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A Tale of Two Diseases



According to the graphic above, the diseases phenylketonuria (PKU) and scurvy (vitamin C deficiency) couldn’t be more different.  One, PKU, has a “highly genetic” etiology, whereas the other, scurvy, has an entirely behavioral/environmental cause.  Both diseases nonetheless have the same mode of treatment:  attention to one’s diet.  Reasoning back from the “cure”, we might say both diseases are dietary diseases.  However, another way of looking at it is that both diseases are caused by an enzymatic deficiency, and enzymes, as proteins, are specified by our genes.  From that perspective, we might label both diseases “genetic”.  In resolving these apparent paradoxes, we will also shed some light on why the nature/nurture debate is so thorny, and hopefully also dispel some errors in the way most people think about genetics, and errors in the way they think about diet.

The Cause of PKU

The reason PKU is placed on the far genetic end of the graphic is that its genetics are well-understood.  PKU is an autosomal recessive disease – autosomal, meaning it is inherited via a non-sex chromosome, and so is equally likely to occur in males and females; recessive, meaning the disease-causing gene must be inherited from both mom and dad, making the disease relatively rare (for PKU, 1 in 12,000), and meaning it can occur in children whose parents show no signs of the disease themselves.

As I’ve written before, genes are segments of DNA that provide the recipe for making proteins from the chemical building blocks of proteins, amino acids.  The gene that is disrupted in sufferers of PKU is called the PAH gene.  This gene specifies the recipe for making phenylalanine hydroxylase.  Babies born with PKU essentially have a bad recipe for making this enzyme, such that the enzyme just doesn’t work the way it’s supposed to – the way it does in the vast majority of people without PKU.

So what does phenylalanine hydroxylase do normally?  It converts the amino acid phenylalanine into tyrosine:


In sufferers of PKU, who lack a functional phenylalanine hydroxylase, this reaction doesn’t happen.  This is bad – very bad.

Why?  Well let’s back up a bit.  We’ve already established that genes are recipes for making proteins.  We often hear things like our genes define who we are.  Well – if all genes do is allow us to make proteins, then it must be equally true that our proteins define who we are.  Yes, some gene specifies our eye color, some other gene our blood type – but the color of our eyes is determined by the proteins we make, and our blood type is named for a protein sticking through the membranes of our blood cells.  Some proteins define differences between people, like eye color or blood type, but others determine whether we live or die.  They determine the chemistry of our body, making some proteins absolutely essential for life.

When and how do we make proteins?  When is all the time.  We are constantly making proteins in every one of the 30 trillion cells in our body.  We are massive protein factories.  We never take a break from this activity until death.  How we make them is that certain organelles in our cells interact with certain molecules in our cells to build our proteins one amino acid at a time.  (A small protein like insulin has several dozen amino acids; larger proteins can have hundreds or thousands.)  Again, genes specify the sequence of amino acids for a given protein.  A mutation in a gene is a change in this code.  The consequences of a mutation can be nil (if for example the change doesn’t alter the amino acid code), virtually nil (if a single amino acid is mis-specified but this amino acid doesn’t change the shape or electrical charge of the protein enough to alter its function), moderate (if the protein’s function is compromised slightly), or severe (if the protein becomes non-functional, as in the case of PKU).

In any event, having the right recipe to make a protein is only part of the problem.  After all, if you have the right recipe to bake a cake, that’s not going to help you make a cake if you don’t have eggs and milk and flour in your kitchen.  Likewise, having the recipe for making a protein is one thing – having the right amino acids is another.

We use about 20 amino acids to make all of our proteins.  Of these 20, nine are considered essential amino acids – we must get them from our diet, or we die.  One of these is phenylalanine.

The remaining 11 are not considered essential, because we can make them ourselves – if we have the right enzymes to do so, and if we have the right ingredients to do so.

One of the nonessential amino acids which is very important is tyrosine.  The enzyme we need to make tyrosine is phenylalanine hydroxylase, as shown in the graphic above.

So we’ve identified the first problem that PKU causes: without a functioning phenylalanine hydroxylase enzyme, we can’t make tyrosine – and so a nonessential amino acid suddenly becomes an essential amino acid – we must get it in our diet.  Without sufficient quantities of tyrosine, we can’t make dopamine, norepinephrine, or adrenaline, to say nothing of the hundreds of proteins requiring this amino acid in its recipe.

But the situation is even more dire than this.  If this were just a matter of eating more tyrosine, PKU probably wouldn’t be so devastating.  But the lack of the enzyme affects both sides of the chemical reaction shown in the graphic:  not only does a PKU sufferer produce no tyrosine (the right side of the reaction), but the PKU sufferer will also build up high concentrations of phenylalanine (the left side of the reaction).  This has several effects, including creating stress on the kidney to eliminate the excess.

More devastatingly, high phenylalanine levels disrupt the chemistry of the brain.  The brain is protected by a blood-brain barrier that limits access to the brain by large molecules, presumably to keep toxins from affecting the nervous system.  But this means that there has to be a way to allow needed large molecules access to the nervous system, and this is accomplished by what are called transport molecules.  (These are proteins, by the way.  Again proteins.)  One such transport molecule is responsible for large, neutral charge amino acids.  Think of this molecule like a single-file tunnel that works on a first-come, first-served basis.  The problem is, when there’s excessively high levels of phenylalanine, almost every molecule that lines up for entry to the brain through this tunnel is phenylalanine – leading to low levels of valine, isoleucine, tyrosine, and other amino acids in the brain.

The result is devastating – small head size, severe intellectual delays, behavioral problems, depression, and reduced life expectancy.

How does one fix PKU?  Gene therapy might be nice – that is, stick some cells in the body containing the right gene for phenylalanine hydroxylase, and let those cells crank out the enzyme.  This is being tried, but so far with limited success.

What does work is cwarningpkuareful control of the diet.  All of the problems caused by this single gene are the result to too much phenylalanine and too little tyrosine.  A diet low in the former and high in the latter can completely eliminate the symptoms of this disorder.  This is, unfortunately, a pretty stringent diet, as many proteins in the food we eat contain phenylalanine.  (When we eat the proteins of other species – beef, pork, chicken, rice, beans, corn – we break the proteins down into their amino acids prior to absorbing them.  We then use these amino acids to make our own, human proteins.  Think of amino acids like legos – we can destroy the sbabyPKUpaceship our brother made of legos, rearrange those pieces, and build our own dune buggy.)

This stringent diet has to start right away – in fact, it’s especially crucial during development.  For this reason, most babies have blood drawn within a few hours of birth to test for a small number of problems for which early diagnosis is crucial – and PKU is one of those problems.

With early diagnosis and strict adherence, an entirely genetic-caused disease (see the figure at the top of this post), is completely controllable using an entirely environmental/behavioral therapy.

The Cause of Scurvy

Scurvy, on the other hand, is listed on the extreme environment – nongenetic – portion of the figure.  This is completely justifiable – and yet, just to show how thorny the nature/nurture debate is, I will also show how it would be possible to label scurvy as just as genetic as PKU.

Scurvy was virtually unknown until the age of exploration.  In the early days of ocean voyages, the diet of the sailors (much more so than the officers) was relatively limited, and these voyages might last many weeks.  Magellan’s years-long circumnavigation of the globe started with a crew of 237 and arrived with a crew of 18 – and the loss of men was probably mostly due to scurvy.  (Magellan himself was impaled by a bamboo spear in the Philippines.)  During the Seven Years War (in the mid 1700s) between the British and the French, a few hundred British seamen died from combat, and at least 60 times that number from scurvy.

Scurvy is a dietary deficiency of vitamin C.  The word vitamin is a bit of a misnomer deriving from “vital amine”.  We now recognize many vitamins that are not in the chemical class of an amine, and in fact, vitamin C is one such vitamin.  Its chemical name is ascorbic acid, and it is a sugar acid.  But the “vital” part of the word vitamin does retain its accuracy – vitamins are small molecules that are absolutely required for life, usually in very small amounts, which must be obtained from the diet.  Of the vitamins, we require vitamin C in the greatest quantity, though still on the order of a few dozen milligrams per day.

Lack of vitamin C – scurvy – leads to fatigue and soreness, and then progresses to difficulty breathing (due to loss of red blood cells), bruising, bleeding, loss of teeth, and all sorts of other nasty symptoms as the connective tissues of the body slowly degenerate without repair, as vitamin C is necessary in the formation of collagen, a key component of connective tissue.

Because so little vitamin C is needed in the diet, scurvy can be rapidly corrected by eating foods containing vitamin C.  Citrus fruits are, of course, excellent sources, and the British Naval habit of carrying limes on board for sailors to eat to combat scurvy led to the nickname “limeys” which was first applied to British seamen and later to British people generally.  It is probably not an underestimate to attribute to limes the lion’s share of the credit for the formation and maintenance of the British empire, so devastating was scurvy to the maintenance of a strong Navy.

The rapid amelioration of scurvy by diet explains its position as a “completely environmental” disease on our initial figure.  How then can I attempt to justify scurvy as a genetic disease?

Remember, what makes a vitamin a vitamin is that it must be obtained from the diet or death will inevitably result.  Nutrition labels on ourvitaminC foods typically display the level of vitamin C per serving.  But now check the nutrition label on your dog food or cat food.  You probably won’t find vitamin C listed there, though you may find vitamin A, the B vitamins, and vitamin E.  Why?  Because dogs and cats don’t need vitamin C from their diet.  Neither do rabbits, rats, mice, or lemurs.

Now, all of these species need to make collagen, and amides, and other things vitamin C is used for.  And these species do use vitamin C to do the job.  But unlike humans, dogs, cats, rats, and lemurs can make their own vitamin C from simple sugars.  (Vitamin C is, after all, just a small sugar acid, requiring a simple chemical reaction to synthesize.)  Again, molecular synthesis typically requires the right enzyme and the right building blocks.  Humans have the right building blocks – we eat plenty of sugar – but we lack something that dogs, cats, rats, and lemurs have:  the enzyme L-gulonolactone oxidase.  If we had it, we’d make our own vitamin C.

The image to the right shows a partial evolutionary family tree.  Species connected with the thick, black line, have a functional gene for L-gulonolactone oxidase.  Species with connected with a thick, gray line have a nonfunctional copy of the gene.  From this perspective, scurvy is actually a genetic disease – in the same way PKU is – it’s just a genetic disease that’s inherited by every human on the planet, rather than 1 in 12,000.

A Tale Of Two Diseases

Diseases that can be traced to a single, nonfunctional gene are pretty rare, which makes PKU something of a textbook example of the role of genetics in physiology.  Diseases that can be traced to the lack of a single nutrient are also rare, which makes scurvy something of a textbook example of the role of diet in physiology.  But if you dig a little deeper, these extremes start to disappear – PKU is fully treatable by diet (though it does take considerable effort), and scurvy, in principle, could be fully treatable by gene therapy by providing humans with the L-gulonolactone oxidase gene from a cat or a squirrel.

We are often bombarded with information about the role of genetics or diet in disease that concern the less extreme examples.  We are told that scientists have found a gene associated with schizophrenia, or depression, or leukemia, or diabetes.  We are advised that consuming probiotics, or antioxidants, or vitamin C, or plant protein could keep us healthy, or that too much salt, or cholesterol, or sugar, will make us unhealthy.  Some people take extreme lessons from this deluge of information – maybe that certain problems are inevitable (“it’s in my genes”) or that other problems are easily solved (“just buy this supplement and avoid that food”).

But when the extreme cases are so plastic – when a genetic disorder is cured by diet and a dietary disorder is caused by lack of a gene common in the animal kingdom – how can we possibly take simple lessons that concern diseases we know to be a mixture of multiple genetic contributions and multiple environmental factors?  The involvement of a gene in a disease does not imply inevitability, but it does represent an exciting tool to unlocking the interlocking effects of proteins to physiology – and once discovered, may lead to genetic, pharmacological, or environmental therapeutic approaches.



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