Oedipus, Theresias and Huntington's disease: the prophecy fulfilled

From the moment of the test, Heather knew she would have Huntington's disease, but there was nothing she could have done to prevent it.

"Take the baby to the top of the highest mountain, tie his hands and feet and leave him to die of cold and hunger!" Thus the king commanded, upon the birth of his firstborn son.

This may sound a bit excessive to you. Most parents react more calmly to the birth of their first child, although I admit that we can lose our temper a bit in the delivery room. But Laius had reason to order his servants to kill his son. "If you bring a child into the world, he will kill you in adulthood." It was a fate that Ios was not ready to bear, and he decided to stop the decree of fate and prophecy, by killing the newborn baby.

If you're a James Bond fan, you've probably noticed the trend where the bad guy already catches the spy and tries to execute him with some sophisticated method, instead of putting a bullet in his head and being done with it. This is a method that has taken root so deeply in espionage and suspense films, that the original ways to kill heroes have run out. Villains today are forced to throw their heroes into an acid bath full of sharks with laser guns on their backs - and they still survive. But all this is unrelated, although it is very annoying in the movies. The point is that Laius is also included in the very unprestigious list of supercriminals who fail miserably over and over again. He threw his son on top of a mountain with his hands and feet tied, and left the place. The chance that someone would hear the toddler's screams and come to his rescue was one in a million.

Well, you know what they say about a one in a million chance: it always comes true. And of course a goat herder who happened to be on the mountain came and rescued the baby, and gave him to other parents for adoption. They named the boy Oedipus, and raised him as if he were their original son. The young Oedipus grew up oblivious to cuteness, and did not know at all that he was adopted. Then, one day, he ran into his original father on the road. They did not recognize each other - Laius was sure that Oedipus had died many years ago - but a fight broke out between the two, and Oedipus killed his father, as the prophetess from Delphi had promised.

The legend of Oedipus has been used for many years as food for thought by philosophers, researchers of Greek culture and thinkers. Everyone understands that this is a legend and nothing else - the prophets in Delphi had a very difficult time delivering true prophecies. In fact, they were no more successful than the horoscopes you can read in the papers every morning. But the story of the self-fulfilling prophecy reflects the Greeks' belief in fate: everything is predetermined, and the decree of fate cannot be changed. Beyond that, the very attempt to learn or change the future that has been determined for us by the heavens may end up actually making it come true faster. Laius would not have been murdered by his son, if he had not sent Oedipus to die on the top of the mountain.

These were the legends of the Greeks. These are good legends, but they are only legends. Humans have always tried to read the future in a thousand and one ways. The ancient Babylonians watched the stars and wrote horoscopes. By the way, today's horoscope writers still use the star maps that the Babylonians created, even though the stars have long since changed their places on the map of the sky. I personally always wanted to be an astrologer - you can make a lot of money by scamming people easily. In any case, there are many other methods in which they tried to read the future: by the date of birth, by your first name, by the sediment that remains in a cup of tea after you drink it, by the color and size of the intestines and livers of goats sacrificed especially for this purpose, and so on and so forth. Do you know what the success rate of these methods was? About as we would expect - completely random.

To date, only one method has been able to predict the future of humans, and that too in a very specific case - the case of Huntington's disease. The disease became a bit more well-known recently, when one of the characters in the crew of the television series "House" learned that she has Huntington's disease. More precisely, she is not sick yet. At the moment she is completely healthy, about 35 years old, and without any worries in life. But around age 54, she will almost certainly develop Huntington's disease. No amnesty, no other chance. The only way for her to avoid the disease is to die first in some other way. And she might really want to do it.

One of the most severe cases of Huntington's disease is that of Heather Dugdale from Canada. Heather's mother gave birth to three children: Heather was the eldest, and two other younger brothers. At the age of 26, after giving birth to her last child, the mother began to show signs of Huntington's disease. It started when she was trying to bottle feed the babies, and her hands would shake and move in a jerky and random, uncoordinated way. It was difficult for her to bring the nozzle of the bottle to the baby's lips. She had difficulty moving and walking. Within a few years her physical condition deteriorated further. Her body began to twitch of its own accord, and her face would lose expression due to lack of control over the facial muscles. She lost control of the muscles of her throat, tongue and lips, and could hardly speak, or even chew and swallow. And perhaps the worst thing of all: her intelligence was deteriorating all the time. Think how terrible it is - to know that you are becoming more and more stupid. To open a book you read a year ago and enjoyed its deep philosophical ideas, and realize that suddenly you don't even recognize the longer words in the book. And you will be sad about it, but you won't even be sure why you are sad. And this deterioration in intelligence will continue and get worse until you finally reach a complete loss of senses - dementia.

Huntington's patients usually die around 20 years after the initial symptoms appear. Their instability causes them to fall and get seriously injured, or they have trouble breathing and drinking and get pneumonia or heart disease. This is what happened to Heather Dugdale's mother, and after 14 years of continuous deterioration in her condition, she finally passed away. And that was the end of her sad story, but the children's story was just beginning.

You understand, like any genetic disease, Huntington's disease is also inherited from parents to children. But this does not happen with absolute certainty. Not all children get the disease. And the reason for this is that Huntington's disease is the product of one defective gene located on chromosome number 4 and called, not surprisingly, Huntingtin.

Let's talk about chromosomes for a moment. We said in the previous lesson that the genetic code is like the cell's instruction book. But this is not an accurate description. The genetic code is not one book but a set of encyclopedias. 22 pairs of volumes, to be precise, and two more volumes that are not necessarily a pair called sex chromosomes. A total of 46 chromosomes. Each of the books by itself contains between hundreds and thousands of genes. The genes can be treated like columns, which contain the production instructions for different proteins in the cell. And the proteins, as we remember, are responsible for carrying out a large part of the cells' actions.

As everyone knows, when father and mother want a child, the Hasida comes and transfers part of the father's and mother's chromosomes to the fetus. Each and every one of them contributes 23 chromosomes, or gene books, to the new child. Heather was only supposed to get Huntington's under the condition that her mother bequeathed her the chromosome called chromosome 4, on which the defective huntingtin gene is found. Since the parent passes half of their chromosomes to the new child, there was exactly a 50% chance that Heather would get sick. A simple toss of a coin - on that was her fate of life or madness.

If Heather had lived thirty years ago, she would have had to be patient and try to diagnose herself every day: Does she feel more dizzy than usual? Did her hands just shake? If she failed with her tongue, maybe this is the first sign of mental deterioration? Most of the people who will go through this excruciating experience throughout their lives, will eventually go out of their minds. This is a miserable existence, which I would not wish even on the worst of my enemies. And if you're already living like this, I'm not sure what's worse - finding out that you really have Huntington's, or that you've lived your whole life in fear of a disease that doesn't even exist for you.

If Heather had lived three thousand years ago, she would have gone to the oracle of Delphi, and would have received some kind of fortune telling from her, and based on that she would have determined the rest of her life. It could be that the oracle was wrong, in fact there is a half-and-half chance of that. It's hard to call that a prophecy, exactly. In reality, unfortunately, the oracle was much less accurate than the legends.

Fortunately for Heather, she lives in the twenty-first century, with advanced medicine and methods of genetic identification. And when Heather approached the modern oracle, the doctors took a blood sample from her and checked the page in the gene book where the huntingtin gene was found. And they discovered that her huntingtin gene differs from that of most humans in a very unusual way: it is longer.

We said that each page in the book represents a single garden. But what is written on the page? And in what language? And here we enter the depth of the canvas, and into the language in which the entire genetic code is written.

Languages ​​are based on words, and words are made up of letters. Every language has its own letters. There are languages ​​with a large number of letters, with the most extreme example being one of the versions of the Japanese language Joyo Kanji, which includes 1945 different letters. There are languages ​​like Hebrew, with only 22 letters. And there is the human genetic code which contains only four letters. No more, no less. We call these letters guanine, cytosine, thymine and adenine, or for short - A, C, T and G. These are the letters that make up the entire genetic code. When we say 'DNA' we mean this sequence of letters. And every garden, every page of the book, is written in a language that contains only four letters. And each word in the genetic code is made up of a combination of three letters one after the other. For example: AGG, CTA, GTA, ACT and so on. In total there are sixty-four different words in the genetic code.

When the doctors examined Heather's huntingtin gene, they discovered that it contained the word CAG, which repeats itself a very large number of times. We know from past experience that the greater the number of repetitions of the word CAG in the Huntingtin gene, the earlier the onset of the disease. Forty repetitions of the same word will result in the appearance of the disease at an average age of fifty-nine. Forty-one repetitions - at the age of fifty-four. Forty-two repetitions - at the age of thirty-seven, and so on. We do not know how many times the word CAG repeated itself in Heather, due to circumstances of medical confidentiality, but it is likely that it repeated itself no less than fifty times, since Heather began to experience the symptoms of the disease at the age of 23, and her brother Gerry, is already ill From the age of 21. Both received the defective chromosome 4 from their mother.

How and why do repetitions of the word CAG lead to the development of Huntington's disease? The full explanation is a topic for another lecture. For now we will be satisfied with the fact that the huntingtin gene is responsible for the creation of a certain protein in the cells. The instructions for making the protein are on the gene's page. When the word CAG appears many times in the middle of the page, a protein with a different structure than desired is formed. These proteins tend to stick to each other, accumulate inside the nerve cells in the brain in large clumps and cause the cells that control muscle movement to die.

Matt Ridley wrote in his book 'Genome' that science could bring us to the situation of Theresias, the blind Greek soothsayer. As a young man, Theresias came to the bank of a river and saw the goddess Athena bathing there. Athena noticed him, got angry at his lack of tact and punished him with blindness for the rest of his life. Afterwards, when she realized that he had not come there specifically to watch her, she repented and gave him as compensation the ability to see the unborn and the future to come. This may seem like an outstanding compensation to you, but in fact it was another curse. He could only see the future, but not change it. And as Tiresias said to Oedipus at the beginning of the lecture, "It is nothing but sorrow to be wise where wisdom is of no use."

And here we return to the topic we started with - the prophecy and its reward. King Laius knew that his son would kill him, and tried to cancel the fulfillment of the prophecy by trying to kill the young Oedipus. He tried to break fate without success. Some would say that the genetic testing of Huntington's disease today is similar to the decree of fate of the Greeks. As Tiresias says, we gain knowledge and wisdom, but these do not help us at all. From the moment of the test, Heather knew she would have Huntington's disease, but there was nothing she could have done to prevent it.

You may accept the blind prophet's claim, but I don't believe it. All wisdom is useful. Early knowledge may not help Huntington's patients today, but in the future we may have drugs that can stop the progression of the disease and prevent it from breaking out. One of the technologies that can do this is based on genetic engineering of brain cells. We insert a new gene into the cells - a new page in the book - which tells the cells how to make a new protein, which can be called anti-huntingtin. This protein grabs the damaged huntingtin in its tongs, and does not allow it to connect with the other huntingtins and form clumps that will kill the cell.

When will such technology enter human treatment? Not in the near future, and maybe not in the distant future either. What works on mice, does not necessarily work on humans, and as we will learn later, even genetic engineering has limitations, especially when used on humans.

So what is the benefit of foreknowledge, for Heather herself in the present? Does such exist at all? As of today, it does not seem that the news can change the course of the disease. But Heather's realization that she carried the defective Huntington's gene meant that she avoided having children, who could also carry the terrible disease. She should not suffer the guilt that accompanies most Huntington's patients who had children before they knew they had the disease. The cycle of suffering can stop here.

Despite her decision not to have children, the prophecy did not stop Heather's life. She married a loving and understanding husband, who is aware of the future to come. Together, they prepare for a future in which she will lose her sanity and her ability to walk, eat and think on her own. Knowing the future only made the love between them mature and plant deep roots in the ground. The intelligent and complete love holds them together, against all odds.

And maybe that's all it takes.

Sources:

The book 'The Genome' by Matt Ridley

The potential of intracellular antibodies for therapeutic targeting of protein-misfolding diseases. Trends in Molecular Medicine. Volume 14, Issue 9, September 2008, Pages 373-380

Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity. Proc Natl Acad Sci US A. 2002 Jan 22; 99(2): 1002–1007.

Heather Dugdale's website