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She Has Her Mother’s Laugh

The Powers, Perversions and Potential of Heredity

Carl Zimmer
Hardback edition 2018

Our understanding of heredity has come a long way and holds much promise, but we’ll need wise judgement to manage the emerging science of genetic engineering.

In this wide-ranging and extensively researched book, science writer Carl Zimmer takes an up-close-and-personal look at the phenomenon of heredity, our understanding of how it works and the potential of that understanding to improve our lives. The result is an eye-opening treatment of a complex and nuanced topic that’s fundamental to the question of who we are and how we got that way.

Aristotle’s model of inheritance

Zimmer’s account of the evolution of human beliefs about heredity is not only interesting in and of itself, but also a vivid illustration of how scientific knowledge typically advances – with each new discovery providing another piece of a puzzle that often continues expanding in scope long after the subject under investigation is considered “solved.” More than two thousand years ago, the Greek philosopher Aristotle contended that procreation was caused by the male’s semen triggering a transformation of fluids inside the female, with organs curdling into existence in an unfolding sequence. He believed that men were the true biological parents because they alone produced the seeds of life, which were nourished inside women’s bodies by menstrual blood – whose influence on children’s traits was similar to that of the surrounding soil on a plant’s development. While the ancient Greek physician Hippocrates was perhaps more egalitarian in holding that both men and women produced semen that mixed and formed new life, he and his contemporaries were still largely in the dark as to heredity’s mechanism – with many ancient Greeks and Romans believing that acquired traits, such as having lost a finger, were passed on to one’s offspring.

Greeks and Romans believing that acquired traits, such as having lost a finger, were passed on to one’s offspring.

As recently as the 1500s, Europeans relied mainly on such theories to explain how characteristics were passed from parents to children. Over the next few centuries, people came to believe that one’s ancestry was carried in the blood (from which we get the expression that the aristocracy are “of noble blood”). In the 1600s, British physician William Harvey theorized that animals grew from eggs, and not long afterwards, the newly invented microscope enabled Dutch naturalist Nicolaas Hartsoeker to discover sperm, which he believed contained tiny humans. But it wasn’t until the 1800s that someone – specifically, German biologist Rudolf Virchow – realized that every cell comes from another cell, from which its traits are inherited. By then, genealogy had become a full-blown industry in the United States, with people vying to prove that they were related to admired public figures and thus partook of the same inherent virtues. For example, Zimmer recounts that one of the early US senators, John Randolph of Virginia, claimed he was a direct descendant of Pocahontas and boastfully traced his lineage back to William the Conqueror.

Mendel’s Law

Johann Mendel

Around that same time, Austrian monk Gregor Mendel began experimenting with the hybridization of pea plants and observed that certain traits followed particular patterns –which led him to deduce that the traits were determined by certain unknown elements that came in pairs but were inherited as individual units, one from each parent. He concluded – correctly, as it turns out – that some traits were dominant, in the sense that they would be physically expressed in the plant regardless of which other “unit” (the unknown element) their own unit was paired with; while other traits were recessive, in the sense that they would only be physically expressed if their own unit was paired with a unit representing that same trait. Mendel’s work paved the way for the discovery of genes and gave heredity numerical clarity by ascribing to each parent a 50-50 chance of passing down either of their two copies of a given gene.

Since each trait is determined by a pair of genes (Mendel’s unknown elements), one from each parent, there are only four possible gene-pair combinations for a given trait: recessive from father paired with recessive from mother, recessive from father paired with dominant from mother, dominant from father paired with recessive from mother, and dominant from father paired with dominant from mother. Of those four possible combinations, only the first one (recessive from father paired with recessive from mother) will allow the recessive trait to be expressed – thus creating a three-to-one ratio between the physical expression of dominant and recessive traits.

Chart of the characteristics of pea plants - Gregor Mendel
Also, around the same time, British naturalist Charles Darwin came up with a theory about heredity that he dubbed “pangenesis,” which postulated the existence of tiny particles that coursed through the body and determined the organism’s characteristics. Not everyone agreed with Darwin, but pangenesis wasn’t officially discredited until a contemporary, the German zoologist August Weismann, correctly concluded that organisms were composed of two types of cells: germ cells, which produced sperm or eggs; and somatic cells, which comprised the rest of the body. Weismann also tested the theory of the transmission of acquired characteristics by cutting off the tails of mice, observing that none of the offspring had shortened tails.

As Zimmer notes, all of this work in establishing heredity as a scientific question and looking closely at how it was transmitted set the stage for scientists to finally appreciate Mendel’s earlier discovery (now known as Mendel’s Law), which remains one of the most important in the history of science. Within a decade after blood types were discovered in 1900, it was observed that they followed Mendel’s Law, with types A and B dominant over type O, so that only those who’ve inherited an O gene from both parents have blood type O. However, as often happens, it took a while for that knowledge to percolate down through the rest of society. Zimmer recounts that when the film star Charlie Chaplin was sued for paternity in 1944, a jury found him to be the father, despite the fact that his blood type exonerated him scientifically because the child had type B blood (and thus was either B-O or B-B, since A-B results in type AB blood), the mother type A (and thus was either A-O or A-A) and Chaplin type O (and thus was O-O, since O is recessive to both A and B).

A Double-Edged Sword

DNA, the molecular basis for biological inheritance. Each strand of DNA is a chain of nucleotides, matching each other in the center to form what look like rungs on a twisted ladder.

By the 1920s, scientists had already discovered DNA (deoxyribonucleic acid, the double-stranded molecule that encodes genes and is located in threadlike structures called chromosomes). By the 1940s, Zimmer notes, genetics was “a precise molecular science in the hands of some, and a monstrous rationale for oppression and genocide in the hands of others.”

For example, the concept of race had long been used to justify enslaving or discriminating against groups of people – who were conveniently considered genetically “inferior,” despite the scientific absurdity of those beliefs. Hitler not only embraced the concept of racial inferiority, but also the “eugenics” theories of American psychologist Henry Goddard, who had waged a vigorous campaign to use compulsory sterilization on the “feebleminded” to stop them from reproducing, for fear that they’d contaminate the national gene pool.

Some of the most important early lessons about race came from studying other species, including the fruit fly Drosophila pseudoobscura, which was studied by soviet émigré Theodosius Dobzhansky at the California Institute of Technology.

He considered the way the Nazis used a biological definition of race to persecute Jews disgusting, vicious and antiscientific and, starting the late 1930s, began pointing out that the popular notions of human races and white superiority had no basis in biology. Dobzhansky explained that populations of any animal species were a mix of genetic variants, so there was no such thing as a “pure race.” One of his protégés, Richard Lewontin, found that the genetic differences between races accounted for only 6.3% of the total genetic diversity in humans. Lewontin realized that the concept of race is taxonomically useless because it is defined by obvious features (such as skin color) that are influenced by a small number of genes – while ignoring all the other of genes people carry. In 1998, Oxford University researchers did a computer analysis of the genetic variation in people all over the world and found that the overwhelming amount of genetic diversity was between individuals – with genetic differences between major groups accounting for only 3% to 5% of that diversity. Zimmer also notes that in addition to the many movements and mixings of human populations over the ages, scientists have discovered evidence of “ancient encounters that introduced DNA into our gene pool from Neanderthals and other extinct humans.”

Today, scientists estimate that intelligence is about 50% inherited.

Another example of genetics being misused as a rationale for discrimination involved intelligence. Thanks in large part to the development in the early 1900s of a means of testing it (rather than relying on subjective assessments), scientific understanding of intelligence had evolved considerably by then from where it had been less than a century earlier – when the eminent British scientist Francis Galton was convinced it was related to the circumference of the head. Nonetheless, when newly developed intelligence tests were given to millions of soldiers, American psychologist Lewis Terman interpreted the results as confirming that intelligence was mainly due to heredity – and that the low scores of immigrants, who mainly came from southern and southeastern Europe, were due to their genetic inferiority to northern Europeans. However, the results also showed that the longer the immigrants had been living in the US, the higher they scored on the intelligence tests – a fact that Terman conveniently failed to register, but that showed the tests to be dependent on a high degree of familiarity with American life, something the recent immigrants lacked.

Today, scientists estimate that intelligence is about 50% inherited but have identified only 52 intelligence-related genes, which collectively account for just a small percentage of the variation in people’s intelligence test scores. Zimmer explains that as hard as it’s been for scientists to find the genes involved in intelligence, it’s even harder to map the influence of environment, although environment definitely plays a huge role (for example, the children of mothers with high blood levels of pesticides score lower on IQ tests than do their peers, and giving iodine supplements to those who are iodine-deficient can boost their intelligence scores).

Chart explaining epigenetics

woman drinking inside a circle with a line through it

The harmful impact of alcohol on the unborn child is not just limited to the Mother’s alcohol consumption during pregnancy but is also affected by the Father’s alcohol consumption prior to conception.

Ironically, some of the latest and most cutting-edge discoveries in the field of genetics have shown that the ancient belief that acquired characteristics can be inherited actually holds true in some cases. For example, recent experiments on mice have shown that certain experiences, such as learning to fear a certain scent, can be transmitted through the father’s sperm, even though this information isn’t carried on genes. The explanation, Zimmer tells us, may lie in something called the epigenome, which he defines as “that collection of molecules that envelops our genes and controls what they do.” The epigenome can actually alter the way genes work and possibly even play a role in storing memories in our brain. There’s even evidence that, because of epigenetic alterations in the sperm, fathers who drink alcohol before their partners conceive can contribute to fetal alcohol syndrome in the children – something that, previously, was believed to be caused only by the direct effect on the fetus of alcohol consumed by the mother during her pregnancy.

illustration of autosomes and sex chromosomes

The 22 autosomes are numbered by size. The other two chromosomes, X and Y, are the sex chromosomes. This picture of the human chromosomes lined up in pairs is called a karyotype.

The latest discoveries in the field of genetics are also being used to trace people’s ancestry. However, in so doing, those discoveries have brought to light several paradoxes that, in a sense, make family trees largely meaningless beyond a few generations. As Zimmer explains, the number of ancestors doubles with every generation back, and there’s only so much room in our genomes (an organism’s complete sequence of DNA) – which means that “beyond a few generations, we share little or no DNA with our ancestors.” What’s more, in 1999, Yale mathematician Joseph Chang found that if you go back far enough with any human population, there’s a point at which all of the individuals who have any living descendants are the ancestors of all living people. All humans alive today get their mitochondria (fuel-generating organelles within each cell that are inherited only from the mother) from one woman who lived about 157,000 years ago in Africa, and all men alive today get their Y chromosome from an African man who lived 190,000 years ago (chromosomes in each cell carry hereditary information and, in humans, come in 23 pairs, one of which determines the person’s gender – with women having two X chromosomes and men having an X and a Y).

Chimeras and Mosaics

A plate showing a “Free Martin” from the collected works of John Hunter. Freemartinism is a distinct form of intersexuality that arises as a result of a vascular anastomosis of the adjacent chorioallantoic sacs of male and female fetuses in multiple pregnancies. The majority (~95%) of female fetuses in male/female twin pregnancies are affected. – Timothy J. Parkinson, in Veterinary Reproduction and Obstetrics, 2019

As we’ve discovered more about genetics, we’ve learned that heredity isn’t quite as straightforward as we’d come to believe. For example, in 1945, American biologist Ray David Owen discovered that the bodies of freemartin cows (female cows born with a male twin) – were made up of cells belonging to different lineages. He realized that this was because in utero, the twins had transplanted their stem cells (cells that can generate other types of cells) into each other’s bone marrow – so that the freemartins had inherited some cells from their brothers and became a combination of two different animals in one. British physician Peter Medawar built on Owens’ work to develop a deeper understanding of the immune system and pave the way for the modern practice of organ transplantation.

Medawar called creatures such as freemartins chimeras, from the ancient Greeks’ mythical monster that was held to be a mix of various creatures. When British doctors discovered a real-life human chimera (in the genetic sense, that is), Medawar studied her with interest and found out that she had inherited the genes for type O blood from her parents but, in the womb, had acquired some of her twin brother’s type A stem cells, which established themselves in her bone marrow. In the 1990s, Dutch researchers studied hundreds of sets of human twins and discovered that 8% were chimeras – and then found that 21% of the triplets they studied were chimeras. Not long afterwards, it was discovered that pregnancy can cause a chimeric state in females, and that most mothers experience it. In fact, research has shown that at the 36th week of pregnancy, all mothers have fetal cells in their bloodstream, and that as many as half of all mothers still carry such cells decades after giving birth. A 2016 study found that more than 13% of girls had Y chromosomes (normally only found in males), which had come from their brothers, were left behind in their mothers after birth (or from male fetuses that had been miscarried or aborted) and then came into the girls in the fetal stage. Another study looked at the cadavers of older women and found that 63% had Y chromosomes in their brains.

Eyes from a woman with one brown eye and one hazel eye

Mosaicism is the presence of two different genotypes in an individual which developed from a single fertilized egg. As a result, the individual has two or more genetically different cell lines derived from a single zygote. (photo by flamma)

Another curiosity of heredity is the phenomenon of mosaicism, which occurs when not all of the cells within an individual have the same genetic makeup. As Zimmer explains, such an occurrence is not surprising when you consider that, for example, a fertilized human egg will multiply into 37 trillion cells by the time that person reaches adulthood, and “each time one of those cells divides, it must create a new copy of its three billion base pairs of DNA. For the most part, our cells manage this duplication with stunning precision. If they make a mistake, one of their daughter cells will acquire a new mutation that was not present at conception. … Some researchers have estimated that there might be over ten quadrillion new mutations scattered in each of us.” So, as Zimmer puts it, “a single genome can no longer define us, because our inner heredity toys with DNA, altering just about every piece of genetic material we inherit.” Mosaicism has been discovered to be the cause of a number of diseases – including the condition that afflicted the famed Elephant Man – and scientists have even found some people whose mosaicism can actually heal, at least partially, certain genetic conditions, including skin diseases, anemia, liver disorders and muscular dystrophy.

A New Tool

Our knowledge of heredity is helping us use genetic engineering to do a variety of things – from improving the yield of crops and making them resistant to pests, to mass-producing the medication insulin, which is used to treat diabetics. It’s also helping us find entirely new ways to prevent and treat diseases. A key tool in that effort is something known as CRISPR, which was discovered in 2013. Based on a system of molecules that bacteria use to alter their own heredity, CRISPR (an acronym for “clustered regularly interspaced short palindromic repeats”) is “a versatile, cheap way to control the heredity of just about any species,” says Zimmer. Unlike previously developed techniques, such as using X-rays to try to cause random genetic mutations (which, for example, was used by scientists in an attempt to trigger new, desirable mutations in corn and other plants), CRISPR enables scientists to synthesize short pieces of DNA from scratch and, potentially, make any kind of change they want to the genes of any species. Thus, its many potential applications include correcting genetic defects, treating and preventing the spread of diseases and improving crop yield and quality.

Graphic illustrating gene editing

Double strand DNA breaks introduced by CRISPR-Cas9 allowing genetic manipulation by exploiting endogenous (internal) DNA repair mechanisms. (by Guido4)

Scientists have begun using CRISPR to edit the genes of human cells. CRISPR has also helped them determine that only about 10% of all the protein-coding genes in the human genome are essential, and that many genes are expendable because if they fail, there are other genes that can take over the same functions. Scientists have also discovered that CRISPR can not only alter somatic cells, but can change the DNA in germ-line cells as well. This prospect has frightened many people, because it raises the ugly specter of Nazi eugenics. It’s also alarmed many scientists, who feel that tinkering with the germ line should be taboo for a variety of reasons – some of them ethical, some of them practical. Even the originator of the term “genetic engineering” – a microbiologist named Rollin Hotchkiss, who came up with the term in 1963 and felt the procedure had tremendous potential – was horrified at the idea of altering genes in a person’s germ line, because those alterations would be passed down to future generations.

It’s argued that the risks of CRISPR are too great (e.g., it might miss its target and rewrite a different gene), that altering a child’s genes is an affront to his or her individuality and that, even if successful, CRISPR could create unprecedented social woes, with the rich engineering their children’s genes to avoid diseases, while the poor remain unable to afford such measures.

Ethical and Practical Implications

As scientists grappled with the implications of using CRISPR on humans, others focused on the implications of gene drives (defined by Zimmer as any systems of “biased inheritance” that allow a genetic element to pass from parents to offspring more than would occur under Mendel’s Law). Those scientists concluded that the technology could make life better in many ways, such as making mosquitoes malaria-proof, saving thousands of lives a year; making mice resistant to Lyme disease, breaking the diseases cycle; and fighting the evolution of herbicide-resistant weeds – but that it might also wreak havoc, because it might not work as planned, and if it caused harm, it might not be possible to undo the damage. A 2016 National Academy of Science report warned that gene drive has the potential to cause “irreversible effects on organisms and ecosystems.”

Regarding the possibility of unintended consequences, Zimmer says that, for example, “It’s possible that changing how mosquitoes and other animals respond to one disease could lead them to carry others. Perhaps getting rid of mosquitoes might disrupt ecosystems in ways we can’t yet imagine.” What’s more, he says, we “owe future generations a careful, forward-looking consideration of the world they will inherit.”

Despite such reservations, some scientists around the world have begun experimenting with CRISPR on humans, and some doctors, including Harvard geneticist George Church, feel it could be used, for example, to treat the elderly for such conditions as osteoporosis. In 2017, the National Academy of Sciences endorsed using CRISPR in clinical trials to treat serious diseases for which there are no alternative treatments.

Zimmer argues that this is not much different from what the medical profession is already doing with other treatment modalities. However, he acknowledges that using genetic engineering on germ cells is different from using it on somatic cells. Still, he points out that “when people wring their hands about what genetic engineering might do to the human gene pool, they often forget that it’s actually more like a human gene ocean.” What’s more, Zimmer says, gene-pool arguments “treat the collective DNA of our species as if it were inscribed in stone tablets long ago and passed down unchanged ever since,” when “in fact the human gene pool has always been changing and will continue to change, regardless of what we do to it.”

Zimmer feels that instead of focusing so narrowly on such things as CRISPR, we should instead think more broadly about heredity. For example, he suggests that the epigenetic side of plant biology, which has only started to emerge, may hold the key to improving crops, and notes that plants sometimes change their epigenetic profile naturally.

Still, there’s no denying that today, we’re close to being able to alter human heredity. “We certainly need to come to a collective decision about using CRISPR on human embryos, to use it only in ways that help people without creating serious dangers of their own,” Zimmer says. “But this shorthand about heredity poses dangers, too. We risk coming to see ourselves as merely the product of the genes we inherited from our parents, and the future as nothing more than carrying those genes forward. … This shorthand makes it hard to think clearly about genetic heredity. It leads us to overvalue our ambiguous knowledge of how genes work and dismiss the other factors that shape our lives – and could be reshaped to improve the world.”

 

About the Book’s Author: Carl Zimmer is an award-winning science writer, a columnist for the New York Times and a frequent contributor on Radiolab.

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