometimes even completely changed as new evidence accumulates.  This is not how our system 1 evolved to interpret the world our distant ancestors woke up in.  The things our intuitions inform us of, that seem like common sense, are not always a good model of truth.  Getting my brontosaurus back told me that it is really hard to change your mind and update your model of the world.  Being open to change means feeling comfortable with some degree of uncertainty.  Not an easy thing, but something we can train ourselves to get better at accepting.  I was lucky this time, but the next beloved fact that is overturned will probably not be set back to zero again.  Oh well, I’m a scientist and I will continue to try my best to embrace the changes that are coming as science sheds new light on our world.    In the meantime, welcome back brontosaurus, I missed you!

Tuesday, June 23, 2015

Atomic Tuesday: The Pauling Scale

The Pauling scale is a convenient way to compare the electronegativity of two or more atoms.  An atom's electronegativity is the attractive force it has for an electron.  The Pauling scale gives a relative magnitude for this attraction.  Linus Pauling, the Nobel winning chemist, contributed enormously to areas of chemistry such as molecular bonding theory.  He devised this scale with the maximum electronegativity set to 4.0.  Fluorine is the most electronegative atom and has a Pauling value of 4.0.  Francium, on the opposite corner of the periodic table from Fluorine, as the lowest Pauling value for any of the elements, and is 0.7.

If two atoms have a large difference in their Pauling values, then they are more likely to form ionic bonds since one of the pair will have a much greater attraction for an electron then the other.  If on the other hand, the pair of atoms have very similar values, then they are likely to form covalent bonds, since both atoms have equal or close to equal attraction and therefore share the electron between them.    Even in covalent bonds, unless the two atoms involved are of identical type there will still be a subtle difference in electronegativity that will create an imbalance in the location of electrons in that bond.  This is a polar bond, and accounts for a lot of interesting chemistry to occur due to placing a partial negative charge on one atom and a partial positive charge on the other.

The atoms on the periodic table are not sitting randomly with respect to their electronegativity .  One of the many valuable features of the periodic table is that you can predict, based on location in the table, which elements will have higher or lower Pauling values than other elements found at other locations on the table.

Monday, June 22, 2015

Mutation Monday (Your Mutation Station): Cytosine deamination

Due to simple chemistry, the nucleotide base cytosine undergoes a common, but unintended reaction  with water, resulting in loss of its ammonia and conversion of the base from cytosine to uracil.  This is known as cytosine deamination and is a natural process, that results in a constant assault on our DNA, causing damage due to the aqueous environment surrounding the DNA molecule.  This leads to a point mutation, but is usually easily picked up by the proof-reading properties of DNA polymerase (the enzyme that copies the DNA molecule).

It is easily picked up because uracil is not a natural base in DNA.  It is found normally in RNA, and it is quite possible that RNA evolved first in the earliest life on earth, and when DNA took over the role it has today of storing genetic information thymine was substituted in place of uracil so that the deamination process could be detected and repaired.  In other words, if uracil was a natural base in DNA, there would be no way for the proof-reading machinery to detect that a base change occurred.  Pretty ingenious of nature, don't you think?

     Cytosine  Uracil


Sunday, June 21, 2015

Origins Sunday: Building blocks of nucleotides

The building blocks for nucleotide bases seem to be capable of forming in hot conditions, like those found around deep sea hydrothermal vents.  Nucleotides are made of rings of carbon with nitrogen atoms in the ring structure.  These rings were not thought to form easily in the cold conditions of the gas clouds in space, but may form readily in these hydrothermal vent conditions.  On early earth this might of provided the building blocks for DNA and RNA molecules.

And...Happy Father's Day!


Thursday, June 18, 2015

Why the Horta would not have looked like a rock monster

Why the Horta would not have looked like a rock monster.
By Rich Feldenberg

In the original Star Trek series the U.S.S. Enterprise, on its heroic five year mission to explore strange new worlds, to seek out new life and new civilizations…, comes across many fascinating and unusual alien species.    In one episode in particular, “The Devil in the Dark”, they make contact with a creature with an entirely different kind of biochemistry from the typical carbon based biochemistry seen elsewhere on earth and throughout the galaxy.  Captain Kirk and the crew of the StarShip Enterprise first encounter the alien after they respond to a distress call sent from a mining colony on the planet Janis VI.  When the Enterprise arrives, Kirk learns that routine mining operations have been disrupted by a strange life form native to the planet.  The creature doesn’t register as a life form on the tricorder, lives deep in the darkness of the mines, and can eat through solid rock due to it’s highly corrosive nature.  Once Spock learns that the mines contain a multitude of spherical shaped silicon nuggets, he has a hunch.  As usual, Spock’s hunch turns out to be correct.  The round silicon nuggets are the eggs of a silicon based life form.  Spock is able to use his mind melding abilities to communicate briefly with the creature, and learns that it is called a Horta, and that the miners have been destroying its eggs, causing it to face total extinction.

While I applaud the episode for thinking outside the box when it comes to attempting to imagine “life as we don’t know it”, I suggest that making the silicon based Horta, essentially a living rock, showed a poor understanding of both organic and inorganic chemistry.  So first let me say what was outstanding about the idea before I lay into it with my chemistry degree equivalent of a phaser set on kill.  

Ok, it was great that there was any attempt at all to speculate on the astrobiology of an organism that was not carbon based back in a 1960s TV show.  By non-carbon based I’m not talking about energy beings here, but legitimate speculation about an alternative chemical system, as we’ll discuss below.  This certainly went well above the usual laziness and poverty of imagination of portraying an alien as a human with pointy ears, or a green girl, or, as in the case of the klingons, with angry eyebrows (they hadn’t evolved there forehead ridges yet!).  Now don’t get me wrong, I don’t have anything against a green blooded pointy eared Vulcan.  In fact, Mr. Spock may be my all time favorite fictional character, but it really isn’t terribly creative when you consider how life forms on different worlds would likely have evolved down completely different pathways leading to completely unique body plans.  In other words, even if most life in the universe is carbon based, like us (probably still a good guess), intelligent aliens wouldn’t necessarily appear anything like humans.  Ok, I get it, there were budget issues!

Now, all life on earth is carbon based.  Carbon chains form the backbone of all the major classes of biomolecules, such as DNA, protein, carbohydrate, and lipids.  Because carbon can form so many complex molecules, it has it’s own special branch of chemistry devoted to it - organic chemistry.  The chemistry of every other element falls under the heading of inorganic chemistry.   That seems really unfair, right?  I mean one element out of the 92 naturally occurring elements, and it gets it’s own branch of science!  Well it actually is fair when you consider that the number of possible organic molecules far exceeded the number of inorganic molecules combined by orders of magnitude.  There are an estimated 10 million carbon compounds in existence.  There are a lot of ways that carbon can react depending on what other atoms are near it on a molecule.  Carbon is element number 6.  It has 6 electrons in orbitals around a nucleus containing 6 protons and 6 neutrons (at least for carbon12, the most common isotope).  Because carbon is in group 14 of the periodic table, its electron configuration is 1S2, 2S2, 2P2.  Each S orbital can only hold two electrons but the P orbital can hold up to 6 electrons so there are 4 vacant spots in carbon’s P orbital.  There is a tendency for an element to move towards a noble gas configuration, meaning that for reasons related to finding the lowest energy state, and hence the greatest stability, the element will either shed electrons or gain them to mimic the electron configuration of the closest noble gas atom.  This is known as the Octet Rule.  

Metals typically lose an electron to this end, and non-metals typically gain them.  In the case of the non-metal carbon, if it fills its four vacant orbitals with electrons it will have the electronic configuration of the noble gas neon (Ne) with 10 electrons, and, ah that feels so good!   Well, how is poor carbon to get four more electrons?  That’s where covalent bonding comes in.  It shares electrons with other atoms, so carbon will try to form 4 bonds with up to four other atoms.  These could be 4 single bonds, in which case carbon is attached to 4 different atoms, or it can also form a combination of single, double, or triple bonds.  Both single and double bonds are very common in organic chemistry.  The reactive double bonds in carbon based molecules account for a lot of the action in organic chemistry.  The really special thing about carbon compounds are that carbon can bond to another carbon, which can bond to another carbon, and so on.  In fact, it is very common to see very long chains of carbon bound together making something like a huge protein or DNA molecule, for instance.  This would seem to make carbon the best suited element in the periodic kingdom for producing life forms.  I’m surprised nature never thought of that, oh wait it did!!

So what about the poor Horta?  The Horta is silicon based.  Silicon (Si) is in group 14 of the periodic table.  Hold on, thats the same column as Carbon (C)!  It also means that like carbon, silicon will also want to gain 4 electrons to fill it’s orbitals.  By the way, this is why the periodic table is so useful.  You can tell a lot about an atom by where it sits on the periodic table.  The reason you can go around the table to the next row down and find another element like the one in the row above it is why it is periodic!  There are repeating patterns.  Anyway, silicon is element number 14, and its electron configuration is 1S2, 2S2, 2P6, 3S2, 3P2.  If it can just gain four more electrons it will have the stable electron configuration of the noble gas Argon (Ar).  It is for this reason that people have speculated that if there is any other element in the periodic table that could cast a little carbon-like magic, it would have to be silicon.  The other great thing about silicon is that it is common, really common.  It is the 8th most common element in the universe (carbon is the 4th most common element in the universe), and is second only to oxygen, as the most common in the earth’s crust.  It is found in rock and sand all over the earth.  You certainly wouldn’t want to have a life form based on a very rare element like Lanthanum (element 57), for instance, where there isn’t enough of it around to make anything  useful.  You want your building materials to be lying around everywhere.


Unfortunately, the problems faced by silicon based life forms would be many.  First of all, while silicon is capable of forming a variety of silicon compounds, and even forming chains of silicon (silanes) that resemble the long chain alkanes of carbon, the number of actual silicon compounds is far lower than for that of carbon.  The Si-Si single bond is weaker than a C-C single bond due to the silicon atom being larger, and thus the silicon atoms are further apart.  This makes silicon bonds unstable, and you don’t see very long chains of Si show much permanence.  They break apart quickly, and in fact, are so reactive that they will spontaneously combust in an oxygen atmosphere.  Really very bad for any oxygen breathing lifeforms.  Also, whereas, carbon readily forms double bonds, silicon is less likely to form many double bonds, which again limits the kind of chemistry it can undergo.  Double bonds expose electrons to “attack” by other molecules - this is the beauty of organic chemistry - so fewer double bonds in Si lead to fewer potential chemical reactions.  Again, boring chemistry equals inert substances, not vibrant living materials.

Carbon also loves to form carbon rings, even rings that include double bonds that provide a special stability due to a property called resonance associated with the electrons in the ring system.  This is a bit like a little electric circuit in the molecule where the electron can have room to move around and make the bonds between atoms even stronger.  These kind of compounds are called aromatic compounds and are extremely common in living things on earth.  Si doesn’t form rings very readily so the equivalent sorts of aromatic Si compounds would be unlikely to exist.    
Remember, life is all about lots of interesting chemistry.  Interesting chemistry may not explain the purpose of life, but it’s one way to sum up what life is.  It seems most likely that life would only thrive and evolve if it’s chemistry allowed a lot of diversity and potential to form many varieties of stable compounds.  Limitation in the number and stability of compounds and number of reactions is like a death blow to the odds of life.  But what about the Jurassic Park law of biology that says, “life finds a way”?  Yeah, that may be so, but it found carbon chemistry out of all the other useless junk on the periodic table.   

In addition to these problems, there is the problem of how silicon would be recycled throughout it’s biosphere.  Carbon is well suited for recycling due to it’s ability to form the simple gas CO2 (carbon dioxide).  As we all know, CO2 is taken up by plants, and using the energy of the sun, uses the carbon to make glucose (a carbon compound in a ring shape) and releases the waste product molecular oxygen (O2).  Animals eat the plants, thereby gaining the glucose for energy and delivery of a carbon source to make more kinds of carbon compounds.  For both animals and plants the glucose can be oxidized - burned in the presence of oxygen in the tiny midi-chlorians in the cell (sorry, I meant mitochondria)- to release the energy stored in the carbon bonds.  This is the process of chemical respiration.  Once the animal dies, its body decomposes (oxidizes!), and CO2 is released back into the atmosphere where plants can take it in again.  This is the carbon cycle, and it makes life on earth sustainable for billions of years.

For silicon life forms there would need to be some sort of silicon cycle.  This is problematic since SiO2, while common, is solid and not a gas.  It is also not soluble in water, so how it would circulate through the biosphere to become accessible to the silicon life forms that need it may create an insurmountable dilemma.  With no silicon cycle, even if silicon based life could somehow get a foothold with it’s weak and limited bonding capabilities, it would quickly shut down once the available silicon became trapped in all the dead silicon organisms.  

Ok, so I’ve tried to illustrate why silicon based life forms probably won’t exist to begin with, but let’s say, for the sake of argument, the Horta really was based on Si chemistry.  Why wouldn’t look like a big rock?  This is the thing that really irks me!!  The whole point of invoking the possibility of Si life is because silicon has some chemical similarity to carbon due to its similar electron configuration.  So our imagining a Si based creature to be essentially a living rock is analogous to an intelligent silicon based species speculating that carbon based life forms would be like living lumps of coal or dangerous diamond creatures that can scratch glass.  It might make for a good episode of space Sci-Fi for our silicon based friends to watch on TV, but you can see that this is obviously an incorrect interpretation.  There is a huge diversity of life on earth but we don’t have living coal or diamond creatures.  The reason, of course is that carbon forms very complex compounds with itself and with lots of other kinds of atoms.  Coal and diamond are basically crystallized forms of carbon.  Crystals are not suitable for the basis of life because they don’t allow a lot of rapidly changing chemistry to happen within them.  

If the Horta was silicon based, the whole point would be that Si would be mimicking the complexity and diversity of carbon, and its tissues should be no more rock-like than earth creatures are diamond-like, but instead have soft squishy muscles, nerves, intestines, kidneys, blood, and so on.  It could be conceivable that the Horta could have a hard outer shell made of silicon dioxide (SiO2) but it’s whole body would not be silicon based rock.  This misinterpretation was brought home when Dr. McCoy was asked to treat the phaser wounded Horta and replied, “I’m a doctor, not a bricklayer”.  Captain Kirk appropriately reprimands McCoy telling him, “Your a healer, there’s a patient, that’s an order”.  

At the end of the Star Trek episode, Kirk realizes that the Horta was only a protective mother and didn’t wish to harm the miners or their equipment.  The crew of the Enterprise is able to make the miners understand that the Horta means them no harm if they leave her eggs alone.  In fact, the natural mining abilities of the Horta could make a collaboration between the miners and the Horta very profitable.  As the Enterprise leaves orbit, the many Horta eggs are getting ready to hatch.  Too bad that due to their silicon chemistry they are likely to spontaneously combust when they are exposed to the oxygen rich atmosphere that the humans are breathing!    

1. Wikipedia entry on silicon:  http://en.wikipedia.org/wiki/Silicon
2. General Chemistry, Principles and Modern Applications, third edition
By Ralph H. Petucci.
3. Inorganic Chemistry; third edition,  by James E. Huheey.

Sunday, June 14, 2015

Is “Bad Luck” really a diagnosis?
By Rich Feldenberg

Earlier this year the mainstream media reported findings from an article published in the prestigious journal Science, which investigated the causes of human cancer.  This would have been all well and good except that it resulted in the appearance of sensational news headlines across many top outlets, featuring the shocking conclusion that approximately two-thirds of cancer in adults is due to sheer bad luck.  Yes, you read that correctly, bad luck is apparently the main cause of cancer!  The title of the original research paper doesn’t actually mention “bad luck”, and the Science article is really about demonstrating a correlation between tissues that undergo high numbers of stem cell divisions with those tissues that have a high incidence of developing cancer.  There is a strong 1:1 correlation, showing that as the number of cell divisions increase in a given tissue type, the development of de novo malignancy also increases, and tissues that undergo low levels of stem cell divisions have a low chance of developing tumors.  That seems to make sense, and is not terribly surprising given that clinical medicine has known for decades that tissues with rapid cell turnover are tissues where cancer is more likely to crop up, such as bone marrow and intestinal epithelium, just to give a couple examples.  

The title of the original research article, “Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions”, was published in the Jan. 2nd, 2015 edition of Science.   In the popular media the lead author, cancer researcher Bert Vogelstein at Johns Hopkins University School of Medicine was quoted as saying, “all cancers are caused by a combination of bad luck, the environment, and heredity, and we’ve created a model that may help quantify how much of these three factors contribute to cancer development”.  A nice sound bite, to be sure, but attention immediately focused on the bad luck part of the explanation, as most people already assume that environment and heredity have something to do with it.  This became the essence of the mainstream new headlines.  For example, CNN reported that, “bad luck can cause cancer”, and Fox News reported that, “Study concludes that many cancers are caused by bad luck in cell divisions”.
So what does bad luck have to do with all of this?   Are cancer researchers a superstitious lot?  Does invoking bad luck have any real explanatory or predictive power, and does doing so benefit the patient or clinician in any way?  My initial reaction to these headlines was that by describing a phenomenon as lucky or unlucky one seems to be crediting some kind of conspiring supernatural force out in the universe, intent on doing harm to the unlucky, and protecting the favored lucky ones.  It’s probably more likely -I hope- that the author of the study chose to use this sort of language for it’s shock value to gain the media attention.  The language used is almost certainly why the media picked up on this story bringing it to front page status.  If the authors had stuck with wording such as “cancer risk is related to stem cell divisions”, then it is unlikely that it would have drawn nearly the amount of media attention as was obtained by the more provocative “bad luck” statement.

The philosophy of luck can be reasoned about in several ways, and it’s this ambiguity that has the potential to create some problems and unnecessary confusion.  Wikipedia defines luck in one of two major categories, as prescriptive or descriptive.  It is this prescriptive definition that I worry many people will incorrectly assume to be the meaning, when sickness or disease is attributed to bad luck.  In the Wikipedia article, the prescriptive sense is defined as “ a deterministic concept that there are forces (e.g. gods or spirits) that prescribe that certain events occur”.   The same article defines the descriptive sense of luck as when, “people speak of luck after events that they find to be fortunate or unfortunate, and maybe improbable”.

What Vogelstein is referring to as bad luck is actually the unpredictable random gene mutations that occur more frequently in the tissue where stem cells divide more rapidly.  This appears synonymous with bad luck because it seems to defy a satisfying explanation, but it’s not bad luck in the magical prescriptive sense.  The universe is not conspiring against the person who get cancer anymore than it is protecting the person living a long cancer free life.  The prescriptive definition of luck also hints at the idea that your luck can’t be changed until something happens to change it.   You have bad luck, after all, so why should you expect the future to hold any different sort of fortune.  If you got cancer because of bad luck, well then you’re probably not going to be very lucky in the treatment for your cancer, or the way you handle chemotherapy, or if your wife is going to support you through this challenging time, and so on.

Well, let’s look at what the original article is really telling us.  Why are more frequently dividing stem cells more likely to turn into cancer cells?  When a cell divides through the process of mitosis, the complete set of nuclear DNA is copied so that each new daughter cell can begin it’s life with the same DNA as the parent cell.  The cellular machinery to copy DNA is sophisticated and there are both proofreading and repair methods to ensure high fidelity of the DNA copy.  However, if a mistake is made in the copy process that escapes the proofreading and repair mechanisms then it remains as a new mutation.   Keep in mind that at this point, we are not even talking about the mutations that can arise from radiation or cancer causing mutagens, such as stray cosmic rays from space, an X-ray from that chest X-ray taken at the hospital, or even the carcinogenic chemicals inhaled from second-hand smoke.  We’re simply talking about mistakes made during the normal process of cell division.  In this case you couldn’t have ducked behind a steel beam as the cosmic ray zipped through the atmosphere from deep space or held your breath as you passed those smokers on the sidewalk.  These mutations are going to happen because you’re a working machine that acquires wear and tear as you go about the business of living.  Despite billions of years of evolution to minimize such mistakes, they have to happen at a certain rate because the proofreading and repair processes simply aren’t perfect, and cells have to divide a lot to get you from a fertilized egg to a full grown human being.  Some cells continue to divide even after maturity to maintain the cell line.  This is true for red blood cells derived from the bone marrow, for example, since the circulating RBC has only a limited life span in the bloodstream of around 120 days and needs to be replaced by stem cells in the bone marrow to prevent anemia.  Even though the error rate in DNA copying is incredibly low, only about 1 in 1011 (that is one in a 100 billion), when you consider that there are about 3 billion (109) base pairs in the genome of each and every human cell, and that there are trillions of cells in the human body, the number of base pairs being copied is rather astronomical!  It’s actually amazing that the process is as efficient as it is.  

There are several factors that make it impossible for perfect fidelity to ever be achievable in the replication of DNA.  One such factor is a chemical reaction known to affect the nucleotide bases in DNA known as tautomerization.  The nucleotide bases are what accounts for the genetic information encoded in the DNA molecule.  The DNA also contains a sugar called deoxyribose, and a phosphate backbone.  The four DNA bases are adenine, thymidine, cytosine, and guanine, usually referred to as A, T, C, and G respectively.  These bases contain complex functional groups (in the language of organic chemistry) such as keto-groups and conjugated dienes.  There is a rapid interchange in chemical structure that naturally takes place so that the keto-group transforms into an enol and back again.  These two forms of the molecule interchange so quickly that they are really considered the same molecule, and are a special type of isomer.  The keto-form, is the “right” form for base pairing to the proper nucleotide on the other DNA strand, and if it happened to have flipped to the enol form during he critical period of base pairing, then it will have paired with the wrong base.  Most of the time the base will be in the keto-form, but in about 1 in 105 bases the other tautomer will be found.  

This lead to mutation due to the incorrect base being copied from the DNA strand opposite the enol-form of the base.  The cell’s proofreading machinery will not be able to tell that a mistake was made in this case.  And so, some low level of gene mutation is inevitable.  For this type of mutation forming process, everyone has essentially the same risk.  Cells that replicate more often would be expected to accumulate these types of replication errors more often.  Even without processes like tautomerization, the replication machinery will simply put the wrong base in the wrong place at some low level rate, and occasionally this will escape detection by the proof reading part of the process.  Mistakes just happens!  Poor DNA polymerase is held up to an unrealistically high standard.

Besides replications errors, other cancer causing mutations may vary depending on your exposure to high risk situations, but still occur to some degree even under low risk, normal conditions.  Examples are exposure to radiation, carcinogens, or inherited genes that raise the risk of cellular malfunction.   There is a constant low level background exposure to radiation from uranium, and other radioactive elements, in the rocks and ground, or from cosmic radiation from space.  Carcinogens are all around us, and include exposure to tobacco smoke, but also many other naturally occurring carcinogens such as aflatoxin B produced by fungus growing in peanut butter and nuts and even certain viral infections such as Hepatitis B and Human Papilloma virus.  Well known types of inherited gene mutations that increase cancer risk considerably include BRCA1 and BRCA2 in relation to breast and ovarian cancer, but there are most likely many other more subtle gene variants that alter your odds of other cancers, as well.  This is the environment and heredity part of the equation.  

It should also be kept in mind that mutations that do arise supply the variation necessary for evolution by natural selection.  Now, most mutations will be silent, meaning they don’t produce any noticeable effects at all.  This is due to the fact that most of the DNA in our cells are not part of genes, and do not code for any particular proteins.  Only about 2% of DNA is codes for protein.  Another small percentage of the non-coding regions (it’s unclear and how much and different sources report different amounts) of DNA have the job of regulating which genes are expressed and when to express them, and a small bit more code for RNA that serve in protein synthesis.  Most of the DNA has no known function and appears to be remnants of ancient viral infections and gene duplication events.  The term junk DNA has been used to describe this wasteland of the genome, and while the term is not without controversy, since there is almost certainly more functional parts of the genome in there yet to be found, it is probably true that the majority of it is dead weight, being replicated from generation to generation without any true utility.  Mutations here will not cause disease, but are very useful for making phylogenetic trees to identify which organisms are more closely related to each others by comparing the similarities and differences that accumulate over time showing common decent.  

Some mutations, however, may chance to happen in an actual protein coding gene, but in such a way that the protein expressed is unchanged due to the redundant nature of the genetic code.  More than one of the triple DNA base codons (the code that DNA uses to specify an amino acid) can code for the same amino acid.  Other mutations, however, will alter the gene in some important way, such as placing the wrong amino acid in the protein altering the protein’s function is some critical way.  Sickle Cell anemia is a classic example of this where a mutation has turned the codon GAG into an alternate codon GTG, so instead of glutamic acid being placed in the hemoglobin protein, horrible valine is placed there instead.  This alters the chemistry of hemoglobin considerably.  Even worse, a mutation might turn a codon for a particular amino acid into a stop codon instead, which tells the cell to end production of the protein, resulting in a shortened protein missing vital parts needed to function.  If such mutations happen in a gene necessary for regulation of the cell cycle then a cancer cell might just have been born.  

As a pediatric nephrologist I care for children that often have very serious kidney disease, that may sometimes lead to kidney failure making chronic dialysis or kidney transplant necessary in order to survive.  As you might imagine, this can be a devastating blow to a family.  It is quite common and natural for the parents of my patients to ask why their child got their particular disease.  Although we’re continually learning more about the genetic and molecular basis for diseases like cancer or kidney disease, the fact is most of the time we have no good explanation for why one particular individual out of thousands got the disease.  It is usually not very satisfying for either the parent or the physician to simply say, “I don’t know”, although that is often the honest answer.   I recall one of my professors while I was in my nephrology fellowship training at Yale, who responded to a parent asking why their child had a very serious type of kidney disease, known as Focal Segmental Glomerulosclerosis (FSGS), that has a high likelihood of leading to kidney failure despite any available treatment options.  My professor’s response was, “Damn bad luck”.  While that particular family seems to accept that assessment, I’ve witnessed other physicians use that same line with less pleasant results, even to the point of a parent becoming extremely offended by talk of bad luck.  It was almost like the diagnosis of bad luck was the same as being told that someone had placed a Voodoo spell on them.  Personally, I most often simply state that we just don’t really understand why some people get a particular disorder and most people don’t, and move on from there to what we do know about the condition.  I’ve found this to usually be effective in moving the conversation forward.  

I’ve also seen many patients that do seem to have one unfortunate event after another happen in their lives.  For example, a patient with a congenital birth defect of the heart may have to go through many heart surgeries and life threatening events only to later down the road develop a cancer, and the treatment of the cancer may inadvertently lead to kidney failure, and so on.  It seems natural to think of bad luck when you consider their situation.  The “law of large numbers” would be a more logical explanation, even if it is not always a satisfying one to the family.  This concept reminds us that if you have a large enough sample size (our sample is the entire human population) then essentially anything that is possible will eventually happen, no matter how unlikely it appears to be.  Even if that particular sequence of events has only a one in a million chance, if your sample size is a million, it should happen at least once.  My guess is that for the example given above the chance is actually a lot more likely than a million to one.

The results of random chance can appear like bad luck due to the way our human minds process information.  Human minds evolved to detect other minds that contain thoughts and intentions like our own, evolved to react in an emotional manner to events so that decision making would be quick and helpful in many commonly occurring situations, and evolved to find patterns even in random background noise.   Unfortunately, this leads to many false positive results, so that the human mind may therefore perceive an intelligent agent where none exists, give an emotional response unfair weight over a rational interpretation of events, and find significant patterns in random noise.  

So, is bad luck really a diagnosis?  It is! But only if it is clear that this is being used as short hand for random, unpredictable events, and not evil forces with intent on harm.  Many people are superstitious and naturally assume that there are universal powers out there, with an interest in us, benign or otherwise, and playing with our fates.  The prescriptive sense of the term implies some sort of universal apathy in the case of bad luck, or empathy in the case of good luck.  There is no objective evidence that this is the case.  Our minds didn’t evolve to see statistical patterns.  It takes work to find statistical patterns (usually by conducting well designed scientific studies - something our distant ancestors didn’t do), and even then a statistical explanation may not feel satisfying or even to agree with “common sense”.  Our brains try to find patterns where none might exist.  If an unusual event happens to us or a loved one, we have the need to try to explain that unlikely occurrence through some narrative, not realizing that many rare events are happening all the time.

Bad luck, the kind of bad luck that has any real meaning, is the product of random chance.  Just a statistical roll of the dice, and that’s what this paper in Science is really showing.  The universe is not trying to help us succeed, but neither is it trying to wipe us out.  It is absolutely indifferent to us being here.  Even our DNA polymerase that replicates and proofreads our DNA is not trying to help us.  DNA polymerase has simply evolved to be only as effective as necessary to propagate the genes for making more DNA polymerase.  It has no reason to be more efficient than that, but can’t be less efficient either or else it won’t survive into the coming generations.  We are the ones that care what happens to each other.  We have the brain power to decipher the world and have an interest in what happens to ourselves and our fellow humans. By taking luck out of the equation we can search for the real explanations for how things work and the events that transpire in our lives.  Science is the tool to do so and has so far been an invaluable tool for finding true patterns in events that once seemed random.  We still have a lot more to learn, but bad luck should never be the full diagnosis, just the short hand notation for when don’t have enough information to give a satisfactory explanation.  Even then it should only be used carefully so not to misguide the patient.  It is ok to admit when we don’t know why, but reassure the patient that we will keep looking for the answer, and in the meantime will provide the best care using the available science-based evidence.