As an example, suppose Anne had abusive parents. Is it theoretically possible to deduce this from her genome even if she didn't inherit this quality (of being an abusive parent)?
It might seem pernickety but you often can't deduce from a genome; you can only infer from it. For many characteristics about a person, there are only rough, probabilistic associations between genotype and phenotype. Not one-to-one relationships.
You can take an educated guess that someone with a certain genotype could be a social person of European ethnicity with a low risk of psychosis, which might suggest things about their parents. But there are likely many genes that influence those characteristics and still more non-genetic factors. So you couldn't be certain.
For a factor like whether the persons parents had abusive personalities, I think the genetic differences would be so subtle (if existent) and there would be so many other factors (such as the habits and choices of the parents) that you would be very unlikely to be able to draw any conclusive associations. Articles and studies about linking human genetics with a person's characteristics are listed below. If any of the genes in question are linked with those characteristics then the parents of someone with the gene could possibly have those genes and characteristics too.
Personality types including belligerence, charisma, cynicism, housekeeping, lack of personality, obsessive-compulsive behaviour and gullibility.
Psychosis and Schizophrenia risks.
Ethnicity and European ethnicity, which in turn correlate with geographical location, language and certain phenotypes.
If anyone would like to suggest additions to that list, I'll happily add them.
Not the kind of complex phenotype that you describe (because nobody knows for example if/how "being abusive" is written in the genome), but yes, some things can be determined.
The easiest is through sex chromosomes.
For example: if you look at the X chromosome of a man, you can tell for sure that it comes from his mother (because the Y can only come from the father, quite logically) so any allele that you see there is also part of the mother's genome - but since she has a second copy, maybe it does not translate into a phenotype.
Sometimes you can even guess the phenotype of one of the parents: if you study a woman's X chromosomes and see that both have alleles that cause color-blindness (encoded on this chromosome) it means that the only X chromosome of the father has this allele, so the father is probably color-blind.
The Making of a Serial Killer
These creepy Ted Bundy quotes patently summarize the main traits of a psychopath: A callous, exploitive individual with blunted emotions, impulsive inclinations and an inability to feel guilt or remorse.
The causes of psychopathy remain a mystery. We don’t even have a satisfactory answer to the question of whether psychopathy is a product of Mother Nature or a feature of upbringing. One of the best sources of information about whether traits are a result or nature of nurture comes from the Minnesota Study of Twins Reared Apart. The Minnesota Twin Study is a project originally led by Minnesota Professor of Psychology Thomas Joseph Bouchard, Jr. The Minnesota twin study has shown that psychopathy is 60 percent heritable. This percentage indicates that psychopathic traits are due more to DNA than to upbringing. Recent genetic studies of twins indicate that identical twins may not be as genetically similar as hitherto assumed. Though only a couple of hundred mutations take place during early fetal development, the mutations likely multiply over the years, leading to vast genetic differences. This leaves open the possibility that psychopathic traits are largely genetically determined.
If psychopathy is genetically determined, one should expect some abnormality in the brain, the immediate source of psychopathic traits. A possible candidate for this abnormality has recently been identified in a study at University of Wisconsin, Madison. Brain scans revealed that psychopathy in criminals was associated with decreased connectivity between the amygdala, a subcortical structure of the brain that processes negative stimuli, and the ventromedial prefrontal cortex (vmPFC), a cortical region in the front of the brain that interprets the response from the amygdala. When the connectivity between these two regions is low, processing of negative stimuli in the amygdala does not translate into any strongly felt negative emotions. This fits well into the picture we have of psychopaths. They do not feel nervous or embarrassed when they are caught doing something bad. They do not feel sad when other people suffer. Though they feel physical pain, they are not themselves in a position to suffer from emotions hurts.
The Wisconsin, Madison study shows a correlation between criminal psychopathy and brain abnormality. As this brain abnormality in the majority of cases of psychopathic criminals is not abruptly acquired, there is good reason to think that it's grounded in the psychopath's DNA.
There are, however, some limitations of this study. The study measured criminal psychopaths. But not all psychopaths are criminals. Most psychopaths are manipulative, aggressive and impulsive but these features far from always lead to criminal activity. It remains to be seen whether non-criminal psychopaths, like their criminal counterparts, have reduced activity between the amygdala and the vmPFC. Another limitation of the study is that it doesn’t show that reduced activity between the amygdala and vmPFC is an abnormality specifically linked to psychopathy rather than to a range of mental conditions that have been associated with serious crime, including paranoid schizophrenia and extreme sexual fetises.
Though the Wisconsin study sheds some light on what may bring about the traits of psychopathy, psychopathy remains puzzling. We don't know the reason behind the reduced connectivity in the emotional system. It could be caused by a dysfunction of neurotransmitters, for example, by a disturbance to the main excitatory neurotransmitter glutamate. Alternatively, it could be a degenerative disease that leads to a reduction of the brain’s white matter, which is responsible for connectivity among neurons. The answer to what causes reduced connectivity in the brain’s emotional system would help answer some of the bigger questions about psychopaths, for example, the question of whether disorder is partially due to social (or other environmental) factors or is primarily genetically based.
Social factors have some (even if only small) role to play in generating psychopathy. But after many years of investigating the minds of psychopaths, researchers have been unable to find any factors that could contribute to the development of psychopathic traits. Early childhood abuse or neglect often leads to posttraumatic stress disorder or phobias (e.g., in terms of making commitments). But anxiety disorders are typically associated with either greater connectivity between the amygdala and the vmPFC or a dysfunction of vmPFC that makes it unable to modulate negative information from the amygdala. We cannot exclude that childhood abuse or neglect may be a factor in making psychopaths commit crimes, but it's not a likely contributing factor to psychopathy itself. Furthermore, though serial killers like Charles Manson were abused and neglected as children, the list of serial killers with a normal childhood is long. Famous serial killers such as Ted Bundy, Jeff Dahmer and Dennis Rader grew up in healthy households with supportive family members.
Elsa Ermer and Kent Kiehl of the University of New Mexico, Albuquerque, discovered that psychopaths have difficulties following rules based on moral sensibility, despite fully understanding the rules. The blunted emotions of psychopaths appear to play a role in preventing them from following rules. But this is possibly correctable. We know that people with autism spectrum disorder have difficulties picking up on social cues or do the right things in social contexts. But higher functioning autists can normally learn to make the right kinds of signals in social situations. For example, they can learn to make eye contact, back-channel during conversation and express an interest in other people. Sometimes this requires years of training with a therapist or medical professional. They have to learn to do what others learn by interacting with family members and peers. If people with high-functioning autism, an inheritable disease, can learn social cues, then presumably some psychopaths can learn to follow moral rules by going through extensive training.
One social factor in turning a genetically disposed individual into a psychopath, then, may be a negative one: They have not been given special training in following rules. Perhaps given their dull affect, one could experiment with training programs that increase negative emotion processing artificially and then teach them to associate these heightened negative emotions with morally bad actions. Certain hallucigenics, such as psilocybin, might be an effective tool.
It is worth noting here that a large number of the most gruesome crimes were committed by psychotics, not psychopaths. Psychosis and psychopathy are different kinds of mental disorders. Psychosis is a complete loss of one's sense of reality. Psychopathy is a personality disorder, much like narcissistic personality disorder. Personality disorders are potentially more permanent and less curable than psychotic diseases.
Psychotics and psychopaths can have traits in common, such as blunted emotions, but they differ in terms of whether they are in touch with reality. Psychopaths are calculating and manipulative but they do not suffer from hallucinations or delusions. They do not hear the voices of strangers in their heads or hold elaborate false theories about the world. Serial killer Coral Eugene Watts strangled several women because he saw evil in their eyes. Belle Sorenson Gunness slaughtered her husbands because she believed men were evil. Ed Gein mutilated, skinned and gutted his graveyard goodies and his only live victim because he wanted to be a woman and believed he needed body parts for a sex change (or maybe to make a replica of his mother). Richard Trenton Chase drank and bathed in his victims' blood. He believed he had to do this to prevent Nazis from turning his blood into powder with a poison they had hidden beneath his soap dish.
One hypothesis about psychotic diseases, such as schizophrenia and bipolar disorder, is that the glutamate system is dysregulated. Overstimulation may lead to manic phases, delusions and hallucinations. Lack of stimulation could lead to blunted or negative affect. The overstimulation and lack of stimulation may happen at the same time at different receptor sites. The mechanism underlying psychopathy and psychosis may thus overlap with respect to the blunted or negative affect.
- Most commonly, a single base is substituted for another. Sometimes a base is deleted or an extra base is added. Fortunately, the cell is able to repair most of these changes. When a DNA change remains unrepaired in a cell that will become an egg or a sperm, it is passed down to offspring. Thanks to mutation, we all have some new variations that were not present in our parents.
- The work of the Human Genome Project has allowed researchers to begin to understand the blueprint for building a person. As researchers learn more about the functions of genes and proteins, this knowledge will have a major impact in the fields of medicine, biotechnology, and the life sciences.
- Fertilization- depending on which sperm fertilises which egg, the resulting zygote will carry that characteristics: so in other words which individuals mate with which
- A gene consists of a length of DNA with a base sequence, the different alleles of a gene have slight variations in base sequence, new alleles are formed from other alleles by gene mutation.
- A mutation is a random change to the base sequence of a gene.
- Two factors that can increase mutation rates are:
- Radiation: increases mutation rate if it has enough energy to cause chemical changes in DNA. Gamma rays and alpha particles from radioactive isotopes, short-wave ultraviolet radiation and X-rays are all mutagenic.
- Chemical substances: some cause chemical changes in DNA and therefore are mutagenic. Ex: benzo(a)pyrene and nitrosamines found in tobacco smoke and mustard gas used as a chemical weapon in WW1.
- Ex: consequences of nuclear bombing and accidents at nuclear power stations such as bombing of Hiroshima+Nagasaki and the nuclear accidents at Chernobyl.
- Radioactive isotopes were released, people and the enrvionment were exposed to potentially dangerous levels of radiation.
- A random change to an allele that developed by evolution over millions of years is unlikely to be beneficial, therefore most mutations are harmful or neutral. In these cases little evidence of later impact, but many direct.
- Cancer: mutations of the genes that control cell division can cause them to divide endlessly and develop into a tumour
What if sideline rage could be nipped in the bud with a quick genetic test that told Mom and Dad what sports &ndash if any &ndash Junior could master? The Boulder, Colo., company Atlas Sports Genetics today began selling just that sort of product: for $149, it says it will screen for variants of the gene ACTN3, which in elite-level athletes is associated with the presence of the muscle protein alpha-actinin-3. The protein helps muscles contract powerfully at high speeds, which may explain why the combination of ACTN3 variants that produce it has been found in Olympic sprinters.
The company's president, Kevin Reilly, tells ScientificAmerican.com that parents shouldn&rsquot view the test as the final word on whether their child will excel at a particular sport. But, he says, it is more useful than physical tests in determining a child's athletic abilities before age 9.
At that age, "they don&rsquot have the physical maturity and motor skills to do well," Reilly says. "That&rsquos where the genetic test can come in [handy] for looking for early indicators of talent in performance areas.
"It&rsquos a question of their motivation. This is a tool, not the tool," he says of consumers. "If they're relying on the genetic test as the only performance indicator to tell whether they will do good or bad in sports, they're going to be disappointed, because it's not for that purpose. If it&rsquos a tool along with other components, you can use it to select what may be the best sport for you or for a child."
It takes about three weeks to get the results of the saliva test, which looks for three combinations of ACTN3 genes, with a child getting one variant from his mother and one from his father. (Reilly says that the Atlas Genetics screen is the only one commercially available in the U.S. that tests for fitness-related genes.) Kids who have two copies of the X variant from both parents don&rsquot make alpha-actinin-3, and might excel at endurance sports such as cross-country skiing, distance running or swimming, according to the company's Web site. Those with one copy of the X variant and one of the R variant will make some protein, Reilly says, and may excel at endurance or "power" sports such as soccer or cycling. And children with two copies of the R variant will make more alpha-actinin-3, setting them up for possible achievement in power or endurance sports including football, weight-lifting or sprinting.
We asked Stephen Roth, an assistant professor of exercise physiology, aging and genetics at the University of Maryland in College Park, to explain what is and isn&rsquot known about the relationship between DNA and sports performance. Roth is a co-author of the Human Gene Map for Performance and Health-Related Fitness Phenotypes, a catalog of genes associated with sports-related fitness. The map was last published in 2006 in Medicine and Science in Sports and Exercise, a journal of the American College of Sports Medicine. The new edition will be available shortly.
This is an edited transcript.
To what extent do genes determine athletic ability?
Nobody knows the answer for sure and it depends on how specifically you define athletic ability. Most research suggests that genetics contribute significantly to sports performance, but it's very hard to put a number on. It's very hard to quantify football performance, for example. Most studies look at very specific endpoints: how much a gene contributes to muscle strength or maximal aerobic capacity, because those endpoints are very easy to measure from a research standpoint. If you try to parse it out, as much as 50 percent of muscle strength is determined by genetic factors.
The question is, what does that mean? To say there's some sort of heritable component to a trait tells us something can be passed on in a family that can contribute to performance, but what are the specific genes? How important, how predictive are those genes? We have no idea what is going on when it comes down to it. Some people are just genetically gifted, but we have just scratched the surface in defining what we mean by genetic advantage.
How many genes play a role in sports talent?
We don't know. I'm a co-author on a review published every few years where we catalog genes that have been studied in relation to performance. There are 200 genes we are cataloging as having some positive association with fitness-related performance &hellip and there are 20,000 genes in the genome, so we're scratching the surface in relation to those studied.
Are those genetic factors just related to muscle strength, or do they show a variety of factors that are related to athleticism?
A wide range of factors. Because sports performance is so complex, we find muscle strength measures to metabolism performance measures or cardiovascular performance measures.
Atlas Sports Genetics is marketing tests for variants of the ACTN3 gene. Are there tests that pick up whether a person has other fitness-related genes?
ACTN3 is probably the most convincing of the genes studied so far, the most consistently associated [with sports-related fitness]. People who are the XX genotype do not have alfa-actinin-3 in their muscles. The idea is that in people who are lacking this protein, their muscles won't work as well and that will prevent them from reaching the upper echelon of power performance. That&rsquos been indicated in a number of studies. But is the association about muscle fatigue? Contractile strength? As research starts to delve into these more refined traits, we don&rsquot feel confident saying how the XX genotype is contributing to performance.
Another gene is ACE, which has been studied in relation to endurance performance. But the more these genes are studied, the messier the literature becomes. ACE is the most studied and is still a gene of interest, but we're trying to figure out if it's important and how &mdash and the same question is reflected in ACTN3, but not reflected in ads for the test.
The ACE studies are more conflicting. It was originally argued that people with the II variant would be better at endurance and those with the DD variant would be better at strength. But the findings are not as consistent. When you break it down, we don&rsquot see a clear story for how it would be working. If it does have a role, it&rsquos a much smaller role than originally thought. There are larger question marks around ACE that would make it harder to sell as a test.
What can the results of the ACTN3 test tell us?
The results do tell you whether you have this protein in your muscle. That is clear. We have no idea if it contributes to performing at anything but an elite level. Even there, there are contradictions. We have very little information that it affects kids' performance. You may have a disadvantage in sprint performance, but it's likely you'll never see it except at an Olympic level. What 6- or 8-year-old cares about that?
Besides genetic testing, is DNA being used in other ways to promote athleticism?
The major issues out there are gene screening and whether we can predict performance or somehow tailor workout or training programs to particular people or select the sports they participate in in advance. The other is whether we can alter a genetic profile to enhance their performance. It's very similar to gene therapy in medicine. It hasn&rsquot been successful in medicine and never studied in sports performance. It&rsquos a real ethical dark zone, because there are medical concerns even pursuing it and no evidence that it would really work. Anti-doping societies have come out against it. It is definitely a concern. Technology is being developed in the medical arena. It won't take long for someone to push it in the sports world.
Are We Too Close to Making Gattaca a Reality?
Sometime in the not-too-distant future, Marie and Antonio Freeman step into a doctor’s office to design their next child. “Your extracted eggs, Marie, have been fertilized with Antonio’s sperm,” the doctor says.
Sometime in the not-too-distant future, Marie and Antonio Freeman step into a doctor’s office to design their next child.
“Your extracted eggs, Marie, have been fertilized with Antonio’s sperm,” the doctor says. “After screening we're left with, as you see, two healthy boys and two very healthy girls.”
A monitor displays what looks like soap bubbles that bumped into each other on a green background.
“Naturally, no critical predispositions to any of the major heritable diseases,” the doctor says. “All that remains is to select the most compatible candidate. We might as well start with gender—have you given it any thought?”
“We would want Vincent to have a brother, you know, to play with,” Marie says, referring to her first child.
Acknowledging this, the doctor continues: “You have specified hazel eyes, dark hair and fair skin. I have taken the liberty of eradicating any potentially prejudicial conditions: premature baldness, myopia, alcoholism and addictive susceptibility, propensity for violence and obesity—”
“We didn't want—I mean, diseases, yes,” Marie interrupts.
“Right, we were wondering if it’s good to leave a few things to chance,” Antonio says.
“You want to give your child the best possible start,” the doctor replies. “Believe me, we have enough imperfection built-in already. Your child doesn't need any additional burdens. And keep in mind, this child is still you, simply the best of you. You could conceive naturally a thousand times and never get such a result.”
The Freemans are characters in the science fiction film Gattaca, which explores liberal eugenics as an unintended consequence of certain technologies meant to assist human reproduction. Although Antonio and Marie do not exist outside the movie’s imaginary universe, their real-life counterparts could be walking among us sooner than we think—and, in a sense, they already are.
When Gattaca premiered in 1997, doctors had been using laboratory techniques to help women and men overcome infertility for more than a decade. In 1978, Louise Brown of the U.K. became the world’s first “test tube baby”—the first person conceived through in vitro fertilization (IVF), a procedure in which sperm and eggs are combined in the lab to create several viable embryos that are subsequently implanted in a woman’s womb. The first IVF clinic opened in the U.S. in 1980. Today, hundreds of fertility clinics in the country offer IVF and more than one percent of children born in the U.S. are conceived this way.
In the years surrounding Gattaca’s release, doctors were also talking about how to responsibly use another, more controversial technique to help people have children: preimplantation genetic diagnosis (PGD). In this procedure, clinicians vacuum up one of eight cells in a three-day-old embryo created through IVF and analyze the DNA within to find genes associated with debilitating and potentially fatal diseases. Sometimes, doctors wait two more days, when the embryo has become what is known as a blastocyst—a mostly hollow ball of around 100 cells—and collect between 5 and 20 cells for DNA analysis. In most cases, this extraction does not significantly disturb the embryo’s development. PGD can identify embryos that will almost certainly develop disorders caused by a mutation in a single gene, such as cystic fibrosis, sickle cell disease, Tay-Sachs and Huntington’s, as well as disorders that result from an extra chromosome, such as Down syndrome. From its earliest days, PGD has been principally intended for people who have a high risk of conceiving a child with a particular disorder, because it runs in the family or because they happen to harbor a certain genetic mutation.
Couples have also created one child through IVF-PGD in order to save another. At least 30 fertility clinics in the U.S. will help parents conceive a “savior sibling”—a child whose umblical cord blood can be harvested as a source of stem cells to treat leukemia, Fanconi anemia or another terrible illness in his or her older sibling. An infusion of stem cells donated by a relative whose immune cells are genetically similar to those of the sick child has a much better chance of succeeding than cells from a stranger. Siblings inherit their immune system genes from the same parents, so they are sometimes an almost exact immunological match—something doctors at fertility clinics can determine by looking at an embryo's DNA.
Nominally, clinics agree to help parents in this way only if the couple had always intended to have several children. But some parents in this situation undoubtedly alter their original family plan out of desperation. So what happens if the treatment fails? How will the inevitable disappointment change the way parents feel about their second child? And how does learning that one’s entire existence hinges on saving someone else’s life warp the psychological development of a child or young adult? In Jodi Picoult’s 2004 novel My Sister’s Keeper, thirteen-year-old savior sibling Anna sues her parents for medical emancipation when they ask her to donate a kidney to her older sister Kate, who has leukemia.
Preventing and treating diseases are not the only reasons people have turned to pre-implantation genetic diagnosis. PGD also makes it possible for parents to predetermine characteristics of a child to suit their personal preferences. In a few cases, people have used PGD to guarantee that a child will have what many others would consider a disability, such as dwarfism or deafness. In the early 2000s, lesbian couple Sharon Duchesneau and Candy McCullough—both deaf from birth—visited one sperm bank after another searching for a donor who was also congenitally deaf. All the banks declined their request or said they did not take sperm from deaf men, but the couple got what they were looking for from a family friend. Their son, Gauvin McCullough, was born in November 2001 he is mostly deaf but has some hearing in one ear. Deafness, the couple argued, is not a medical condition or defect—it is an identity, a culture. Many doctors and ethicists disagreed, berating Duchesneau and McCullough for deliberately depriving a child of one of his primary senses.
Much more commonly, hopeful parents in the past decade have been paying upwards of $18,000 to choose the sex of their child. Sometimes the purpose of such sex selection is avoiding a disease caused by a mutation on the X chromosome: girls are much less likely to have these illnesses because they have two X chromosomes, so one typical copy of the relevant gene can compensate for its mutated counterpart. Like Marie and Antonio Freeman in Gattaca, however, many couples simply want a boy or a girl. Perhaps they have had three boys in a row and long for a girl. Or maybe their culture values sons far more than daughters. Although the U.K., Canada and many other countries have prohibited non-medical sex selection through PGD, the practice is legal in the U.S. The official policy of the American Society of Reproductive Medicine is as follows: “Whereas preimplantation sex selection is appropriate to avoid the birth of children with genetic disorders, it is not acceptable when used solely for nonmedical reasons.” Yet in a 2006 survey of 186 U.S. fertility clinics, 58 allowed parents to choose sex as a matter of preference. And that was seven years ago. More recent statistics are scarce, but fertility experts confirm that sex selection is more prevalent now than ever.
“A lot of U.S. clinics offer non-medical sex selection,” says Jeffrey Steinberg, director of The Fertility Institutes, which has branches in Los Angeles, New York and Guadalajara, Mexico. “We do it every single day. We did three this morning.”
In 2009 Steinberg announced that he would soon give parents the option to choose their child’s skin color, hair color and eye color in addition to sex. He based this claim on studies in which scientists at deCode Genetics in Iceland suggested they could identify the skin, hair and eye color of a Scandinavian by looking at his or her DNA. "It's time for everyone to pull their heads out of the sand,” Steinberg proclaimed to the BBC at the time. Many fertility specialists were outraged. Mark Hughes, a pioneer of pre-implantation genetic diagnosis, told the San Diego Union-Tribune that the whole idea was absurd and the Wall Street Journal quoted him as saying that “no legitimate lab would get into it and, if they did, they'd be ostracized." Likewise, Kari Stefansson, chief executive of deCode, did not mince words with the WSJ: “I vehemently oppose the use of these discoveries for tailor-making children,” he said. Fertility Institutes even received a call from the Vatican urging its staff to think more carefully. Seifert withdrew his proposal.
But that does not mean he and other likeminded clinicians and entrepreneurs have forgotten about the possibility of parents molding their children before birth. “I’m still very much in favor of using genetics for all it can offer us,” Steinberg says, “but I learned a lesson: you really have to take things very, very slowly, because science is scary to a lot of people.” Most recently, a minor furor erupted over a patent awarded to the personal genomics company 23andMe. The patent in question, issued on September 24th, describes a method of “gamete donor selection based on genetic calculations." 23andMe would first sequence the DNA of a man or woman who wants a baby as well as the DNA of several potential sperm or egg donors. Then, the company would calculate which pairing of hopeful parent and donor would most likely result in a child with various traits.
Illustrations in the patent depict drop down menus with choices like: “I prefer a child with Low Risk of Colorectal Cancer “High Probability of Green Eyes” "100% Likely Sprinter" and “Longest Expected Life Span” or “Least Expected Life Cost of Health Care." All the choices are presented as probabilities because, in most cases, the technique 23andMe describes could not guarantee that a child will or will not have a certain trait. Their calculations would be based on an analysis of two adults’ genomes using DNA derived from blood or saliva, which does reflect the genes inside those adults’ sperm and eggs. Every adult cell in the human body has two copies of every gene in that person’s genome in contrast, sperm and eggs have only one copy of each gene and which copy is assigned to which gamete is randomly determined. Consequently, every gamete ends up with a unique set of genes. Scientists have no way of sequencing the DNA inside an individual sperm or egg without destroying it.
“When we originally introduced the tool and filed the patent there was some thinking the feature could have applications for fertility clinics. But we’ve never pursued the idea, and have no plans to do so,” 23andMe spokeswoman Catherine Afarian said in a prepared statement. Nevertheless, doctors using PGD can already—or will soon be able to—accomplish at least some of what 23andMe proposes and give parents a few of the choices the Freemans made about their second son.
Since Steinberg’s contentious proposal in 2009, researchers have developed a much clearer understanding of the various genes responsible for the pigments in our bodies. Forensic geneticist Manfred Kayser of Erasmus MC and his colleagues have published many studies in which they have accurately identified people’s eye and hair color by looking at their DNA. Their tests cannot recognize every possible shade, but they are specific enough to distinguish between brown, blue and mottled brown-blue eyes, as well as brown, black, blonde and red hair. Such studies are intended to help solve crimes, but clinicians at fertility clinics could easily adapt the strategies for PGD. Based on ongoing research, Manfred thinks he and other scientists will soon be able to confidently identify skin color by looking at someone’s genes as well. In the more distant future, he adds, researchers will probably learn enough to deduce the texture of a person's hair, the shape of his or her face, and the person's height.
Today, genetic analysis can also reveal the likelihood of various quirks of human biology that some people find fascinating and others might consider trivial. Take, for example, the probability that someone will experience “Asian glow." The ALDH2 gene codes for an enzyme named aldehyde dehydrogenase that converts a toxic byproduct of alcohol metabolism into a benign acid. People with only one or no working copies of the gene feel nauseated and flush red when they drink alcohol. Around 50 percent of East Asians have underactive aldehyde dehydrogenases. Earwax consistency is also relatively easy to predict with a genetic test because it is controlled by a single gene: one version of the gene produces sticky amber ear wax the other makes dry, gray, flaky earwax. A single gene also largely determines one’s ability to taste certain bitter compounds commonly found in Brussels sprouts, coffee, cabbage and other foods.
These examples of relatively straightforward relationships between genes and traits are exceptions to the daunting complexity of human genetics. Most characteristics of the human body—even seemingly simple ones like earlobe attachment, dimples and hair whorls—have stumped researchers with far more convoluted genetics than they anticipated. That's why confidently reporting eye and hair color based on DNA is a relatively recent accomplishment. In high school, you may have learned that eye color is a simple Mendelian trait in which one or two dominant copies of a gene produces brown eyes whereas two recessive versions result in blue eyes. In fact, more than a dozen genes likely interact to determine the hue of your iris. So, when it comes to something as multi-faceted as intelligence or personality, we may never have a particularly useful predictive genetic test. For the foreseeable future, then, any possibility of designer babies may be limited to rather basic—though, to many parents, important—human features: essentially, the shape and color of a child's face and body.
IVF presents another set of barriers to tailor-making children through PGD. After all, PGD does not entail actively engineering DNA inside an embryo to fit parents' specifications rather, parents select what they consider the most desirable genetic package from a group of successfully fertilized embryos. And clinicians can only fertilize as many eggs as they collect from a woman's ovaries Currently, IVF retrieves between 8 and 15 eggs on average—enough to provide parents with quite a few options, but not a large enough number to ensure that any one embryo will have more than a handful of desired traits.
As scientists continue to examine the human genome from every angle, however, they will undoubtedly uncover new genetic associations that—if they cannot promise a particular feature—will at least divulge a probability. 23andMe claims that, by sequencing your DNA, it can tell you something interesting about 60 "traits," many of which are physical characteristics or talents of some kind. As that type of knowledge continues to surface, some people will not be able to resist it, even when it rests only on a few preliminary studies. A clinic could take advantage of these insights to discreetly give couples the option of choosing more than just the sex of their child through PGD, framing it as a way to tip the scales, to—as the doctor in Gattaca says—give one's child "the best possible start." One couple would tell another. Some parents—especially the wealthy—may begin to believe they have a choice between leaving their child’s future completely to chance and helping that child in at least some small way. When Gattaca appeared in theaters in 1997, much of what the film depicted was not yet possible. Now, some of it is. What separates our society from a proto-Gattaca today is not so much scientific understanding or technology as people’s attitudes towards that technology—a much more delicate membrane.
“Unfettered development of PGD applications is providing parents and fertility specialists an increasing and unprecedented level of control over the genetic make-up of their children,” wrote Tania Simoncelli, Assistant Director for Forensic Sciences within the White House Office of Science and Technology Policy, in 2003. “Indeed, if ever there was a case for a ‘slippery slope,’ this is it. Advances in PGD, together with cloning and genetic engineering, are tending towards a new era of eugenics. Unlike the state-sponsored eugenics of the Nazi era, this new eugenics is an individual, market-based eugenics, where children are increasingly regarded as made-to order consumer products.”
An era of market-based eugenics would exterminate any lingering notions of meritocracy. Perseverance, adaptability, and self-improvement would become subordinate to to what people would see as innate talent and near certain prosperity preordained by one’s genes. Despite laws meant to prevent genetic discrimination, the world of Gattaca is a highly stratified one with two distinct classes: the valids—who have the right genes, the most prestigious jobs and the highest quality of life—and the in-valids, who were conceived in the typical fashion and are relegated to menial work and relative poverty. Eugenics also risks creating a genetically homogenous population that is far more vulnerable to disease and freak deleterious mutations than a diverse one.
But that could never happen this side of the silver screen, right?
“The demand is up,” Steinberg says. “People are liberalizing. You will see PGD done on almost every embryo in the future.”
The Girl Who Turned to Bone
Unexpected discoveries in the quest to cure an extraordinary skeletal condition show how medically relevant rare diseases can be.
When Jeannie Peeper was born in 1958, there was only one thing amiss: her big toes were short and crooked. Doctors fitted her with toe braces and sent her home. Two months later, a bulbous swelling appeared on the back of Peeper’s head. Her parents didn’t know why: she hadn’t hit her head on the side of her crib she didn’t have an infected scratch. After a few days, the swelling vanished as quickly as it had arrived.
When Peeper’s mother noticed that the baby couldn’t open her mouth as wide as her sisters and brothers, she took her to the first of various doctors, seeking an explanation for her seemingly random assortment of symptoms. Peeper was 4 when the Mayo Clinic confirmed a diagnosis: she had a disorder known as fibrodysplasia ossificans progressiva (FOP).
The name meant nothing to Peeper’s parents—unsurprising, given that it is one of the rarest diseases in the world. One in 2 million people have it.
Peeper’s diagnosis meant that, over her lifetime, she would essentially develop a second skeleton. Within a few years, she would begin to grow new bones that would stretch across her body, some fusing to her original skeleton. Bone by bone, the disease would lock her into stillness. The Mayo doctors didn’t tell Peeper’s parents that. All they did say was that Peeper would not live long.
“Basically, my parents were told there was nothing that could be done,” Peeper told me in October. “They should just take me home and enjoy their time with me, because I would probably not live to be a teenager.” We were in Oviedo, Florida, in an office with a long, narrow sign that read The International Fibrodysplasia Ossificans Progressiva Association . Peeper founded the association 25 years ago, and remains its president. She was dressed in a narrow-waisted black skirt and a black-and-white striped blouse. A large ring in the shape of a black flower encircled one of her fingers. Her hair was peach-colored.
Peeper sat in a hulking electric wheelchair tilted back at a 30-degree angle. Her arms were folded, like those of a teacher who has run out of patience. Her left hand was locked next to her right biceps. I could make out some of the bones under the skin of her left arm: long, curved, extraneous.
“It’s good to finally meet you,” she said when I walked in. Her face was almost entirely frozen she spoke by drawing her lower lip down and out to the sides. Bones had immobilized her neck, so she had to look at me with a sidelong gaze. Her right hand, resting on her wheelchair’s joystick, contained the only free-moving joint in her body. It rose and swung toward me. We shook hands.
Peeper’s condition is extremely rare—but in that respect, she actually has a lot of company. A rare disease is defined as any condition affecting fewer than 200,000 patients in the United States. More than 7,000 such diseases exist, afflicting a total of 25 million to 30 million Americans.
The symptoms of these diseases may differ, but the people who suffer from them share many experiences. Rare diseases frequently go undiagnosed, or misdiagnosed, for years. Once people do find out that they suffer from a rare disease, many discover that medicine cannot help them. Not only is there no drug to prescribe, but in many cases, scientists have little idea of the underlying cause of the disease. And until recently, people with rare diseases had little reason to hope this would change. The medical-research establishment treated them as a lost cause, funneling resources to more-common ailments like cancer and heart disease.
In 1998, this magazine ran a story recounting the early attempts by scientists to understand fibrodysplasia ossificans progressiva. Since then, their progress has shot forward. The advances have come thanks in part to new ways of studying cells and DNA, and in part to Jeannie Peeper.
Starting in the 1980s, Peeper built a network of people with FOP. She is now connected to more than 500 people with her condition—a sizable fraction of all the people on Earth who suffer from it. Together, members of this community did what the medical establishment could not: they bankrolled a laboratory dedicated solely to FOP and have kept its doors open for more than two decades. They have donated their blood, their DNA, and even their teeth for study.
Meanwhile, the medical establishment itself has shifted its approach to rare diseases, figuring out ways to fund research despite the inherently limited audience. Combined with Peeper’s dedication, this sea change has enabled scientists to pinpoint the genetic mutation that causes her disease and to begin developing drugs that could treat, and possibly even cure, it.
Although rare diseases are still among the worst diagnoses to receive, it would not be a stretch to say there’s never been a better time to have one.
When Peeper’s parents received their daughter’s diagnosis, they didn’t tell her. She enjoyed a kickball-and-bicycles childhood in Ypsilanti, Michigan, and only became aware of her disorder when she was 8.
“I remember vividly, because I was getting dressed for Sunday school,” she told me. She realized that she could no longer fit her left hand through her sleeve. “My left wrist had locked in a backwards position”—the result of a new bone that had grown in her arm.
Peeper’s doctors took a muscle biopsy from her left forearm. Afterward, she wore a cast for six weeks. When it came off, she couldn’t flex her elbow. A new bone had frozen the joint.
Over the next decade, as Peeper grew more bones—rigid sheets stretching across her back, her right elbow locking, her left hip freezing—she became accustomed to pain.
But, like most kids, she adapted. When she could no longer write with her left hand, she learned to use her right. When her left leg locked, she put a crutch under her arm and tipped her body forward to walk. She even learned how to drive. After graduating from high school, Peeper lived on her own in an apartment, taking classes at a local college.
When pain from a fall kept her in bed for three days, her parents, who had recently retired to Florida, begged her to move in with them. She caved, enrolling at the University of Central Florida. There she earned a bachelor’s degree in social work, interning at nursing homes and rehabilitation centers. In 1985, three weeks after graduating, Peeper tripped over a blanket in her parents’ home. “My hip hit the corner of an end table,” she said, “and that changed my life.”
Her body responded to the fall by growing another bone. She could feel her right hip freezing in place. She knew that if she couldn’t stop it, she would probably never be able to walk again. Before the fall, Peeper had been planning on getting a job as a social worker. Now she couldn’t even get dressed by herself. On top of it all, she was lonely. She assumed that, of the 6 billion–odd people in the world, she was the only one with a second skeleton.
“I don’t know how to explain it,” she told me. “I never dwelled on it—Is there someone else? Could there be someone else?—in my thinking. I thought I was the only one with this condition. That’s all I had ever known.”
Peeper asked her doctors back in Michigan about getting one of her locked hips replaced with an implant. They referred her to a National Institutes of Health physician named Michael Zasloff. Zasloff had been trained as a geneticist, and sometimes he would encounter patients with rare genetic disorders in 1978, he met a young girl with FOP. “I’d never seen anything quite like it,” Zasloff told me. “I had no idea what it was.”
When Zasloff asked his adviser, Victor McKusick—at the time the world’s greatest clinical geneticist—what caused fibrodysplasia ossificans progressiva, McKusick told him he didn’t have a clue. So Zasloff headed to the medical library.
The first detailed report of the disease dates back to 1736. A London physician named John Freke sent a letter to the Royal Society about a patient he had just seen:
Freke noted how superfluous bones arose from the boy’s every neck vertebra and rib: “Joining together in all Parts of his Back, as the Ramifications of Coral do, they make, as it were, a fixed bony Pair of Bodice.”
In the generations that followed, doctors recorded almost nothing more about the disease. Zasloff found only two papers from the 20th century. He was in the worst position a doctor can be in: he didn’t know how to help a young patient in pain, and he had nothing to tell her distressed parents. He decided to adopt FOP as part of his research.
As a geneticist at the National Institutes of Health, Zasloff had the greatest medical resources he could desire at his disposal. But he still struggled to get his hands on information about FOP—largely because he was hard-pressed to find anyone who had it. Zasloff took over the care of a few patients who had been referred to McKusick, and he began accepting new referrals. But many doctors didn’t even know what the disease was, let alone how to diagnose it. Over a decade, Zasloff managed to examine 18 people with FOP. That made him the world’s expert on the disease.
When Peeper visited Zasloff in 1987, he told her that a hip implant would be impossible. He had learned this lesson the hard way. Years earlier, he’d taken a biopsy from a patient’s thigh, and the trauma had triggered the growth of a new bone. He suspected that the biopsy Peeper’s doctors had taken from her arm years earlier had caused it to freeze.
Before meeting Peeper, Zasloff had mostly treated children, whose youth and parents had buffered them from a full awareness of their fate. But in Peeper, Zasloff could sense the encroachment of profound solitude. She knew no one who could begin to understand her experience. So although Zasloff could offer her no medicine, he realized he could put her in touch with his other patients.
To Peeper, the list of 18 names Zasloff gave her was a revelation. “I thought, I need to do something to connect everyone, to let everyone know all these people are out there,” she said. Back home in Florida, she sent a letter and questionnaire to everyone on the list. Some of Zasloff’s patients had died, but 11 surviving ones wrote back: an artist and a bookkeeper, a little boy and a middle-aged woman.
Peeper responded to each letter, and she and her correspondents became friends. She began arranging to meet some of them, in order to lay eyes for the first time on someone else with her condition. “I just assumed that everybody was going to look like me,” she told me. But FOP is fickle in the positions in which it freezes people. One woman Peeper met was locked in a horizontal position and lived on a gurney. Another’s torso was angled backwards. Peeper met a girl who had lost an arm to a misdiagnosis: her doctors had thought the swelling in her left arm was a tumor. When they performed surgery, her arm began bleeding uncontrollably and they had to amputate it.
Four times a year, Peeper sent out a newsletter she called “FOP Connection.” She included questions people sent her—What to do about surgery? How do you eat when your jaw locks?—and printed answers from other readers. But her ambitions were much grander: she wanted to raise money for research that might lead to a cure. With a grand total of 12 founding members, she created the International Fibrodysplasia Ossificans Progressiva Association ( IFOPA ).
Peeper didn’t realize just how quixotic this goal was. FOP had never been Zasloff’s main area of research. As the director of the Human Genetics branch of the NIH, he had discovered an entirely new class of antibiotics, and in the late 1980s, he left the NIH to develop them at the Children’s Hospital of Philadelphia. His departure meant that no one—not a single scientist on Earth—was looking for the cause of FOP.
And no one was likely to. Zasloff’s powerful position in the scientific establishment had afforded him the liberty to study the disease, but for younger scientists looking to make their names, rare diseases were a big risk. FOP was just as complex as diseases that were 100,000 times more common. But with so few patients to study, the odds of failing to discover anything about it were high. When the NIH’s grant reviewers decided which projects to fund, those odds often scared them away.
For Peeper’s plan to work, she’d need someone who was prepared to risk his or her career.
One day last November , Frederick Kaplan, the Isaac and Rose Nassau Professor of Orthopedic Molecular Medicine in Orthopedic Surgery at the University of Pennsylvania, was sitting cross-legged on the floor of an exam room. Kaplan, 61, is a small, precise man. On the day I visited his clinic, he was dressed in a blue shirt, charcoal pants, and a tie covered in faces that looked like they had been drawn by children.
“How’s kindergarten?” he asked, looking up.
Above him, sitting in a chair, was a dark-haired 5-year-old from Bridgewater, New Jersey, named Joey Hollywood. His parents, Suzanne and Joe, sat in the corner of the exam room. Joey liked towering over his doctor. He smiled down at Kaplan as he kicked his legs under one arm of the chair and then slipped them under the other. “I ride the bus,” he said.
“Joey,” Kaplan said, “let’s play Simon Says.” Kaplan stood up and slapped his hands to his sides. Joey swung out of his chair and stood as well. Kaplan twisted his head to the left to look at Joey’s parents. Joey did not turn his neck. Instead, he pivoted on his feet to turn his entire body. Kaplan turned back to Joey and raised his arms to the ceiling. Joey tipped up his hands at his sides.
“He’s quite adaptive,” Joe said. “At school they were horrified to find he was using his face to turn on light switches. So they gave him a stick.”
“Can we slip that nice shirt off?,” Kaplan asked. “I’m just going to check your back.”
Joey let Suzanne draw his shirt over his head, revealing two tangerine-size mounds on his back, each faintly filigreed with veins.
Joey was born with malformed big toes, like Peeper and most other people with FOP. A few months later, a lump appeared on his back. “When I saw it,” Suzanne told me, “I said, ‘That can’t be normal.’ ”
Joey’s symptoms came and went, but not until the fall of 2011, when he was 4, did it become clear that something was seriously wrong. Bones had grown in his neck, freezing it hard as stone. The Hollywoods were referred to Kaplan, who has replaced Zasloff as the world’s leading FOP expert. A few months later, Joey’s right arm fused to his ribs, and more swellings appeared on his back.
As Joey munched on pretzels, his parents asked Kaplan about the risks of hearing loss (in young patients, ear bones sometimes fuse together), and about what had happened to Kaplan’s other patients.
“I’ve seen 700 patients with FOP around the world, and it’s clear that there’s a lot of different ways to divide patients,” Kaplan said. One identical twin might be only mildly affected, while the other would be trapped in a wheelchair. Some patients developed a frenzy of bones as children, and then inexplicably stopped. “I’ve seen it go quiet for years and years.”
“So it’s very unpredictable,” Joe said, hopefully.
Suzanne looked over at Joey. “This is my son every day,” she said. “I don’t want to have him look back at his childhood and say, ‘My parents were always sad.’ ”
“When you’re here, we focus on FOP,” Kaplan told her. “Remember the things that are important and helpful for Joey to live as safe a life as he can.” He shrugged his shoulders. “And then forget the FOP.”
When Kaplan started out as an orthopedic surgeon in the late 1970s, he treated patients with a wide range of common bone diseases, such as osteoporosis and rickets. In the mid-1980s, however, he became interested in genetics. He suspected that for many of his patients’ treatments, a pipette of DNA would become more useful than a bone saw.
In 1988, Kaplan met Michael Zasloff. Zasloff had just left the NIH and moved to Philadelphia, but he was still hoping to find someone to take up his FOP research. He’d heard through the Penn grapevine that Kaplan had become interested in genetics, so when he spotted him at a clinic, Zasloff introduced himself and immediately asked Kaplan whether he had heard of the disease.
Kaplan did in fact have two adult patients with the condition, but it held no unique interest for him. Then Zasloff told Kaplan about an idea he was playing around with. Some scientists had recently injected a kind of protein called BMP into mice and found that the animals developed little bony marbles in response. Zasloff wondered whether extra BMP might be the secret to FOP.
He could tell Kaplan was curious. He suggested they work on the disease together.
“I don’t think you want me in your lab,” Kaplan told him. “I’m an orthopedic surgeon. I’m not a scientist.”
Zasloff persisted, asking Kaplan to join him for some upcoming appointments he had with young FOP patients, including a baby named Tiffany Linker.
“That was it,” Kaplan told me. “In an adult, you see what’s already past. When you meet a child, it’s like seeing a beautiful building, and a plane’s about to destroy it.”
Kaplan began by setting up a space in one of Zasloff’s labs and learning how to conduct molecular-biology experiments. Within two years, his obsession had surpassed even Zasloff’s, and he’d devoted himself entirely to the disease. His colleagues were mystified at the time, rare diseases were still considered professional suicide. “They would say, ‘You are absolutely insane to work on this,’ ” Kaplan recalls.
Meanwhile, in Florida, Peeper was building her network. When families got an FOP diagnosis, they would find their way to her organization and talk with Peeper. She put her education in social work to good use, introducing frightened families to the logistics of life with FOP. “She gave me a lot of hope,” says Holly LaPrade, a Connecticut woman who was 16 when she first spoke to Peeper. “She told me how she went to college, how she had a degree, how she had founded this organization, and about all the people she had become friends with.”
Peeper asked Kaplan, whom she’d met through Zasloff, to become IFOPA ’s medical adviser, and he traveled to Florida to attend the occasional gatherings Peeper organized for fellow patients and their families. These events were a medical boon for him, offering the rare opportunity to examine dozens of patients in a single weekend. From those exams and conversations, Kaplan began assembling a natural history of the disorder.
The group’s members gave him more than their stories and DNA: they began raising money. Nick Bogard, whose son Jud had been diagnosed with the disease at age 3, organized a golf tournament in Massachusetts that raised $30,000. That money allowed Kaplan to host the first scientific conference about FOP, in 1991. Other families hosted barbecues, ice-fishing tournaments, swim-a-thons, bingo nights. In 2012 alone, Peeper’s organization raised $520,000 for research. That’s not much compared with, say, the $1 billion that the NIH distributes each year for diabetes research. But these funds were crucial for Kaplan, who sought to escape the rare-disease trap. IFOPA ’s money—as well as gifts from other private donors and an endowment accompanying Kaplan’s professorship at Penn—made it possible for him to work single-mindedly on FOP for more than two decades.
In 1992, Kaplan hired a full-time geneticist named Eileen Shore to help establish a lab for the disorder. Shore had worked on fruit-fly larvae as a graduate student, and as a post-doctoral researcher, she had studied the molecules that allow mammal cells to stick together as they develop into embryos. Kaplan didn’t mind that Shore knew almost nothing about FOP. What he wanted in a geneticist was an expertise in development: the mystery of how the body takes shape.
First, they set out to understand how the disease worked. Based on their conversations with patients, they learned that bone growth could be caused by even slight trauma to muscles. A tumble out of bed or even a quick brake at a stoplight might cause a flare-up—a swelling that may or may not lead to new bone growth. A visit to the dentist could do the trick, if the jaw was stretched too far. Even a flu shot to the biceps was enough. Some flare-ups subsided without any lasting effect, while others became nurseries for new bone.
Most people with the condition develop their first extra bone by the age of 5. Their second skeletons usually start around the spine and spread outward, traveling from the neck down. By 15, most patients have lost much of the mobility in their upper bodies.
Ninety percent of people with FOP are misdiagnosed at first, and many doctors take biopsies before they realize what they’re dealing with. “I see the scars, and I say to the parents, ‘Can you get me the biopsy?,’ ” Kaplan says. “Because it’s sitting in a closet somewhere. Those samples are like gold.”
Examining the biopsies, Kaplan, Shore, and their students worked out the microscopic path of FOP: At the start of a flare-up, immune cells invade bruised muscles. Instead of healing the damaged area, they annihilate it. A few progenitor cells then crawl into the empty space, and in some cases give rise to new bone.
“Your muscle isn’t turning to bone,” says Shore. “It’s being replaced by bone.”
Everything Shore and Kaplan observed fit nicely with Zasloff’s original theory: FOP is the result of cells that produce too much BMP. To test that idea, Shore and Kaplan drew blood from their patients. (This procedure doesn’t trigger new bone growth, remarkably enough.) In 1996, they reported in The New England Journal of Medicine that the blood cells of people with the condition contain an abundance of a particular protein called BMP4. For the first time, scientists had found a molecular signature of the second skeleton. They hoped they had also found a path toward a cure.
Eighty percent of rare diseases are caused by a genetic mutation. For example, severe combined immunodeficiency—the “bubble boy” disease that robs children of an immune system—most commonly arises when a gene called IL2RG is altered. Normally, the gene helps signal immune cells to develop. If the signal goes quiet, children never gain a full immune system and can’t fight infections.
To treat rare diseases, scientists first look for the broken gene. Kaplan and Shore suspected that FOP was caused by a genetic mutation that led the body to make too much BMP4. In the early 1990s, they didn’t have access to today’s sophisticated genome-sequencing tools, so they began sorting slowly through the human genome’s 20,000 genes.
“Based on what we already knew about FOP, we could make an educated guess and say, ‘I think this is a likely gene,’ ” Shore told me. “And then we sequenced it and looked for mutations.”
The first candidate was, of course, the gene that produces BMP4. Shore and Kaplan sliced this gene out of cells from people with FOP, sequenced it, and compared it with a version taken from people without the condition. Unfortunately, the two versions were a perfect match.
When Kaplan’s colleagues heard the disappointing news, they offered him their sympathies. A mutation of the BMP4 gene would have been such a nice story, they said. Kaplan kept searching. If the culprit wasn’t that particular protein, he reasoned, it might be one of its known associates. By the late 1990s, scientists had discovered a few of the other genes that BMP4 depends on to get its job done—genes that are required to switch the protein on, for example, and genes that make receptors onto which it can latch. Kaplan and Shore inspected gene after gene, year after year. But they failed to find a mutation unique to people with FOP.
Meanwhile, IFOPA set up a Web site, which attracted anxiously Googling parents, many from other countries. The group arranged for some of those families to attend its gatherings, along with foreign doctors who wanted to learn how to recognize the disorder. When these doctors went home, they added more patients to the network. Eventually, this broadening community led Kaplan to patients who had children who also suffered from the disorder.
Studying families is one of the best ways to pinpoint a mutated gene. By comparing the DNA of parents and children, geneticists can identify certain segments that consistently accompany a disorder. Because most people with FOP never have children, Kaplan and Shore had assumed they couldn’t use this method. But then the online patient network began surfacing exceptions: a family in Bavaria, one in South Korea, one in the Amazon. All told, seven families emerged Kaplan traveled to meet a few of them and draw their blood.
Back in Philadelphia, Shore and her colleagues examined the DNA from these samples and narrowed down the possible places where the FOP gene could be hiding. By 2005, they had tracked the gene to somewhere within a small chunk of Chromosome 2. “It was a huge step,” says Shore. “But there were still several hundred genes in that region.”
By a fortunate coincidence, scientists at the University of Rochester had just studied one of those several hundred genes. They had discovered that the gene, called ACVR1, made a receptor. The receptor grabbed BMP proteins and relayed their signal to cells. In the margin of the paper in which the scientists described ACVR1, Kaplan wrote, “This is it.”
Shore and her staff inspected the gene as it occurred in people with FOP. The same mutation appeared in precisely the same spot in every patient’s cells. Once they had double- and triple-checked their results, once they had written a paper describing the mutation, Kaplan and Shore planned a press conference. In the spring of 2006, Kaplan called Peeper to tell her something she had doubted she would live long enough to hear.
“We need you to come to Philadelphia,” he said. “We’ve found the gene.”
A rare disease is a natural experiment in human biology. A tiny alteration to a single gene can produce a radically different outcome—which, in turn, can shed light on how the body works in normal conditions. As William Harvey, the British doctor who discovered the circulation of blood in the 17th century, observed more than 350 years ago, “Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows tracings of her workings apart from the beaten paths.”
Take Jeannie Peeper’s second skeleton: In many ways, it is profoundly normal. The new bones contain marrow. If fractured, they heal nicely. They are much like the bones of other mammals, of reptiles, of fish. In all those animals, bones develop under the control of the same network of genes—a network that, having shaped the bodies of our pre-vertebrate ancestors, is older even than bone itself.
What is not normal is when these bones form. Normally, new bones develop only in embryos. As children grow, those bones extend when those bones break, new cells repair them. But almost no one develops entirely new bones outside the womb.
Finding the FOP mutation was a coup, but Kaplan and Shore still had no idea how it worked. They set about studying baby teeth from young patients, as well as mice they genetically altered, to observe the mutation in action. Seven years later, they had pieced together an understanding of the far-reaching effects. The ACVR1 receptor normally grabs onto BMP proteins and relays their signal into cells. But in people with FOP, the receptors become hyperactive. The signal they send is too strong, and it lasts too long. In embryonic skeletons, the effects are subtle—for example, deformed big toes. Only later, after birth, does the mutation start to really make its presence known. One way it does this, Shore and Kaplan learned, is by hijacking the body’s normal healing process.
Say you bruise your elbow, killing off a few of your muscle cells. Your immune cells would swarm to the site to clear away the debris, followed by stem cells to regenerate the tissue. As they got to work, the two kinds of cells would converse via molecular signals. Shore and Kaplan suspect that BMP4 is an essential part of that exchange. But in someone with FOP, the conversation is more of a screaming match. The stem cells kick into overdrive, causing the immune cells not just to clear the damage but to start killing healthy muscle cells. The immune cells, in turn, create a bizarre environment for the stem cells. Instead of behaving as if they’re in a bruise, these cells act as if they’re in an embryo. And instead of becoming muscle cells, they become bone.
In the context of FOP, new bone is a catastrophe. But in other situations, it could be a blessing. Some people are born missing a bone, for example, while others fail to regenerate new bone after a fracture. And as people get older, their skeletons become fragile old bone disappears, while bone-generating stem cells struggle to replace what’s gone.
FOP may be an exquisitely rare bone condition, but low bone density is not: 61 percent of women and 38 percent of men older than 50 suffer from it. The more bone matter people lose, the more likely they are to end up with osteoporosis, which currently afflicts nearly one in 10 older adults in the United States alone. For decades, doctors have searched for a way to bring back some of that bone. Some methods have helped a little, and others, such as estrogen-replacement therapy, have turned out to have disastrous side effects in many women.
Giving someone a second skeleton is not a cure for osteoporosis. But if Kaplan and his colleagues can finish untangling the network of genes that ACVR1 is a part of, they could figure out how to use a highly controlled variation on FOP to regrow bones in certain scenarios. “It’s like trying to harness a chain reaction at the heart of an atom bomb,” he told me, “and turning it into something safe and controllable, like a nuclear reactor.”
This would not be the first time the study of a rare disease unearthed new treatment options for more-common afflictions. In 1959, Don Frederickson of the National Heart Institute discovered a strange disorder, now called Tangier disease, which caused tonsils to turn orange. The color resulted from a buildup of cholesterol, he found. Forty years later, scientists identified the mutated gene that causes Tangier disease and figured out how it helps shuttle cholesterol out of cells. Researchers are now trying out drugs that boost the performance of this gene as a way to lower the risk of heart disease.
Only recently, though, has medicine begun to formally recognize the value of the “secret mysteries” that rare diseases can reveal.
Kaplan’s office at the University of Pennsylvania is loaded like a well-packed shipping container. When I visited him there in November, he had to scooch through the narrow spaces between his desk and filing cabinets filled with X‑rays and medical reports. Framed photographs of his patients covered most of the surfaces and blocked part of his narrow window.
Kaplan pointed to a picture of Tiffany Linker, the patient who, as a baby, had persuaded him to stake his career on FOP. He told me that last July, at 23, Linker had passed away. “It’s been a rough year,” he said.
When I talked with young people with the disease, though, I was struck by their optimism. In the 1980s, Peeper had to type out letters to reach a dozen other people with her condition. Today, someone recently diagnosed with FOP can hop on Facebook, pose a question—how to drink from a glass if you can no longer raise it to your mouth, for example—and get an immediate answer from one of hundreds of people with the same disease.
One frequent topic of conversation within today’s FOP community is the possibility that a cure, or at least a treatment, may not be far away. As Kaplan, Shore, and other scientists decipher the cause of the disease, some promising drugs are emerging that may be able to stop it. At the Children’s Hospital of Philadelphia, for example, researchers have been testing a drug based on a certain type of molecule that can prevent new bone from growing in FOP mice by breaking the chain of signals that command progenitor cells to turn into bone.
The search for a cure is accelerating, thanks in part to new programs designed to incentivize the study of rare diseases. A different drug option, currently being investigated by a team of scientists at Harvard Medical School, has benefited from these programs. In a broader experiment in 2007, the scientists tested more than 7,000 FDA-approved compounds on zebra-fish embryos, watching for whether any of them affected the animals’ development. One molecule caused the zebra fish to lose the bottom of its tail fin. When the scientists looked more closely at this compound, they discovered that it latched onto a few receptors, including ACVR1—the receptor that Shore and Kaplan had recently discovered was overactive in FOP patients.
The Harvard researchers wondered whether the drug could work as a treatment for FOP. They tinkered with the compound, creating a version that had a stronger preference for ACVR1 than other types of receptors. When they tested it on mice with an FOP-like condition, it quieted the signals from ACVR1 receptors, thereby stopping new bones from forming.
After publishing its results in 2008, the Harvard team failed to find a pharmaceutical company willing to invest in pushing the drug into human trials. The problem wasn’t that drugs for rare diseases can’t turn a profit. In fact, once they’re on the market, they can be quite lucrative. Insurance companies are willing to cover drugs that can cost tens of thousands of dollars a year if they eliminate even-more-costly types of care. But bringing a drug to market can be a hugely expensive gamble—one that companies weren’t willing to take for a potential treatment for a rare disease.
In 2011, the Harvard scientists found a backer: a new NIH program called Therapeutics for Rare and Neglected Diseases. This program collaborates with scientists to develop rare-disease drugs that can’t survive the harsh economics of the pharmaceutical establishment.
“They’re almost like the pharmaceutical company and we’re the scientific advisory board,” says Ken Bloch, one of the Harvard scientists. “From my perspective, it’s spectacular, because it fills that gap.” Researchers from the NIH program are currently running preclinical tests of the Harvard team’s drug on mice to make sure it doesn’t have any unexpected toxic side effects. They’re also tinkering with the drug to see whether they can create more-potent forms—all with an eye to getting it ready for clinical human trials.
If this particular drug, or any other one, gets to clinical trials, it will face another set of hurdles. A typical trial for a drug treating a common disease like diabetes might involve thousands of patients. That scale makes it possible to run statistical tests ensuring that the drug really is effective. It also allows scientists to detect side effects that might affect relatively few patients. But even if you enrolled every FOP patient in the United States, a trial would still be a fraction of the size of a conventional one.
In recent years, the FDA has responded to this bind by smoothing out the approval of drugs for rare diseases. If doctors can’t find thousands of patients to enroll in a clinical trial, they are now allowed to conduct smaller trials that meet certain guidelines. Obtaining a detailed medical history for each subject in a smaller trial, for example, makes his or her individual response to a certain drug all the more revealing.
This strategy can only work, however, if a high percentage of patients with a rare disease are willing to join a clinical trial. And that’s where people like Peeper become invaluable. Thanks to the active global community she created, any clinical trial for an FOP drug now has hundreds of potential participants.
On one of my visits to Philadelphia, Kaplan took me to see Harry. We met in the pillared entryway of the College of Physicians of Philadelphia, a medical society founded in 1787. Kaplan was wearing a tie covered in skeletons. We descended a flight of stairs to the Mütter Museum, an eerie basement collection of medical specimens. We passed cabinets filled with conjoined twins, pieces of Albert Einstein’s brain, and a cadaver turned to soap. We walked up to a glass case, which a curator opened for us. Inside loomed a skeleton beyond imagining.
It belonged to Harry Eastlack, a man with fibrodysplasia ossificans progressiva who asked shortly before he died in 1973 that his body be donated to science. Harry stands with one leg bent back, as if preparing to kick a soccer ball, and the other hinged unnaturally forward his arms hover in front of his body his back and neck curve to one side, forcing his eye sockets to gaze at the floor. Before a typical skeleton goes on display, the bones have to be wired and bolted together. Eastlack’s skeleton needed almost no such help. It is a self-supporting scaffolding, its original structure overlain with thorns, plates, and strudel-like sheets.
“The first time I saw Harry, I stood here mesmerized,” Kaplan told me, shining a red laser on a ligament in Harry’s neck that had become a solid bar running from the back of his head to his shoulders. “I’m still learning from him.”
Thanks to Kaplan’s enduring fascination with her disease, Jeannie Peeper can now realistically imagine a time—perhaps even a few years from now—when people like her will take a pill that subdues their overactive bones. They might take it only after a flare-up, or they might take a daily preventative dose. In a best-case scenario, the medication could allow surgeons to work backwards, removing extra bones without the risk of triggering new ones.
At 54, with an advanced case of FOP, Peeper does not imagine that she’ll benefit from these breakthroughs. But she is optimistic that her younger friends will, and that one day, far in the future, second skeletons will exist only as medical curiosities on display. All that will remain of her reality will be Harry Eastlack, still keeping watch in Philadelphia, reminding us of the grotesque possibility stored away in our genomes.
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What Twins Can Teach Us About Nature vs. Nurture
The relative importance of nature and nurture has been debated for centuries, and has had strong — and sometimes misguided — influences on public policy.
The day my identical twin boys were delivered by an emergency cesarean, I noticed a behavioral difference. Twin A, who had been pushed against an unyielding pelvis for several hours, spent most of his first day alert and looking around, while Twin B, who had been spared this pre-birth stress, slept calmly like a typical newborn.
My husband and I did our best to treat them equally, but Twin A was more of a challenge to hold — we called him “our lobster baby” — while Twin B was easily cuddled. As the boys developed, we saw other differences. Twin B rehearsed all the ambulatory milestones — crawling, walking, cycling, skating, etc. — while his twin watched, then copied the skill when it was mastered.
Although they shared all their genes and grew up with the same adoring parents, clearly there were differences in these boys that had been influenced by other factors in their environment, both prenatal and postnatal.
The relative importance of nature and nurture to how a child develops has been debated by philosophers and psychologists for centuries, and has had strong — and sometimes misguided — influences on public policy.
The well-intentioned Head Start program, for example, was designed to give children from deprived environments an academic leg up. But it might have been more effective to teach their caregivers parenting and nurturing skills, as well as how to enrich the children’s environment and resist bad influences.
Children learn from what they see around them, and if what they mainly experience is violence, abuse, truancy and no expectations for success, their chances for a wholesome future are compromised from the start. As my son Erik Engquist, a fellow journalist who was Twin A, put it: “Genes define your potential, but your environment largely determines how you turn out. The few who escape negative influences are outliers.”
However, if the genetic potential is there, having even one loving, supportive adult in a child’s life can make a difference in how he or she grows up.
My sister-in-law Cindy Brody is a classic example. As she tells it, both her great-grandmother and grandmother escaped from abusive relationships and gave their children to family and friends to rear. Cindy’s mother ended up with two nurturing adoptive parents and she, in turn, nurtured and loved her two daughters. But her mother died when Cindy was only 8 years old, leaving her and her sister, she said, “with a cold, aggressive, shaming father who believed in corporal punishment” and remarried a woman with two sons who sexually attacked the girls.
Cindy fled home at 17, determined “not to let anyone hurt me ever again.” Buoyed by an inner strength and the nurturing, strength and independence fostered by the women in her life — her mother, grandmother and an aunt — Cindy said she was able to fend for herself, get a good job, live her dreams and be a nurturing, loving mother for her own son and daughter.
Decades-long studies of identical and fraternal twins — and in some cases, triplets — who had been separated at an early age and reared in what were often strikingly different environments have documented the important interaction of nature and nurture and help to explain the relative contributions of each to how a child develops.
“A strict dichotomy between genes and environment is no longer relevant they work in concert,” said Nancy Segal, a psychologist at California State University, Fullerton, and herself a fraternal twin who has made a career of twin studies, starting with the famous Minnesota Twin Family Study. She is the author of “Born Together — Reared Apart: The Landmark Minnesota Twins Study,” published in 2012 by Harvard University Press.
The many studies of thousands of pairs of identical and fraternal twins, both those reared together and those reared apart, have made it possible to assess the relative contributions of genes and the environment to a large number of characteristics.
“It’s trait-specific,” Dr. Segal said, with different ratios depending on the characteristic in question. “In an individual person, the contributions of genes and the environment are inestimable,” she explained, “but on a population basis we can estimate how much person-to-person variation is explained by genetic and environmental differences.”
The studies of reared-apart twins have shown that in general, half the differences in personality and religiosity are genetically determined, but for a trait like I.Q., about 75 percent of the variation, on average, is genetic, with only 25 percent influenced by the environment.
Furthermore, there can be gender differences in the influence of genetics. A study of 4,000 pairs of twins in Sweden found that genetics has a stronger influence on sexual orientation in male twins than in female twins.
As I observed in my own sons and know from studies of heart disease, genes confer a potential, but the environment often determines whether that potential is expressed. For example, perfect pitch tends to run in families and may even be tied to a single gene, but without early musical training, the trait is unlikely to be expressed.
In the documentary “Three Identical Strangers,” about identical male triplets separated at birth, there were differences in their susceptibility to mental illness, with the one who was reared by an authoritarian father more seriously affected than the two with warmer, more nurturing parents.
Genetics researchers now know that while an individual’s DNA is essentially immutable, a wide range of environmental factors can confer what are called epigenetic differences. Epigenetics influences which genes in an individual’s genome may be turned on or turned off. Such factors as exercise, sleep, trauma, aging, stress, illness and diet have been shown to have epigenetic effects, some of which can be passed on to future generations.
Researchers are seeking ways to deliberately alter gene expression in hopes of finding preventives or treatments for diseases like diabetes with a strong genetic component.
There can also be changes in the genome of an identical twin when the egg divides, resulting in a defect in a particular gene, Dr. Segal said. In a pair of identical twin girls, one can experience a phenomenon called X-linked inactivation. Two of the identical Dionne quintuplets were colorblind as a result of such a genetic effect.
Dr. Segal, who has also written “Twin Misconceptions: False Beliefs, Fables, and Facts About Twins,” said the studies highlight the importance of keeping twins, especially identical twins, together when they are adopted. As was depicted in the documentary, Dr. Segal said, “The triplets deeply resented having been separated. They lost out on wonderful years they could have had together. There was an immediate bond, an understanding of one another, that was obvious as soon as they found each other.”
What are the laws of inheritance?
Interestingly enough, genes are passed down from generation to generation in certain patterns, which were first studied by Gregor Johan Mendel. Mendel was originally a priest, but his keen and observant eye drove him to study the characteristics of pea plants. He spent years studying the differences in their height, the color of their flowers, the type of seeds, etc., based on the pairings of their reproduction, and his praiseworthy research earned him the title by which he is now known: the father of modern genetics.
Characters of pea plants studied by Mendel (Photo Credit: Emre Terim/Shutterstock)
Before we deal with the laws of inheritance, let us take a look at alleles: an allele is, in simple terms, an alternative form of a gene. Any gene can have several alleles. For example, a gene for height will have two alleles, short and tall. A gene for color can also have two alleles, such as red and white. Alleles in a certain combination result in a trait!
According to Mendelian genetics, there are three laws of inheritance. The Law of Dominance states that in one gene, one allele is dominant over the other. This &ldquoother&rdquo allele is called a recessive allele. Generally, a pea offspring with one tall allele and one dwarf allele proves to be tall. This means that the tall allele is dominant over the other.
The Law of Segregation states that alleles separate during the formation of the male and female gametes, which means that only one allele for height comes from the father, while the other allele comes from the mother. These alleles combine randomly when the sperm and ovum fuse. Finally, the Law of Independent Assortment states that alleles of one gene do not mix with alleles of another gene. For example, an allele for height won&rsquot mix with an allele for eye color!
While it’s clear that parents have a large influence on their children’s intelligence, how they raise their children may be just as important as which genes they pass on. For example, a 2012 study from Washington University in St. Louis found that having a loving and nurturing mother significantly contributed to a child’s eventual intelligence. In the study, the team observed that children whose mothers nurtured them early in life had a larger hippocampus, an area of the brain linked to learning and memory.
“I think the public health implications suggest that we should pay more attention to parents’ nurturing, and we should do what we can as a society to foster these skills because clearly nurturing has a very, very big impact on later development,” lead study author Dr. Joan L. Luby explained in a statement.
Other research has suggested that playing a musical instrument early in life could be a strong predictor of academic success. In a 2014 study, researchers from the University of Toronto found that musicians' brains were more active than the non-musicians' brains, and they performed better on cognitive tests.
Does Music Make You Smarter? Brain Imaging Technology Says Yes, In More Ways Than One: Read Here
Genes And Intelligence: It's All Or Nothing When It Comes To Academic Success In All Subjects: Read Here