THE GENE: A Very Personal Story – A Summary of an Oncologist's Book

Pulitzer Prize -winning medical oncologist Dr. Siddhartha Mukherjee's 2nd book, "THE GENE: A Very Personal Story", again presents a chronology compiled with tremendous effort (see the review of his first book). As he himself says, this is the story of what came before cancer. The hero before turning into the villain... Once again, I will share my thoughts on the book with you.

"We used to think that our future was in the stars. Now we know it is in our genes." James Watson

The History of Heredity

How heredity works and how it is transmitted is a subject philosophers have pondered for many years. It is a question prompted mainly by children resembling their parents. How can organisms produce other organisms that resemble them so closely, sometimes to an extreme degree under certain conditions? In those years, when nothing called a cell was known, the first theories proposed that this hereditary information was contained in the man's semen. The woman merely allowed a human to develop from this information, like a field in which a seed had been planted. In other words, a mother's connection to her child was no closer than a stranger's. Aristotle, however, pointed out that this idea was wrong, because children also resemble their mothers, and that this resemblance sometimes persists even generations later. Yet Aristotle also described the mother's contribution as an environment rather than a transfer of information, and the living organism as the joint result of environment and information. But what was the information coming from the father like? Was it information wrapped in parchment? How did this information enable semen to turn into a human being? Unable to resolve this question at the time, thinkers devised a much simpler solution. There was a miniature human in the semen, expanding and growing in the mother's womb. Biologists found this explanation so convincing that, when the microscope was invented, they searched frantically for that miniature human. Some even claimed to have seen it. If such an idea were true, it would mean that there were miniature humans inside this miniature human too. After all, they had proposed the theory by saying that there was no hereditary information: if there was no information, humans always emerged from a template. This made a human resemble a matryoshka doll.

Charlis Darwin – On the Origin of Species

The most unconventional theory of heredity came from Charlis Darwin. Even today, many people find it a difficult theory to accept. Darwin discovered this theory after his exploratory journey in South America. During his trip, he took fossil specimens from each island and sent them to London, but he thought these specimens belonged to different birds. He had made an error in classification, but only an expert eye could recognize that all these birds were a type of finch. Their beaks and claws were so different that it was possible to look at a bird and tell which island it came from. Each island had its own particular type of finch. After his journey, Darwin slowly began forming his theory in his mind. For his theory to hold, he needed 2 different mechanisms: natural selection and mutation.

Natural selection means that, under changing environmental conditions and limited resources, organisms with the best-adapted inheritance survive while the others disappear. In short, the strong live and the weak die. Of course, the strong here are those best suited to those environmental conditions. According to natural selection, genetic diversity in an environment should decline after a while. What if the changing environmental conditions were then reversed? The organisms carrying genes suited to the old conditions would have disappeared, leaving no adapted organisms and bringing the lineage to an end. But we know that this did not happen. Populations somehow maintained their genetic diversity. Darwin explained this through mutation. Through mutations, however rarely, populations produced organisms with different genetic structures.

He published this idea in his book "On the Origin of Species" in 1859. All the books sold on the first day. Incredibly appreciative comments began pouring in. People said that, if confirmed, it would be a revolutionary work. On the other hand, Darwin had also drawn the anger of many. Regarding human evolution, he said only, "Light will be shed on the origin and history of humanity", deliberately avoiding the subject and keeping his lips sealed. But according to the philosophical implications of the theory, humanity was no exception.

From Natural Selection to Artificial Selection

Every new thing we learn about nature brings to mind the question, "How could I do this artificially, or how could I manipulate this process?" This identifies a number of possible applications. But when the subject is genetics, these applications may not be as harmless and beneficial to everyone as building an elevator using the pendulum principle in physics (apart from elevator accidents). The greatest example is Nazism, which biologist Fritz Lenz called "...nothing other than applied biology".

This process accelerated when the Nazis came to power and parliament gave Adolf Hitler unlimited authority to enact laws. The Nazis were not the first to propose these practices. As people's knowledge of genetics grew, conferences described as "human improvement" discussed allowing only intelligent, successful and beautiful people to reproduce for the benefit of society, while sterilizing others. Many respected scientists attended these conferences and supported the movement. But the Nazis took it beyond the limits of imagination. Practices that began with sterilization escalated to executions. To do this, they sold people dreams. Cinemas across the country began showing films depicting what "defective" people were like. These films featured women and children with schizophrenia. Meanwhile, the muscular, flawless bodies of the German Olympic team, like Greek statues, presented genetic perfection to audiences. People enchanted by these dreams did not speak out against sterilizations. After a while, the laws began including dangerous criminals too. Opponents, journalists and writers were also included in these crimes. By around 1934, approximately 5 thousand people were being sterilized each month. Hitler wanted to promote these sterilization efforts to euthanasia but feared the public reaction. Fortunately for him, the opportunity he wanted came his way. A family requested euthanasia from Hitler for their child, born blind and with disabled limbs. They would thereby have served their nation. Seizing the opportunity, Hitler would expand this practice and get rid of defective children nationwide through the euthanasia program. A name had even been found for these children: "lives unworthy of life". The reason for going this far was simple: sterilization protected the future, while euthanasia protected the present. Even textbooks stated that a defective person cost the German government 50,000 Marks.

The Role of Genes in the Phenotype?

To better understand the determining influence of genes on humans, it was necessary to establish the effect of the environment on identical genetic structures. Did genes have the absolute say, or did the environment play a major role during the expression of these genes? The best way to understand was to study identical twins. Many studies of twins showed that they had differences as well as similarities. One study even showed that, in a genetically related disease such as Type 1 diabetes, similarity between siblings was around 35%. But in some characteristics, twins could behave in opposite ways to show those around them that they were different from one another. Could this arise from a reaction to their genes rather than a genetically produced difference? A different approach was needed to resolve this, and behavioral psychologist Thomas Bouchard found a way. He placed a newspaper advertisement and sought twins who had been adopted into different families at birth. This was an enormous opportunity. By comparing twins raised apart with twins raised in the same home, Thomas Bouchard could reveal the relationship between genes and environment. Data gradually accumulated. Meticulous questionnaires were prepared to determine the twins' socioeconomic classes. For example, clever questions such as "Was there a telescope, an encyclopedia or original artwork at home?" were used to establish their cultural class. For 11 years, the twins underwent various physiological and psychological tests. The results were very interesting. The tests consistently preserved the degree of similarity between twins. Correlation in physical characteristics was already expected. What was truly interesting was that even the basic elements of temperament, personality, preferences, behaviors and attitudes showed a correlation between 0.50 and 0.60 in independently conducted tests. This rate in identical twins raised apart was even roughly the same as in identical twins raised together. As noted above, even type-1 diabetes, whose genetic nature is beyond dispute, showed a correlation of 0.35.

The study had astonishing results. The similarity in social and political tendencies in twins raised apart was the same as in those raised together. If one sibling was liberal, the other was liberal; if one was conservative, the other was conservative. There was also strong agreement between siblings in religiosity and belief. Either both siblings were religious or both were distant from religion. Traditionalism, or as the test called it, "a tendency to submit to authority", also showed high agreement. The contribution of genes was undeniably large.

Another example concerned sex and gender. In academic circles in the 1960s, there was a widespread belief that gender identity was not innate but was instilled in children through social performance and cultural imitation. Psychiatrist John Money of Johns Hopkins University was one of the strongest proponents of this view. He advocated "assigning gender anew" by directing gender identity through behavioral and hormone therapy. One day, a boy whose penis had been badly damaged by a surgeon's incompetence during circumcision came to Money's clinic. This child, born in 1965, was Bruce Reimer. Money advised the family, who were ready to do anything for their child, to have the child castrated and raise him as a girl. Following Money's advice, Bruce's name was changed to Brenda, and the child was dressed and treated as a girl. The hair was grown long. A rag doll and a sewing machine were given as toys. Teachers and friends were never told about the matter.

Brenda also had an identical twin, a boy named Brian. He continued to be treated as a boy. Money regularly called the children into his clinic for checkups. As puberty approached, Brenda began estrogen treatment, and on reaching puberty underwent surgery to create an artificial vagina. Money published articles about this success. The articles were widely cited. According to Money's writings, Brenda had adapted wonderfully to the new identity.

In reality, the idea was a complete fiasco. At age 4, Brenda cut up the girls' clothes that the child was forced to wear. Being told to walk and behave like a girl brought nervous breakdowns. Although Brenda obeyed and used the girls' toilet at school, the child urinated standing with legs apart. Brenda was a complete tomboy. After 14 years, Brenda put an end to this nonsense. Vaginal surgery was refused. Estrogen pills were stopped and the fullness that had developed in the chest was removed. Testosterone injections began again. The name was changed to David. In 1990, David married a woman but could not escape episodes of anger, denial and depression because of what had happened. He lost his job. His marriage failed. In 2004, after a bitter argument with his wife, he died by suicide. The David Reimer case was not unique. Many similar cases were recorded in the 1970s and 1980s.

A point should be made here. On the one hand, we speak of a gene governing a person's sex, while on the other we now see gender identities as a spectrum rather than black and white. This sex gene, known as SRY, clearly determines whether a cell is male or female. But imagine that there were a gene called TGY that strongly resisted the activity of the SRY gene in the brain. The body would then detect the male signal and become male, but the brain would have difficulty understanding this signal and might perceive itself psychologically as female. Thus, while the SRY gene is at the top of the hierarchy in gender, various modifying mechanisms lie below it (such as the environmental and epigenetic mechanisms we will discuss later).

Are Genes the Sole Determinant of the Phenotype?

Looking at twin studies, we see how influential genes are. But how can we measure the effect of the environment? For this, we need to look at a study conducted in 2010. In the 1990s, a gene called 5 HTTLPR was found to be associated with psychological stress. This gene encodes a protein that manages signals between certain neurons. Its short variant, called "high risk", has often been associated with alcoholism, trauma and depression. In 2010, a group of researchers started a project called "Strong African-American Families" in a disadvantaged rural area of the American state of Georgea. This was an area with very high crime rates, single mothers supporting households alone and syringes lying on the ground. They found 600 African-American families with adolescent children. The families were randomly divided into two groups. One group received intensive education on alcoholism, impulsivity and drug use for 7 weeks. The 5 HTTLPR gene variations were sequenced for the children in both groups.

The study's first result was as expected. Children with the short variant in the control group were 2 times more likely to engage in high-risk behaviors. These children drank more alcohol and used more drugs. In short, this agreed with previous findings that it carried high risk.

The second result was surprising. When supported, children with the short variant in the intervention group both normalized fastest and achieved the most striking changes. Apparently, this variant encoded a stress sensor that made them psychologically sensitive, and this sensor made children more responsive to both negative and positive interventions. Children without this variant may not have been greatly affected by adversity, but they also reacted less to positive changes in their environment and were indifferent. Social engineers took this further and proposed placing more sensitive children in better schools to obtain maximum benefit and make better use of limited resources. Since this enters the realm of ethics to some extent, I will examine it under another heading.

Epigenetics

The field literally named above the genes is epigenetics, DNA sequence changes not being the source of the heritable phenotypic variations it includes. The most famous example is the "Hongerwinter" event etched into the Dutch national memory. During the Second World War, German soldiers cut off the Netherlands' food routes and starved the population. This famine began in the winter of 1944 and lasted until 1945; tens of thousands of women, men and children died of hunger, while millions survived. During these years, researchers had an opportunity to observe the effects of a sudden famine on humans. Outcomes such as growth retardation from malnutrition were already expected. Children who survived that winter developed chronic problems such as depression, anxiety disorders, heart problems, gum problems, osteoporosis and diabetes. In the 1980s, however, something interesting was noticed. It emerged that the great majority of children of women who had been pregnant during the famine developed conditions such as extreme obesity and heart disease as they were born and grew up. It may not seem very surprising that these children in the womb were affected by the famine. But in the 1990s, something more interesting was found. The same health problems were also widespread among the grandchildren of those affected during the famine years. However the harsh famine years had affected these people's genes, the effect continued for 3 generations. The event had therefore been etched not only into the nation's memory but also into the memory of its genes.

We should also mention that some scientists argue that the real problem with Hongerwinter lies in the studies: parents who had experienced nutritional problems caused such an effect by intervening in their children's eating habits and choices. According to this view, what is passed down through generations is not genetic but a cultural or dietary choice.

But how could this factor, which did not alter the genes, be inherited? Did genes have their own memory? How did that memory work?

Only 2% of the genome encodes proteins, and this protein-coding process is itself regulated by proteins. In this respect, each gene is like a switch. The switch for a needed gene is activated by a protein, and expression begins. Genes that are not needed are silenced by turning off the switch. The organism does this through histone methylation. In other words, without changing the DNA, it places marks on it to indicate that these regions will be synthesized and those regions will not. This is how the epigenetic mechanism works.

Ethics in Genetic Engineering

In the book, the author also presents technological developments in genetics chronologically. We recently discussed this subject in our article. In this article, we therefore addressed the questions raised by these developments rather than the technological developments themselves. I would like you to recall the experiment involving African-Americans described above. What would have happened if our ability to intervene in genes had been highly developed and we had known only about the short variant of the 5 HTTLPR gene and its association with bad habits such as alcoholism, without having more detailed research? Would we then have removed this short variant from the genome pool without hesitation, saying that it was for society's good? Would we unknowingly have made all humanity more indifferent? We now know more about the relationship between the 5 HTTPLR gene and the environment. But what if we discover another feature in the future that we do not yet know about? We have all seen what happened when the authority to intervene in heredity was transferred to governments. In the future, we will all see the consequences when this intervention is transferred to individuals. For now, we still have a long way to go.

"We humans alone want to own the future too." -Tom Stoppard, The Coast of Utopia