Welcome back to an Introduction to Human Behavioral Genetics. This is the fifth and last module of lecture unit 1. And today what we're going to be talking about is a very important human genetic disorder called phenylketonuria. Or I'll just say PKU. PKU illustrates several basic principles that we'll be using throughout this course. One, the nature of gene function. There are genes that code for behavior, genes code for basic, biological functions. In this case, what I'm going to talk about a gene that codes for an enzyme. Secondly, a term that's not going to mean a lot to you now, but I'm going to illustrate it through PKU, is the notion of pleiotropy. The genes don't just have one effect, but they rather have multiple effects. And then finally, a topic that will be very important throughout this course, is the notion that genes don't really work in opposition to the environment, but work together in the environment, with the environment, to affect individual differences in outcomes. And in here we'll talk about the, the important concept of gene environment interaction. So what is phenylketonuria? What is PKU? Well, let's begin at the beginning when it was discovered in 1934 by a Norwegian Pediatrician named Asbjorn Folling. Folling observed a sibling pair that had a very distinctive set of characteristics. First of all, they had severe intellectual disability, both of them did. And we now know that individuals if untreated with phenylketonuria will have IQs below 50. They were also irritable, hyperactive, and subject to seizures. So there were some neurological complication. They had eczema and hypopigmented skin. And finally, they had a musty odor. Now one of the odd things about phenylketonuria, but also one of the important things is, why do these four things go together. In fact, there is a reason they all go together in, in this particular disorder. And we'll get to that in a second. But first, the basic defect in phenylketonuria. What phenylketnuria is, is a defect in the enzyme that exists in your liver, called phyenlalanine hydroxylase. Phenylalanine hydroxylase in your liver is responsible for converting a product called phenylalanine to another product called tyrosine. The enzyme phenylalanine hydroxylase is coded for by a gene in your genome. You have two copies of that gene, two alleles. And people with PKU have two deficient forms of that gene, so they don't produce a functioning enzyme. They can't make the conversion of phenylalanine to tyrosine in their liver. It turns out that phenylalanine is a essential amino acid. That means it's it's essential, it's important, you need it, but you don't produce enough of it for, to build proteins in your body, so you need to get it through your diet. And phenlyalanine is in virtually almost any protein that you eat. So people with phenylketonuria can't convert what's in their normal diet, the phenylalanine, to this other amino acid tyrosine. A little bit of terminology here. First of all, genotype, and the term genotype was defined in the early twentieth century. Genotype is that which you inherited. In this case, individuals with phenylketonuria is inherited two deficient forms of what we would call alleles of the gene that codes for the enzyme phenylalanine hydroxylase. Second term, phenotype, that which is expressed or observed. In this case, the phenotype that goes along with the PKU genotype are these diverse set of symptoms. Musty odor, intellectual disability. And the question is, well, how do they go along. How does the genotype map onto the phenotype? Now this is a very complicated figure, but it really illustrates why with phenylketonuria, you get these diverse symptoms based upon one underlying defect. Again, the defect here is an inability to convert phenylanlanine to tyrosine. Well, if you're not convening converting phenylanlanine to tyrosine, and you're ingesting phenylanlanine, it has to go somewhere. Somewhere in your body. So we could shunt it off into another pathway. That shunting off of phenylalanine to this other pathway proves to be neurotoxic. So the intellectual disability is a consequence of phenylalanine being broken down in other ways and producing a neurotoxic substance. It also, if it's being shunted off into some other pathways, it's producing metabolites that we are not accustomed to smelling. So the musty odor of the sibling pair with phenylketonuria wasn't a problem with hygiene. It was that they're producing metabolic products at levels that our noses aren't accustomed to smelling. So they just smell different. So those two symptoms were really a consequence of phenylalanine being shunted off into some other pathway. But what about the other? The neurological complications, the hypopigmentation. Well, if you look at this pathway, right? If you're not converting phenylalanine to tyrosine, you have too little tyrosine. And if you look down here, you'll see that there are various neurotransmitter systems within the brain that are, then are going to be deficient because you don't have enough tyrosine. Probably the neurological complications are a consequence of deficiency in this pathway. And if you look down lower here, you see melanocytes as a consequence of this pathway as well. So the hypopigmentation, the eczema, is also probably the consequence of the reduced tyrosine. Phenylketonuria is a beautiful example of what geneticists call pleiotropy. Pleiotropy is the notion that genes don't have just one effect, they tend to have multiple effects. In phenylketonuria, intellectual disability, neurological complications, musty odor, and, hypopigmentation. The third thing that phenylketonuria, or PKU, illustrates for us is the notion of gene environment interaction. And, it's actually for this reason, I think probably phenylketonuria's every human geneticists' favorite disorder to talk about. And the reason it's every geneticists' favorite disorder to talk about is that it's been an extraordinary public health success. Folling discovered the disorder in 1934, and within 13 years, we understood what the basic metabolic defect is. We understood that it was a problem in this enzyme in the liver converting phenylalanine into tyrosine. Subsequent to that, the first successful treatment program was instituted in 1954. What's the treatment program? Well, go back to that complicated pathway. If you're producing too much phenylalanine that gets shunted off and causing intellectual inability, then what you want to do is reduce phenylalanine intake. You have to be very careful about this because you still need some phenylalanine. It's an essential amino acid. But if you tightly regulate the phenylalanine intake, you can reduce levels of mental, of intellectual disability. Also, you would give tyrosine supplements. So understanding the basic biological defect led to a very successful treatment intervention. And the last aspect of a successful public health story here was in 1963, newborn screening for phenylketonuria was begun. Approximately one out of every 10 to 15 thousand babies born in the United States has phenlykatonuria. But every state in the US and, and, many, many countries across the globe screen for phenylketonuria in every newborn. So, the, they, they are detected. And this is, if you've had a baby, you might see that, that they take a little usually a little prick of the, of the heel. They take a small amount of blood and they do a genetic test. And among other things with that genetic test, they're testing your baby as to whether or not he or she has PKU. And the reason for that is that you can successfully treat it. And here I'm going to show you a short, very short YouTube clip, that just illustrates the power of the intervention here. What the, what you'll see is two young women, one, both of them have phenylketonuria. Sadly, one woman didn't receive the treatment, and the other woman fortunately did. >> [FOREIGN] She doesn't stop, but she doesn't dig more of the the powder. You know, we, we need to refer or be [INAUDIBLE]. Supplementational vitamin. >> Before she said give her milk of magnesia. >> You cold in your feet? >> No. >> No? Okay. >> [FOREIGN] She's walking better. [FOREIGN] Walking better. [FOREIGN]. [MUSIC] So you can see that it, I mean, it's very sad for the young woman who, who didn't get treatment. I'm not sure why she wouldn't get treatment. Virtually any child now born with phenylketonuria would be identified at birth and receive treatment. But you can see the profound impact treatment has for this genetic disorder. So again, thinking back to the, the notion of genetic determinism, our behavior isn't genetically determined. If we can understand how it comes about, we can intervene, hopefully, in, in very positive ways, as it's illustrated in this case. So phenylketonuria is an illustration of a concept that will be very important to us, genotype-environment interaction. That both our genetics and environment is important. That in this case, you only get the intellectual disability phenotype. The expression. If you both have the genotype here, the two deficient forms of this gene, or alleles, and the rearing environment where you're exposed to high levels of phenylalanine. The treatment here, it, it, it turns out that you don't have to worry about the phenylketonuria prenatally. The mother's system will take care of the excess levels of phenylalanine. But you need to start a child with PKU on the reduced phenylalanine diet pretty much, pretty quickly after birth. So you would, you would start treatment pretty early in life. And the treatment is basically, apart from supplementing with tyrosines, you would actually reduce the phenylalanine intake. Very hard to do. Becomes more difficult as the child gets older. Because something like a turkey sandwich might be the the, the amount of phenylalanine, would contain the amount of phenylalanine someone with PKU could have, maybe for a whole week. So you have to tightly regulate their diet, and that becomes more difficult as the child gets older. It was once thought that you could put someone on the phenylalanine reduced diet up until he or she became five or six years old, and then take them off, because that's when the brain was fully developed. We now know that the brain continues to develop throughout adolescence, and even some, to some extent, early adulthood. So people with phenylketonuria are, you try to keep them on the diet as long as possible. One of the unfo, or unfortunate consequences of the early treatment of phenylketonuria is first of all, people would go off the diet as they got older, once their brain was developed. And when women who had phenylketonuria but were successfully treated became pregnant and produced a child, their child, their children suffered from very high levels of intellectual disability. And the reason for that was that they were no longer on the diet, the mothers, and the mothers had very high levels of phenylalanine in their blood system, because they couldn't metabolize it. It wasn't toxic to them, necessarily anymore, because their brain was fully developed. But it was toxic to their fetus, to the brain of the fetus. So, the, we come now to the end of lecture unit 1. What have we tried to accomplish in lecture unit 1? First of all, to discus behavior genetics is really emerging out of the nature-nurture debate. Secondly, that the Eugenics movement had a profound impact upon the field of behavioral genetics, that early on, psychology was a heavy Darwinian discipline. But because of the association with early behavioral genetics has with Eugenics, it discredited the field. And for 30 or 40 years, environmental models of individual differences really dominated within the field. And as we'll begin to talk about next time, it was only in the 60s and 70s when psychologists began to come back to behavioral genetic research. Third, what the field of Behavioral Genetics is. It's a branch of psychology. It really, I don't see it as a branch of genetics. And what we're trying to do in behavioral genetics is to take advantage of the powerful methods that geneticists have developed, to use those to answer questions about the origins of individual differences in our behavior. Fourth, the remarkable John/Joan case as the apex of blank slate thinking. I don't think thinking that really exists at all in psychology today because of behavioral genetic research. And then, finally, phenylketonuria or PKU is an illustration that if we, it's a beautiful illustration that if we could really understand the genetics of a disorder and how it came about, it would really inform us as to how best to intervene. And our hope is that that's what will happen with things like schizophrenia or bipolar disorder or autism. We're not there yet today. But we hope that phenylketonuria is really a model of where we'll be some time in the future. Thank you for your attention in this first lecture unit. And next time we'll begin to talk about twin study method.
