If you're teaching Mendelian genetics, monogenic disorders are on the cards. But which ones are good examples? The IB has once again decided on PKU (phenylketonuria). In this post, I'll show you how I teach it to my 16-18 year olds, and why I think it's a good example to include in a biology syllabus.
PKU is a monogenic disorder involving a mutation in the phenylalanine hydroxylase gene. Homozygous individuals for this allele can't catalyse the reaction that converts phenylalanine into tyrosine, causing a toxic accumulation of phenylalanine and a tyrosine deficiency. The inheritance pattern is very simple: autosomal recessive. (I've written about the problems of Mendelian genetics here).
Contextualising the Disorder
I started by showing students pictures of people who suffer from PKU. They have distinct facial features. Other symptoms, I told my students, include mental retardation, reduced head growth, seizures, a musty odour, and a lack of hair and skin pigmentation. Keep this last symptom in mind as we'll return to it shortly.
The Genetics
I then drew three sets of homologous chromosomes to illustrate how homozygous dominant and heterozygous individuals still produce sufficient functioning enzymes. Those that are homozygous recessive don’t produce any functioning enzymes.
The Mechanism
From here, I wanted to show how PKU produces the observed symptoms—the mechanism. For this, I needed a stock and flow diagram. See this post for more information on these models.
I drew the two stocks seen below, named them, and added the amino acids so students could relate the unfamiliar names with familiar structures. I also added the two inflows and labelled them as "feeding" so that students could see that our source of these amino acids is diet. I told them to assume that we typically obtain relatively equal quantities.
I then wanted to discuss the purpose of these molecules in the system. So I drew an outflow from each stock and labelled them “anabolism”. I asked the students what they thought they’d be used for in anabolism and some suggested protein synthesis (something we’d studied earlier in the course). I then told them that tyrosine is also a precursor to synthesise other molecules, such as melanin, dopamine, and adrenalin.
There is a distinction here that I wanted to make clear to students, so I added the list of examples to the model and pointed out how one list is larger than the other. Therefore, the “anabolic” outflow rate should be higher for tyrosine than phenylalanine.
So, what's the story? If you remember, I told the students to assume that the inflows from feeding were the same. But now, we see that the outflow rates are different. Tyrosine is needed in larger quantities than phenylalanine. So how can we make up for the imbalance?
I taught them that phenylalanine can be converted into tyrosine—a reaction catalysed by the enzyme phenylalanine hydroxylase.
When I added the flow between the two stocks, I asked students what variables we could add to show what regulates this flow. I let them discuss in pairs before taking answers. The conventional answers are temperature—but body temperature is assumed to be invariant in humans—substrate concentration, and enzyme concentration. After this discussion, I added the positive (same) connection from the phenylalanine stock (as substrate) and another variable for the enzyme. From the tyrosine stock, I also added the positive (same) connection to the outflow.
What if?
A central tenet of the variation theory of learning is that meaning can only be ascribed when students experience a variation in a concept. Therefore, I asked students what would happen if both phenylalanine hydroxylase alleles were mutated and the concentration of the functioning enzyme dropped to zero.
I let them mentally simulate the model and discuss it in pairs before engaging in a class discussion.
During the class discussion, a key distinction I pointed out was this:
The feeding rate of phenylalanine is higher than the outflow rate (anabolism). More is entering than leaving. This leads to a toxic accumulation of the phenylalanine.
Because phenylalanine is not converted into tyrosine, the inflow rate to the tyrosine stock is lower than the outflow rate (anabolism). Less is entering than leaving, which leads to a deficiency of tyrosine.
Notice how a deficiency in tyrosine, will lead to a deficiency in melanin. This explains the symptoms of a lack of skin and hair pigmentation.
How can it be regulated?
Next was to discuss treatment. How can we change the system to avoid the toxic accumulation? According to the model, it can be controlled by regulating the inflows—increasing tyrosine intake and decreasing phenylalanine intake. This is how the disorder is treated.
I showed students images of newborn babies undergoing a heel prick test. During pregnancy, the relative amino acid concentrations are regulated by the mother. There is no time to lose when a baby is born. A test is carried out immediately, and if the baby is found to have PKU, they are given a special diet of minimal phenylalanine.
The History
Other mutations can lead to PKU, but this is the most common. It's called "classic PKU" and is a good example of a monogenic disorder (controlled by a single gene). So, what else is there to the story? What makes it a great example to explore in the classroom? Carl Zimmer (2018, 107-135) tells the history of its discovery.
As PKU led to mental retardation, it was in the sights of eugenicists. These people wanted to rid society of its burdensome people, isolating them and preventing their reproduction.
When the disorder was discovered, via a urine test, the American eugenicist, Henry Goddard was happy. In his view, it gave a definitive diagnostic test to identify those to be removed from society. For the eugenicists, genes determine who you are.
Lionel Penrose discovered the genetic cause of PKU but unlike Goddard, he saw it as a way to refute the eugenicists. Penrose realised that suffering PKU might not be inevitable even if it was hereditary. A diet low in phenylalanine would theoretically prevent it. But in the 1930s, these special diets were too difficult, as phenylalanine is abundant. A special diet then would cost a thousand pounds a week.
Nevertheless, Penrose spoke out against the genetic determinism of the eugenicists. Mutations and varied alleles are the rule, not the exception. You'd have to remove all humans on Earth to remove all the deleterious mutations that exist. This is without even discussing the environmental impacts on development.
The story of PKU is one of triumph over genetic determinism because eventually, low phenylalanine diets became available. In the picture above, Kennedy meets two children who are homozygous recessive for the PKU allele. He had passed a law for mandatory testing of newborn babies. The older sister, unfortunately, suffered the disorder, having been diagnosed too late (at 1 year old). But thanks to the law, his younger sister's fate was different—being diagnosed at 1 month old. The environment, technology, and medicine had tamed Mendelian genetics (Zimmer 2018). If you want to learn more about teaching using stock and flow diagrams check out Difference Maker.
My books: Difference Maker | Biology Made Real, or my other posts.
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References
Zimmer, Carl. 2018. She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity. New York: Dutton.