Does testosterone make you mean?

The risk-taking male hormone is blamed for everything from sexual violence to the financial crisis, but some researchers are starting to question the supposed links

Charles Ryan has a clinic in San Francisco at which he regularly relieves men of their testosterone. This chemical castration, as it is sometimes known, is not a punishment, but a common treatment for prostate cancer. Testosterone doesnt cause the disease (currently the third most deadly cancer in the UK), but it fuels it, so oncologists use drugs to reduce the amount produced by the testicles.

Ryan gets to know his patients well over the years, listening to their concerns and observing changes in them as their testosterone levels fall. Because it involves the so-called male hormone, the therapy poses existential challenges to many of those he treats. They know that every day, millions of people from bodybuilders and cheating athletes to menopausal women enhance their natural levels of testosterone with the aim of boosting their libido, muscle mass, confidence and energy. So what happens when production is suppressed? Might they lose their sex drive? Their strength? Their will to win?

The fears are not always groundless. Side-effects can also include fatigue and weight gain. But Ryan has witnessed positives, too. As professor of medicine and urology at the University of California, he has noticed that the medical students who have passed through his clinic in the 18 years that he has been treating prostate cancer invariably comment: Dr Ryan, your patients are so nice. He replies, jokingly: Its because they dont have any testosterone. They cant be mean.

Could there be some truth in that glib reply? Ryan knew his patients hadnt always been so kind. Before being robbed of their testosterone, they might have been personable and adept at small talk, but they werent nearly as interested in other people. He could feel a hypothesis coming on: that as mens testosterone levels lower, their capacity for empathy will rise. In his new book, The Virility Paradox, he argues that the fact that reducing testosterone in these ageing men may lead to increased empathy, more emotional engagement in relationships and a softening of aggression could be something of a silver lining.

Ryan started measuring his patients empathy quotients, using a survey developed for studying autism. Its too early to release detailed results, he says, but we do see increases in the empathy scores in many patients on the treatment.

He also dived into the literature on testosterone, attempting to understand what exactly was happening to them. Try as he might, however, he found little conclusive evidence for many of the claims made about testosterone, such as a link between hormone levels and risk-taking or sexual violence. Theres so much ambiguity in the science, he says. Many of the studies had been carried out on disappointingly small numbers of people.

Ryan is one of several researchers who are questioning the accepted wisdom about testosterone. It is often wheeled out as an excuse for patriarchal society, in arguments along the lines of: women, with their lower testosterone levels, have evolved to nurture and multitask in the domestic sphere, while men are hardwired to take risks, compete and furnish as many women as possible with sperm, thus ensuring the future of the species. But, as Ryan points out, obviously behaviour and cognition are extraordinarily complex and dont pivot on one molecule.

The psychologist Cordelia Fine makes a compelling case that it is our culture rather than our hormones that most influences gendered behaviours. As she writes in Testosterone Rex (winner of the Royal Societys science book prize for 2017) testosterone has been blamed for the financial crash of 2007-08, yet studies show that, although women have lower levels than men, they can have a higher appetite for risk even when it comes to financial decisions. She uncovered similar stories when it came to the evolutionary need for more sexual partners (more babies get made if women sleep around, too) and competition for status.

Fines pluck in challenging the scientific status quo could itself be viewed as classic testosterone-fuelled behaviour. She has cojones, you might say. She asserts that many typically female behaviours, such as deciding to have babies, are riddled with risk, only womens risks dont seem to count when it comes to testosterone mythology.

While Ryan comes at the subject from a different angle, both authors highlight how little research there is into testosterone in women. And yet we know it is vital to them (for example, oral contraception reduces testosterone levels, which can lead to low mood and libido). It can also influence sexual orientation, Ryan writes, with studies showing that self-described lesbians are likely to have [indications of] higher foetal testosterone levels than women who identify as heterosexual.

The lack of research, meanwhile, hasnt prevented a fierce debate about testosterones role in womens sports, with high levels seen as conferring an unfair advantage. The athlete Caster Semenya, who won a gold medal in the womens 800m at the 2016 Olympics, has extremely high natural testosterone levels for a woman. She had to prove her gender, and medically suppress the hormone before competing (although this ruling is currently suspended). Meanwhile, in 2016, the International Olympic Committee ruled that transgender women could compete without having had surgery, on condition that their testosterone levels were no higher than cisgender womens.

Not that testosterone levels are consistent in anyone. They rise and fall all the time, according to season, health, relationship and parental status, age, time of day (higher in the mornings) and emotional responses. When a man hears a woman cry, his testosterone goes down. When a person cares for their child, the bonding or love hormone oxytocin rises, while testosterone falls. If a threat to status or territory is perceived, testosterone rises again. Its the situations, the culture even, that seem to pull the hormones strings. Testosterone, in both men and women, also works in a feed-forward system: when you win at something, you get a spike in testosterone that as well as making you feel dominant and confident, increases your sensitivity to the hormone encouraging further swagger and quests to win.

Another of the hazards when studying testosterone is that there are three significant measures of how strong its force is in you. You can check levels in the bloodstream, but we already know how they fluctuate. The second measure is the number and sensitivity of androgen receptors, which vary significantly from person to person. (Testosterone is one of three hormones known as androgens, and receptors are what allow them to act on the cells in our bodies.) Third is the amount of testosterone to which we were exposed in the womb, most of which is produced by the foetus itself. This exposure is harder to gauge, although the difference between the lengths of the index and ring fingers is often used as a marker. The smaller the difference, the theory goes, the greater that foetal exposure.

This complex web, says Ryan, means that responses to hormonal suppression therapy are highly variable, based on [individuals] intrinsic biology. I have patients whose testosterone I take away and they dont have any [unwanted] side-effects. In fact, they say: I feel better. My brain is less clouded with intrusive thoughts about sex and things like that.

In a sort of mirror-image experiment, the writer Ann Mallen recently told how she accidentally rubbed testosterone cream into her skin every day for a month due to a mixup at the pharmacy. She wrote in the Washington Post that her sexual appetite became a constant distraction, as did her new persistent bouts of irrational anger. She concluded that underneath the high-pitched whine of our sex hormones, we are neither [male nor female].

Because women are more responsive than men to supplemental testosterone, they were used in one of the key studies into how testosterone essentially removes the burden of empathy from moral decision-making. Its known as the trolley car experiment. Picture a runaway tram hurtling down the tracks towards five unsuspecting workers. Theres a lever that would divert the tram to another track, but theres someone working on that track, too. You have to kill somebody to save five others, says Ryan, and you have to act fast.

The researchers at Utrecht University gave some of the subjects a shot of testosterone the night before presenting them with the dilemma. The number of respondents who were willing to kill in order to save people, and their confidence in carrying out the act were enhanced, says Ryan. And the equivocation they demonstrated was significantly reduced.

This isnt to say that empathetic people cant make tough decisions. Hormones are a bit-part in a complex cognitive picture. Aaron, a high-flying lawyer treated by Ryan, was adept at suppressing his empathy in order to win a case. But as his testosterone dissipated, he grew more caring and started asking Ryan about his family. At one appointment he asked whether getting emotional was a side-effect of his treatment, after he had wept at the end of a long-distance visit to his elderly mother. Like many patients, writes Ryan, Aaron regards these developments with a measure of surprise. Hormonal therapy hasnt been as bad as he expected, and he admits he has actually come to appreciate some of the effects it has had on him.

However, this outcome posed one worry for Ryan. A major case is heading to trial and Aaron is the lead attorney. Will having a testosterone level at 10% of normal affect his performance? he writes. The answer, it turns out, is no: Aaron had not lost his killer instinct in the courtroom.

You get the sense that Ryan sees toning down testosterone as a force for social good. Take his patient Marcus, an octogenarian who is still a keen runner. When his cancer risk was sufficiently low, he came off hormone suppression therapy and started taking supplemental testosterone to counter its effects. He would come in and talk about his half-marathon, weightlifting, his younger girlfriend, says Ryan. He never talked about anybody but himself. Eventually, he had to quit the supplements because his markers for cancer rose again. He disappears for more than a year, and comes back and is now taking care of his daughter, picking up his grandkids and being a nice grandpa. I think it is misguided for ageing men to think they should necessarily want to have high testosterone levels, because they may pay a price for that in terms of their relationships. They may be more self-centred, lack empathy.

But again, its complicated and depends on the individual. Many men, as they age, feel sluggish and lose muscle mass, lose their self-esteem, so I dont say we shouldnt ever use supplemental testosterone.

Its estimated that one in 10 men aged over 40 in the UK have low testosterone levels, which is in a large part related to obesity. Fat tissues will produce an excess of oestrogen, says Ryan, which leads to reductions in testosterone. Artificially boosting the latter could help them lose the weight, but any other benefits, Ryan warns, could be transient. A study published in the New England Journal of Medicine found that while [their participants on supplemental testosterone] felt good at first and their libidos went up, there werent long-term beneficial effects.

And, of course, they may end up impairing their capacity for empathetic relationships. But there are non-medical ways to boost empathy. In Testosterone Rex, Fine cites a 10-year US study targeting boys at high risk of behaving antisocially later in their lives. Some of them were given coaching to improve their emotional resilience, relationships and educational performance, while their parents were trained to manage their childrens behaviour. The goal was to enable the boys to respond more calmly and less vociferously to provocation. Years later, when the participants had reached their mid-20s, about 70 were deliberately provoked by someone stealing points from them in a game. Not only were the group who had been given coaching as boys less likely to retaliate; their testosterone levels rose less.

Another way, according to Ryan, is to do more childcare. Testosterone levels are 33% lower in fathers of newborns than in non-fathers, making way for a good 25% more oxytocin. This hormone, says Ryan, induces men to spend more time with their children and respond more quickly to their needs. It enables fathers to play more closely with their children, and get less rattled if they cry. (One of Ryans patients started getting down on the floor to play with his grandkids for the first time during hormone suppression therapy.) Romantic love, friendship and pet ownership open the floodgates to oxytocin, too (even a dogs oxytocin rises when it stares into its humans eyes). Less testosterone, more oxytocin, more bonding, says Ryan. Thats another, perhaps more fulfilling, feed-forward system.

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Will Your Baby Like Cilantro? These Genetic Tests Say They Can Tell

You have instant communication, on-demand entertainment, and dial-up transportation—why should you have to wait nine months to see what kind of baby you’re going to have? Now there’s an app for that.

In a modern-day reboot of Lindsay Bluth’s “Mommy What Will I Look Like” business venture, Denver-based startup HumanCode has introduced BabyGlimpse. It’s a $259 test that uses DNA from each member of a couple to predict how their future child might look and act—from skin, hair, and eye color to preferred kinds of snacks. (With a variant of the SLC2A2 gene your kiddo might have more glucose receptors than average, and therefore a sweet tooth, so goes the scientific reasoning.) Fun, right?

“We’ve coined it sunshine science,” HumanCode co-founder Jennifer Lescallet told the Balitmore Sun last month. “You get to look at the fun part of your potential future baby versus some of the scary stuff.” The scary stuff being more traditional carrier screen genetic tests, which tell couples if they have any disease-related genes they could potentially pass on to their offspring. These are either ordered by a doctor based on family history, or are now increasingly available to buy directly, after an online or phone consultation with a physician.

BabyGlimpse is one of the latest examples of a growing direct-to-consumer genetic testing industry aimed at new, expecting, and aspiring parents. Some, like BabyGlimpse, rely on a combination of each partner’s DNA. Others, like Orig3n’s Child Development test, collect spit or cheek swabs from the new kiddos themselves, and then work with labs to sequence, analyze, and interpret that genetic information. The companies behind these tests say they’re mostly for entertainment, and for educating folks about how genetics work. But doctors and public health officials have concerns that they might, in fact, do the opposite.

“At this point in time, in 2018, consumers should approach these tests with caution,” says Muin Khoury, the director of the Office of Public Health Genomics at the Centers for Disease Control and Prevention. His five-person team tries to help people understand how to use genomics appropriately to improve public health. They currently designate direct-to-consumer tests with a “tier 3” classification, meaning that “there is no evidence for clinical validity or utility of such applications in healthy individuals.”

Khoury says personal genomic testing isn’t harming anyone, but it’s also not conferring any real health benefits. “And we still don’t understand very well the unintended consequences of labeling people,” he says. “Once you think you know certain information, it’ll affect how you think about your baby for life.”

Some things, like knowing about lactose intolerance and peanut allergies from an early age, could certainly make for happier and healthier outcomes. But what about traits like math ability, noise pattern and music learning, and bone strength, which Orig3n claims to be able to tell you something about? The fallout could be subtle, but insidious. Maybe you discourage your kid from playing sports because Orig3n told you she was among the 30 percent of the population with weaker than average bones. Or you don’t give them a hard time about their sub-par math scores. Instead of telling them they can be whatever they want to be, you tell them they can be whatever they want to be, within genetic constraints.


The company gives you percentages, which is as much certainty as the science will allow, but the reality of genetics in the wild is more complicated still. Humans are born with two copies of every gene; one from each parent. The two different versions of each gene combine and interact to make a totally unique genome. Some traits, like eye color, are controlled by only a handful of genes. Others, like height, are likely influenced by thousands. HumanCode and Orig3n use machine learning models trained on a mix of publicly available genomes and proprietary data to come up with what’s called polygenic risk scores for each trait. Basically, a predicted likelihood that your kid will be taller than six feet, say, or be bad at math.

But the thing about these kinds of genes is that they’re not deterministic. (Unlike genetic diseases such as cystic fibrosis, which are clearly linked to changes in a single gene.) What you eat, where you live, what kind of an education you get—all of these things have as much, if not more, of an impact than your DNA. That’s not to say there isn’t strong evidence that certain genetic variants are associated with specific traits. But genes alone can’t predict how tall you’ll grow or how good you’ll be at long division.

Non-geneticists tend not to think too hard about these distinctions. “I think consumers are going to have to learn to differentiate between products that are scientifically rigorous and truly health-related and products that are the genetic equivalent of skin cream for wrinkles, and that’s a big lift,” says Robert Green, who studies direct-to-consumer genetic testing at Brigham and Women’s Hospital. “Genetics is novel and poorly understood and we haven’t yet immunized ourselves against these exaggerated claims. These companies are using our respect for the science of genetics to do an end-run around common sense.”

There may be a day in the future where common sense (and science) dictate that every infant get their genes sequenced upon birth. But until then, maybe save your money and get to know your baby the old-fashioned way, with time.

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Warnings over shock dementia revelations from ancestry DNA tests

Companies have been told to accept moral responsibility and provide counselling for people who inadvertently discover health risks

People who use genetic tests to trace their ancestry only to discover that they are at risk of succumbing to an incurable illness are being left to suffer serious psychological problems. Dementia researchers say the problem is particularly acute for those found to be at risk of Alzheimers disease, which has no cure or effective treatment. Yet these people are stumbling upon their status inadvertently after trying to find their Viking, Asian or ancient Greek roots.

These tests have the potential to cause great distress, said Anna Middleton, head of society and ethics research at the Wellcome Genome Campus in Cambridge. Companies should make counselling available, before and after people take tests. The issue is raised in a paper by Middleton and others in the journal Future Medicine.

A similar warning was sounded by Louise Walker, research officer at the Alzheimers Society. Everyone has a right to know about their risk if they want to, but these companies have a moral responsibility to make sure people understand the meaning and consequences of this information. Anyone considering getting genetic test results should do so with their eyes open.

Alzheimers is linked to the build-up in the brain of clumps of a protein called amyloid. This triggers severe memory loss, confusion and disorientation. One gene, known as ApoE, affects this process and exists in three variants: E2, E3 and E4. Those possessing the last of these face an increased chance of getting the disease in late life.

About 3% of the population has two copies of the E4 variant one inherited from each parent, Professor John Hardy, of University College London, said. They have about an 80% chance of getting Alzheimers by the age of 80. The average person has a 10% risk.

The link with ApoE was made in 1996 and Hardy recalled the reaction in his laboratory. We went around testing ourselves to see which variant we possessed. I found I have two low-risk E3 versions on my genome. But if I had found two E4 versions? By now, having reached my 60s, I would be facing the prospect that I had a serious chance of getting Alzheimers disease in 10 years. I would be pretty fed up.

The ability to find a persons ApoE status has become even easier as a result of the development of genetic tests that provide information about a persons ancestry, health risks and general traits. Dozens of companies offer such services and adverts portray happy individuals learning about their roots 43% African or 51% Middle Eastern often to the sound of Julie Andrews singing Getting to Know You or a similarly happy-sounding track. All you have to do is provide a sample of spittle.

The resulting information about predilections to disease is not stressed but it is given. Kelly Boughtflower, from London, took a gene test with the company 23andMe because she wanted to prove her mothers family came from Spain. The results provided no evidence of her Iberian roots but revealed she carried one E4 version of the ApoE gene, which increases her chances of getting Alzheimers, though not as drastically as a double dose.

I didnt think about it at the time, said Boughtflower. Then, when I took up work as an Alzheimers Society support worker, I learned about ApoE4 and the information has come to sit very heavily with me. Did I inherit the ApoE4 from my mother? Is she going to get Alzheimers very soon? Have I passed it on to my daughter? I have tried to get counselling on the NHS but that is not available for a person in my particular predicament, I was told.

Other examples appear on the ApoE4 Info site, a forum for those whose gene tests show an Alzheimers susceptibility. Have stumbled upon my 4/4 ApoE status. Im still in shock, writes one. Another states: I got paid a $50 Amazon gift-card to take part in a genetic study. I was naive and unprepared.

There is no drug or treatment for Alzheimers and although doctors advise that having a healthy lifestyle will help, the baseline risk for E4 carriers remains high. That is a real problem, said Middleton. Genetic test companies say they offer advice about counselling but that usually turns out to be a YouTube video outlining your risks. Affected people needed one-to-one counselling.

For their part, gene test companies say results about Alzheimers and other such as breast cancer and Parkinsons are often hidden behind electronic locks. A person has to answer several questions to show they really want to open these and is informed of potential risks. But Middleton dismissed these precautions. You know there is medical information about you online and so you will go and find it. It is human nature.

Margaret McCartney, a GP and author of The Patient Paradox, agreed. What worries me is the aggressive way these tests are marketed. People are told all the benefits but there is no mention of the downsides. The NHS is expected to mop these up.

Meanwhile, the gene test company has made its profit and walks away from the mess they have created. I think that is immoral. They should be made to pay for counselling for their customers.

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Deadly gene mutations removed from human embryos in landmark study

Groundbreaking project corrects faulty DNA linked to fatal heart condition and raises hopes for parents who risk passing on genetic diseases

Scientists have modified human embryos to remove genetic mutations that cause heart failure in otherwise healthy young people in a landmark demonstration of the controversial procedure.

It is the first time that human embryos have had their genomes edited outside China, where researchers have performed a handful of small studies to see whether the approach could prevent inherited diseases from being passed on from one generation to the next.

Crispr atom

While none of the research so far has created babies from modified embryos, a move that would be illegal in many countries, the work represents a milestone in scientists efforts to master the technique and brings the prospect of human clinical trials one step closer.

The work focused on an inherited form of heart disease, but scientists believe the same approach could work for other conditions caused by single gene mutations, such as cystic fibrosis and certain kinds of breast cancer.

This embryo gene correction method, if proven safe, can potentially be used to prevent transmission of genetic disease to future generations, said Paula Amato, a fertility specialist involved in the US-Korean study at Oregon Health and Science University.

The scientists used a powerful gene editing tool called Crispr-Cas9 to fix mutations in embryos made with the sperm of a man who inherited a heart condition known as hypertrophic cardiomyopathy, or HCM. The disease, which leads to a thickening of the hearts muscular wall, affects one in 500 people and is a common cause of sudden cardiac arrest in young people.

Humans have two copies of every gene, but some diseases are caused by a mutation in only one of the copies. For the study, the scientists recruited a man who carried a single mutant copy of a gene called MYBPC3 which causes HCM.

This sequence of images shows the development of embryos after injection of a gene-correcting enzyme and sperm from a donor with a genetic mutation known to cause hypertrophic cardiomyopathy. Photograph: (OHSU)/OHSY

When the scientists made embryos with the mans sperm and healthy eggs from donors, they found that, as expected, about half of the embryos carried the mutant gene. If the affected embryos were implanted into women and carried to term, the resulting children would inherit the heart condition.

Writing in the journal Nature, the researchers describe how gene editing dramatically reduced the number of embryos that carried the dangerous mutation. When performed early enough, at the same time as fertilisation, 42 out of 58 embryos, or 72%, were found to be free of the disease-causing mutation.

The work has impressed other scientists in the field because in previous experiments, gene editing has worked only partially, mending harmful mutations in some cells, but not others. Another problem happens when the wrong genes are modified by mistake, but in the latest work the scientists found no evidence of these so-called off target effects

Theyve got remarkably good results, its a big advance. said Richard Hynes, a geneticist at MIT who this year co-chaired a major report on human genome editing for the US National Academy of Sciences (NAS). This brings it closer to clinic, but theres still a lot of work to do.

Today, people who carry certain genetic diseases can opt for IVF and have their embryos screened for harmful mutations. The procedure can only help if there is a chance that some embryos will be healthy. According to Shoukhrat Mitalipov, who led the latest research, gene editing could bolster the number of healthy embryos available for doctors to implant.

More work is needed to prove that gene editing would be safe to do in people, but even if it seems safe, scientists face major regulatory hurdles before clinical trials could start. In the US, Congress has barred the Food and Drug Administration from even considering human trials with edited embryos, while in the UK it is illegal to implant genetically modified embryos in women. The procedure is controversial because genetic modifications made to an embryo affect not only the child it becomes but future generations too. Its still a long road ahead, said Mitalipov. Its unclear when wed be allowed to move on.

In the latest study, the mutation was corrected by a route that scientists have not seen before, with the cell copying healthy DNA from the mothers egg instead of the template. One question scientists need to explore now is whether mutations carried by eggs can be corrected as easily as those carried by sperm.

If all of this holds up for different genes and is also true when the mutation is inherited from the mother, it will be a major step forward, said Janet Rossant, senior scientist and chief of research emeritus at the Hospital for Sick Children in Toronto.

Asked about the potential for gene editing to produce designer babies, Rossant, a co-author of the NAS report on gene editing, said it was a distant prospect. We are still a long way from serious consideration of using gene editing to enhance traits in babies, she said. We dont understand the genetic basis of many of the human traits that might be targets for enhancement. Even if we did, a genetic alteration that enhanced one trait could have unexpected negative consequences on other traits, and this would be an inherited feature for the next generation.

The NAS report came out strongly against any form of gene editing designed to simply enhance human potential, she added.

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We are all mutants now: the trouble with genetic testing

The long read: With so many unknowns in our DNA, using genetics in medical testing doesnt always bring the answers sometimes it brings only doubt

AnneMarie Ciccarella, a fast-talking 57-year-old brunette with more than a hint of a New York accent, thought she knew a lot about breast cancer. Her mother was diagnosed with the disease in 1987, and several other female relatives also developed it. When doctors found a suspicious lump in one of her breasts that turned out to be cancer, she immediately sought out testing to look for mutations in the two BRCA genes, which between them account for around 20% of families with a strong history of breast cancer.

Ciccarella assumed her results would be positive. They werent. Instead, they identified only whats known as a variant of unknown or uncertain significance (VUS) in both BRCA1 and BRCA2. Unlike pathogenic mutations that are known to cause disease, or benign ones that dont, these genetic variations just arent understood enough to know if they are involved or not.

I thought you could have a mutated gene or not, and with all the cancer in my family, I believed I would carry a mutation. I didnt know there was this huge third category, she says. I got no information it felt like a huge waste of blood to get a giant question mark.

Thousands of people have had their BRCA genes tested for increased genetic susceptibility to breast, ovarian, prostate and other cancers. About 5% have learned that they carry a VUS. That number is even higher for other genes: in one study, almost 20% of genetic tests returned a VUS result.

Thats a lot of uncertainty, says Robert Klitzman, a bioethicist at Columbia University in New York. People want genetic tests to be like pregnancy tests, he explains: Youre either pregnant or youre not. Instead, theyre more like a weather report. And most people arent prepared to cope with the probabilities and uncertainties that entails.

When scientists surveyed a group of women one year after they received BRCA gene test results, the women whose results were uncertain or uninformative were feeling much more stress and anxiety than those whose results were clearly either pathogenic or benign. A follow-up study showed that the higher the risk an individual thought her result indicated, and the less tolerant she was of uncertainty, the more likely she was to experience serious long-term distress.

Even before her sequencing results came in, Ciccarella had decided on a bilateral mastectomy, based on her family history. For her, the question of whether she would one day develop breast cancer had been answered, and in the worst possible way. But she still wanted information for her son and daughter so they could know if they had inherited a genetic risk of cancer. Like a number of families, they are learning that genetic sequencing wont deliver answers for everyone.

We are all mutants. The 3bn pieces of DNA that make us who we are were long thought to be constant, chiselled in granite like a classical monument, with only tiny changes made here and there. Scientists used to believe that DNA mutations were largely harmful.

By the late 1990s and early 2000s, as the first sequences of the human genome came rolling in, researchers realised that their view of mutations was completely backwards. Instead of being rarities that almost inevitably harm health, mutations litter the human genome. The average human carries around 400 unique mutations, and most of us are none the worse because of them.

This challenged some basic tenets of genetics, as well as they ways that scientists and physicians interpreted genetic tests.

When Robert Resta, a genetic counsellorat the Swedish Medical Center in Seattle, first began examining genetic test results in the late 1980s, he could identify only chromosomal abnormalities or alterations of massive amounts of DNA. When other types of genetic tests were introduced, such as those for detecting the mutations in the CFTR gene that cause cystic fibrosis, interpretation was still reasonably straightforward. Because most of the people who had their CFTR gene sequenced showed clinical signs of cystic fibrosis, Resta could be reasonably confident that an observed mutation in that gene was the one that had led to the disease. In the past few years, however, the price of genetic sequencing has fallen dramatically, and doctors are increasingly requesting DNA testing earlier in the diagnostic process. As more data is gathered, the sheer number of mutations we all carry becomes more significant.

It turns out mutations are the norm. You expect to find mutations in a gene. Its a very different way of thinking about the human genome. If you dont find a mutation, your machine is probably having technical difficulty, Resta says.

When scientists test for mutations in large numbers of genes with a single test, known as a gene panel, they are virtually guaranteed to find at least one VUS, says Colleen Caleshu, a genetic counsellor at Stanford Universitys Center for Inherited Cardiovascular Disease. The more genes you look at, the more variation youll find, she adds. We all have tons of variations in our genes, most of which are extremely rare and, by the very nature of rarity, uninterpretable. In short, there isnt enough data to know what you are seeing.

Photograph by Catherine Losing/Hattie Newman

This grey area has only expanded as next-generation DNA sequencing has led to the growing use of gene panels to look for mutations in a range of genes that may be related to a patients symptoms. Of the three possible results pathogenic, benign or unknown pathogenic is the least common, says Resta. Youre much more likely to get uncertainty.

If interpreting genetic testing results is difficult for clinicians, its also tremendously hard for patients. Yvonne Bombard has spent the last several years of her career as a genomics health services researcher at St Michaels hospital in Toronto, working to understand how families make sense of genetic testing results.

Theres very little research on the impact of uncertain results on families yet the technology is just too new, Bombard says.

A small study in Psycho-Oncology surveyed 24 women with breast or ovarian cancer who had received VUS results for their genetic testing. Many of them had a distorted perception of what those results meant. Although two-thirds correctly remembered three years later that the variants detected by the test were unclassified, 79% interpreted the results as a higher genetic risk for developing cancer. One-third had also made significant medical changes in their lives based only on their test results, which Resta and Caleshu do not recommend.

Families of children with suspected genetic diseases have similar difficulties. Parents tend to interpret any variant not classified benign as being the cause of their childs disease, explains Caleshu. But she appreciates that its hard not to do that, especially when families have been looking for answers for so long.

Families can feel let down by the medical establishment, who often seem to throw up their hands when a patient defies diagnosis, and in the absence of definitive answers it is all too easy to believe that the genetic variants identified on the test must be whats wrong. One of Caleshus main jobs is providing pre-test counselling so that patients understand the risks and the limitations of testing. She says her team have changed the way they present results, so that patients and doctors dont read too much into a VUS. Even with the right genetic counselling, however, uncertainty can be agonising.

Ciccarella had watched her motherendure chemotherapy, and had undergone a similar gruelling regimen herself. If she could get genetic information that might help her children and any future generations to avoid that agony by using improved screening, reproductive planning and prophylactic mastectomies, then she was determined to make that happen.

She decided to get another lab to review the results of her genetic tests, and requested the data from the sequencing company, Myriad Genetics. They refused. Since they owned patents on the two BRCA genes, no one else could have their proprietary genetic data.

So she followed with interest a lawsuit by the American Civil Liberties Union (ACLU) against Myriads genetic patent, hoping that if the ACLU won, she could get a second opinion on her unclassified variants after all. In 2013, the US supreme court found in favour of the ACLU, invalidating Myriads patents. Myriad still refused to release raw sequencing data, however, saying that doing so would violate the 1996 Health Insurance Portability and Accountability Act (Hipaa).

Ciccarella teamed up with the ACLU and three other people who wanted access to their full sequencing data and prepared to file a suit against Myriad in 2016, arguing that Hipaa actually guarantees patients the right to their own data. On 18 May, one day before the suit was due to be filed, Myriad reversed their stance and released the sequencing data to Ciccarella and the others. She found that Myriad had reclassified one of her VUSs as benign, but when she checked this against public databases of genetic variants, she found that no one else had changed this classification.

So whos right? There are two different opinions thats exactly the problem. One place says one thing, one place says another, and Im stuck in the middle with a daughter who just found a suspicious lump, Ciccarella says.

Ciccarellas case was settled out of court, but another case is showing that the battles over genetic testing uncertainty are just beginning. In February 2016, Amy Williams filed a lawsuit against Athena Diagnostics, ADI Holdings and Quest Diagnostics (Athenas parent company) relating to the death of her son, Christian.

Christian was born a seemingly healthy blond-haired, blue-eyed cherub on 23 August 2005. Just before Christmas that year, he had his first massive seizure. Many more followed. Despite countless medications and tests, no one could figure out what was causing his unrelenting seizures. He had a massive battery of tests in early 2007, including the sequencing of a gene called SCN1A. Athena, which performed the genetic tests, reported that he had a VUS. With no clear genetic answers, his doctors treated him for an undiagnosed mitochondrial disorder, although his treatments had minimal effects on his continuing seizures.

On 5 January 2008, Christian went to bed after celebrating a belated Christmas holiday with his family. Videos taken that day gave no hint that he would be dead by morning. The official cause of death was listed as a seizure.

Six years later, thinking of starting a family again, Williams wanted to get her own DNA sequenced in order to learn whether the disease that had affected her son could affect any future children. Again, she turned to Athena, but as well as her own results, she also requested Christians 2007 lab report. She saw from the revised report they provided that Athena had reclassified Christians VUS as a disease-associated mutation, which suggested he had a form of childhood epilepsy called Dravet syndrome (also known as severe myoclonic epilepsy in infancy). Several of the medications used to treat seizures in young children, including Christian, are toxic to children with Dravet and can increase the risk of death.

Williams believes this means the treatment Christian received was only making things worse. What she now wanted to know from Athena was when and why they reclassified the variant. As Williams, a former special education teacher, taught herself the nuances of scientific literature, she found out that the same SCN1A mutation Christian carried had been identified in an Australian family in 2006, before Christians DNA was tested. Even more concerning was a patent document on the SCN1A gene that listed this mutation (a change in a single amino acid in the gene) as pathogenic. When Athena refused to answer, Williams sued.

Her allegations include that Athena had had enough information to reclassify Christians mutation before he was tested, and that if they had done so, it would have changed his diagnosis and treatment such that his death from a seizure related to Dravet syndrome could have been avoided.

Athena and the other two companies reject these allegations, and argue that the case should be dismissed. They say that the 2007 lab report emphasised the inconclusiveness of the test results, that Dravet could have been the cause of Christians seizures without his medication being implicated, that further testing was strongly recommended (in particular, testing of his parents, which was offered at no additional charge but not taken up), and that a conclusive diagnosis could be reached only by additional testing. Quest, the parent company, declined to comment on this ongoing legal action, but the case has caused many in the genetic sequencing community to consider what changes may be required in the future.

This case reflects the uncertainties of modern genetic testing, and the tension that it can cause for patients and their families, and illustrates the increasing scrutiny of clinical genetic sequencing labs, how they share data on variants, and how this data is interpreted. Regulators, researchers, patients and the sequencing labs themselves will have to work together to find ways to improve these processes.

Tess Bigelow is a bubbly seven-year-old with light brown hair that curls forward into her face, framing a pair of bright pink glasses. A few months after Tess was born, in November 2009, her parents, Bo and Kate, noticed that something was wrong. She wasnt rolling over or meeting other developmental milestones. By June 2010, her parents realised that something was very wrong.

She was not interacting with other people. It was just like she was checked out. We knew she was in there, we just couldnt get to her, her father says.

As she got older, Tess didnt start to speak or communicate, and she continued to have problems walking and standing. A full diagnostic examination revealed nothing, so genetics experts in Boston, and in the Bigelows hometown of Portland, Maine, recommended sequencing all of her genes. The team were hopeful that this would turn up results, but they cautioned the Bigelows not to get their hopes up. Tesss sequencing revealed a mutation in a gene called USP7, but no one could say whether or not this was the cause of her illness.

No matter how much they tell you, you believe youre going to get an answer. Its hard to hear that this is where it ends, Bo Bigelow says.

He began learning everything he could about USP7. There wasnt much. Researchers were just starting to learn what the gene did, and he couldnt find any other families with a USP7 mutation. So he decided to see if he could make those other families come to him. In a public Facebook post he drafted late at night in August 2015, Bigelow described his daughters symptoms, along with her sequencing results. He crossed his fingers and clicked share.

Photograph by Catherine Losing/Hattie Newman

The post went viral. One person shared it to Reddit, from where a graduate student brought it to the attention of Christian Schaaf, a geneticist at Baylor College of Medicine in Houston, Texas. He was working on USP7 and other genes that had been linked to genetic conditions such as Prader-Willi syndrome.

USP7 is part of our cells protein-recycling machinery, making sure that cells dump their garbage quickly enough to prevent the buildup of proteins that are damaged or no longer needed, but not so quickly that it removes healthy proteins. Suspecting that faults in USP7 could lead to disease, Schaaf had searched through Baylors own genetic sequencing databases and other genome data depositories, and found seven clinical cases of children who had mutations in USP7.

By the end of the day on which his post was shared on Facebook, Bigelow had received an email from Mike Fountain, one of Schaafs co-authors on the research paper about the USP7 mutations and their links to disease. On the phone the next morning, Fountain outlined the array of symptoms experienced by the seven other children, and they all sounded remarkably like Tess. It looked as if they had found the smoking gun, but only the results of more laboratory studies will show for sure whether or not this was the cause of Tesss condition.

Like many parents of children with rare diseases and special needs, Bigelow has come to live with the uncertainty. But he and other parents and patients have begun sharing their genetic data through portals such as MyGene2 to help others. Created by Michael Bamshad and Jessica Chong, MyGene2 lets people share their own sequencing results in the hope of facilitating research and finding other families with similar medical problems. Other initiatives are springing up, too, and researchers hope they will reduce the uncertainty that continues to plague genetic sequencing.

Heidi Rehm is a clinical medical geneticist at the Broad Institute in Cambridge, Massachusetts. She led teams at the US National Institutes for Health that created two databases helping to improve sharing and curation of genetic data. ClinVar, launched in 2012, links genetic variants with symptoms. ClinGen, introduced the following year, is described as building an authoritative central resource that defines the clinical relevance of genes and variants for use in precision medicine and research. Using these two resources, commercial and academic sequencing labs can combine their expertise to offer people the most accurate description of what their genetic variants mean.

The depositing of results from large sequencing studies, such as the Exome Aggregation Consortium at the Broad Institute, also promises to help reduce genetic uncertainty. Some of the earliest results of this initiative provided some of the largest reclassifications of VUS results yet, according to Rehm. Nearly all of those reclassifications were shifting a VUS to benign an indication of the sheer volume of normal variation and mutation inherent in all of our genetic blueprints.

At the Institute of Cancer Research in London, Nazneen Rahman is leading the Transforming Genetic Medicine Initiative to address many issues involved in bringing genetics into medicine. When it comes to managing uncertainty in genetic testing, she says we need to change the way we think about VUS and rare variants in general.

Although disease-causing variants are rare, most rare variants do not cause disease, she explains, in the same way that bananas are yellow but most yellow objects are not bananas. Instead of considering a genetic variant guilty unless proven innocent, we should consider all genetic variants innocent unless proven guilty. For example, women with a BRCA VUS should be managed in the same way as women with variants that are known to be innocent.

To get a better handle on all the variation in humans, scientists are going to need to sequence tens of millions of people. And the only way to ever get these kinds of large numbers is by sharing data. But regardless of how good the databases get, and how many people have their genomes sequenced, uncertainty will never completely go away.

Every time our cells divide and copy their DNA, mutations can arise. This uncertainty may be maddening for patients looking for answers, but its as much stamped into our genetic blueprint as the double helix itself.

Main photograph by Catherine Losing/Hattie Newman

This is an edited version of an article first published by Wellcome on It is republished here under a Creative Commons licence

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Biologists Are Figuring Out How Cells Tell Left From Right

In 2009, after she was diagnosed with stage 3 breast cancer, Ann Ramsdell began to search the scientific literature to see if someone with her diagnosis could make a full recovery. Ramsdell, a developmental biologist at the University of South Carolina, soon found something strange: The odds of recovery differed for women who had cancer in the left breast versus the right. Even more surprisingly, she found research suggesting that women with asymmetric breast tissue are more likely to develop cancer.

Quanta Magazine


Original storyreprinted with permission from Quanta Magazine, an editorially independent division of theSimons Foundation whose mission is to enhance public understanding of science by covering research developments and trends in mathematics and the physical and life sciences

Asymmetry is not readily apparent. Yet below the skin, asymmetric structures are common. Consider how our gut winds its way through the abdominal cavity, sprouting unpaired organs as it goes. Or how our heart, born from two identical structures fused together, twists itself into an asymmetrical pump that can simultaneously push oxygen-rich blood around the body and draw in a new swig from the lungs, all in a heartbeat. The bodys natural asymmetry is crucially important to our well-being. But, as Ramsdell knew, it was all too often ignored.

In her early years as a scientist, Ramsdell never gave asymmetry much thought. But on the day of her dissertation defense, she put a borrowed slide into a projector (this in the days before PowerPoint). The slide was of a chick embryo at the stage where its heart begins to loop to one side. Afterward a colleague asked why she put the slide in backward. Its an embarrassing story, she said, but I had never even thought about the directionality of heart looping. The chicks developing heart could distinguish between left and right, same as ours. She went on to do her postdoctoral research on why the heart loops to one side.

Years later, after her recovery, Ramsdell decided to leave the heart behind and to start looking for asymmetry in the mammary glands of mammals. In marsupials like wallabies and kangaroos, she read, the left and the right glands produce a different kind of milk, geared toward offspring of different ages. But her initial studies of mice proved disappointingtheir left and right mammary glands didnt seem to differ at all.

The wrybill uses its laterally curved bill to reach insect larvae under rounded riverbed stones.Steve Atwood

Then she zoomed in on the genes and proteins that are active in different cells of the breast. There she found strong differences. The left breast, which appears to be more prone to cancer, also tends to have a higher number of unspecialized cells, according to unpublished work thats undergoing peer review. Those allow the breast to repair damaged tissue, but since they have a higher capacity to divide, they can also be involved in tumor formation. Why the cells are more common on the left, Ramsdell has not yet figured out. But we think it has to do with the embryonic environment the cells grow up in, which is quite different on both sides.

Ramsdell and a cadre of other developmental biologists are trying to unravel why the organisms can tell their right from left. Its a complex process, but the key orchestrators of the handedness of life are beginning to come into clearer focus.

A Left Turn

In the 1990s, scientists studying the activity of different genes in the developing embryo discovered something surprising. In every vertebrate embryo examined so far, a gene called Nodal appears on the left side of the embryo. It is closely followed by its collaborator Lefty, a gene that suppresses Nodal activity on the embryos right. The Nodal-Lefty team appears to be the most important genetic pathway that guides asymmetry, said Cliff Tabin, an evolutionary biologist at Harvard University who played a central role in the initial research into Nodal and Lefty.

But what triggers the emergence of Nodal and Lefty inside the embryo? The developmental biologist Nobutaka Hirokawa came up with an explanation that is so elegant we all want to believe it, Tabin said. Most vertebrate embryos start out as a tiny disk. On the bottom side of this disk, theres a little pit, the floor of which is covered in ciliaflickering cell extensions that, Hirokawa suggested, create a leftward current in the surrounding fluid. A 2002 study confirmed that a change in flow direction could change the expression of Nodal as well.

The twospot flounder lies on the seafloor on its right side, with both eyes on its left side.SEFSC Pascagoula Laboratory; Collection of Brandi Noble, NOAA/NMFS/SEFSC

Damaged cilia have long been associated with asymmetry-related disease. In Kartagener syndrome, for example, immobile cilia in the windpipe cause breathing difficulties. Intriguingly, the body asymmetry of people with the syndrome is often entirely inversed, to become an almost perfect mirror image of what it would otherwise. In the early 2000s, researchers discovered that the syndrome was caused by defects in a number of proteins driving movement in cells, including those of the cilia. In addition, a 2015 Nature study identified two dozen mouse genes related to cilia that give rise to unusual asymmetries when defective.

Yet cilia cannot be the whole story. Many animals, even some mammals, dont have a ciliated pit, said Michael Levin, a biologist at Tufts University who was the first author on some of the Nodal papers from Tabins lab in the 1990s.

In addition, the motor proteins critical for normal asymmetry development dont only occur in the cilia, Levin said. They also work with the cellular skeleton, a network of sticks and strands that provides structure to the cell, to guide its movements and transport cellular components.

An increasing number of studies suggest that this may give rise to asymmetry within individual cells as well. Cells have a kind of handedness, said Leo Wan, a biomedical engineer at the Rensselaer Polytechnic Institute. When they hit an obstacle, some types of cells will turn left while others will turn right. Wan has created a test that consists of a plate with two concentric, circular ridges. We place cells between those ridges, then watch them move around, he said. When they hit one of the ridges, they turn, and their preferred direction is clearly visible.

The red crossbill uses its unique beak to access the seeds in conifer cones.Jason Crotty

Wan believes the cells preference depends on the interplay between two elements of the cellular skeleton: actin and myosin. Actin is a protein that forms trails throughout the cell. Myosin, another protein, moves across these trails, often while dragging other cellular components along. Both proteins are well-known for their activity in muscle cells, where they are crucial for contraction. Kenji Matsuno, a cellular biologist at Osaka University, has discovered a series of what he calls unconventional myosins that appear crucial to asymmetrical development. Matsuno agrees that myosins are likely causing cell handedness.

Consider the fruit fly. It lacks both the ciliated pit as well as Nodal, yet it develops an asymmetric hindgut. Matsuno has demonstrated that the handedness of cells in the hindgut depends on myosin and that the handedness reflected by the cells initial tilt is what guides the guts development. The cells handedness does not just define how they move, but also how they hold on to each other, he explains. Together those wrestling cells create a hindgut that curves and turns exactly the way its supposed to. A similar process was described in the roundworm C. elegans.

Nodal isnt necessary for the development of all asymmetry in vertebrates, either. In a study published in Nature Communications in 2013, Jeroen Bakkers, a biologist at the Hubrecht Institute in the Netherlands, described how the zebra fish heart may curve to the right in the absence of Nodal. In fact, he went on to show that it even does so when removed from the body and deposited into a simple lab dish. That being said, he adds, in animals without Nodal, the heart did not shift left as it should, nor did it turn correctly. Though some asymmetry originates within, the cells do need Nodals help.

The European red slug has a large, dark respiratory pore on its right side.Hans Hillewaert

For Tabin, experiments like this show that while Nodal may not be the entire story, it is the most crucial factor in the development of asymmetry. From the standpoint of evolution, it turns out, breaking symmetry wasnt that difficult, he said. There are multiple ways of doing it, and different organisms have done it in different ways. The key that evolution had to solve was making asymmetry reliable and robust, he said. Lefty and Nodal together are a way of making sure that asymmetry is robust.

Yet others believe that important links are waiting to be discovered. Research from Levins lab suggests that communication among cells may be an under-explored factor in the development of asymmetry.

The cellular skeleton also directs the transport of specialized proteins to the cell surface, Levin said. Some of these allow cells to communicate by exchanging electrical charges. This electrical communication, his research suggests, may direct the movements of cells as well as how the cells express their genes. If we block the [communication] channels, asymmetrical development always goes awry, he said. And by manipulating this system, weve been able to guide development in surprising but predictable directions, creating six-legged frogs, four-headed worms or froglets with an eye for a gut, without changing their genomes at all.

The apparent ability of developing organisms to detect and correct their own shape fuels Levins belief that self-repair might one day be an option for humans as well. Under every rock, there is a creature that can repair its complex body all by itself, he points out. If we can figure out how this works, Levin said, it might revolutionize medicine. Many people think Im too optimistic, but I have the engineering view on this: Anything thats not forbidden by the laws of physics is possible.

Original story reprinted with permission from Quanta Magazine, an editorially independent publication of the Simons Foundation whose mission is to enhance public understanding of science by covering research developments and trends in mathematics and the physical and life sciences.

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A Patent Decision on Crispr Gene Editing Favors MIT

The fight over who owns the most promising technique for editing genes—cutting and pasting the stuff of life to cure disease and advance scientific knowledge—has been a rough one. A team on the West Coast, at UC Berkeley, filed patents on the method, Crispr-Cas9; a team on the East Coast, based at MIT and the Broad Institute, filed their own patents in 2014 after Berkeley’s, but got them granted first. The Berkeley group contended that this constituted “interference,” and that Berkeley deserved the patent.

At stake: millions, maybe billions of dollars in biotech money and licensing fees, the future of medicine, the future of bioscience. Not nothing. Who will benefit depends on who owns the patents.

On Wednesday, the US Patent Trial and Appeal Board kind of, sort of, almost began to answer that question. Berkeley will get the patent for using the system called Crispr-Cas9 in any living cell, from bacteria to blue whales. Broad/MIT gets the patent in eukaryotic cells, which is to say, plants and animals.

Its confusing. The patent that the Broad received is for the use of Crispr gene-editing technology in eukaryotic cells. The patent for the University of California is for all cells, saysJennifer Doudna, the UC geneticist and co-founder of Caribou Biosciences who co-invented Crispr, on a conference call. Her metaphor: They have a patent on green tennis balls; we have a patent for all tennis balls.

Observers didn’t quite buy that topspin. If Caribou is playing tennis, its looking like Broad/MIT is Serena Williams.

UC does not necessarily lose everything, but they’re no doubt spinning the story, saysRobert Cook-Deegan, an expert in genetic policy at Arizona State Universitys School for the Future of Innovation in Society. UC’s claims to eukaryotic uses of Crispr-Cas9 will not be granted in the form they sought. That’s a big deal, and UC was the big loser.

They have a patent on green tennis balls; we have a patent for all tennis balls.Jennifer Doudna, UC Berkeley

UC officials said Wednesday that they are studying the 51-page decision and considering whether to appeal. That leaves members of the biotechnology sector wondering who they will have to pay to use Crispr as part of a business—and scientists hoping the outcome wont somehow keep them from continuing their research.

Why It Matters Who Wins

Someone is going to make a lot of money licensing Crispr. And someone is going to make lot of money on therapies based on Crispr. Thats why, the day before the decision, the National Academy of Sciences released a long document laying out what kind of Crispr-based human therapies were kosher—so no one goes the full Gattaca.

In fact, the moneymaking part has already begun. Startups are getting funding based on Crispr-based business plans. Editas Medicine, which licenses the Broad patents to work on treatments for genetic disorders in human beings, had a 30 percent stock bump on word of the patent decision. It certainly caused some concerns, because depending on how the courts were going to rule on the two claims, if you went with one, you could lose, right? says Edison Liu, CEO of the Jackson Laboratory, a major source of genetically modified mice used in research. Jackson Labs has licenses from both sides, and since it aims at academic uses, gets better terms than a Silicon Valley biotech startup might.

But not everyone can make multiple deals. Its a bit frustrating that the patent office has done it this way, says Eric Rhodes, CEO of ERS Genomics, which licenses UCs Crispr technology to other companies for non-human therapeutic uses. A lot of people were hoping they would make a decision to go with one group or another.

Commercial outfits hoping to make new therapies will, for now, have to pay both institutions big fees. ERS Genomics, for example, charges from $10,000 to small start-ups to $1 million to large pharmaceutical firms. And an attenuated patent dispute could mean more red tape and lawyers on retainer for biotech scientists.

On the plus side, the patent fight doesnt look likely to slow basic research, or even research with an eye toward commercialization. Neither UC nor Broad will charge academic scientists who want to use Crispr just to better understand plant diseases, lets say. I dont think it’s going to slow down therapeutic development, says Rhodes.

The same goes for people trying to use animal models like mice. Thats good, because the models and the technique are ubiquitous. If youre creating a mouse model, you just have to use this. Its a little bit like, once internal combustion with a carbon source came out, nobody was spending a lot of money on the steam engine, you know? says Liu.

Two Biotech Institutions Enter; One Biotech Institution Leaves

The final outcome of this patent fight may be years away—especially if Berkeley appeals the decision. Its one battle in a larger war, says Jason Sherkow, a bioscience patent law expert at New York Law School. But its a very big, important battle.

There will be paperwork and cross-licensing that will have to be worked out before drugs are commercialized. Hopefully some of this patent situation will work itself out before then.Eric Rhodes, CEO, ERS Genomics

Thats because if a biotech company develops a megahit drug or treatment using Crispr, itmight now have to pay the Broad megabucks in fees. “There will be paperwork and cross-licensing that will have to be worked out before drugs are commercialized,” says Rhodes. “Hopefully some of this patent situation will work itself out before then.” Broad/MIT might even go Hollywood here, taking a small upfront fee in return for points off the gross revenue down the road. It does paint a dark and foggy picture for any of the companies that received licenses that originally came from Berkeley, says Sherkow.

Here’s where things get a little sketchy even for the most basic of basic researchers—because you never know, exactly, what youre going to come up with. If you are contemplating creating something that would be marketed in any way, Liu says, then it is actually the commercial end of it, the sale of the product, that will probably require a license.

This isn’t the first time universities and companies have fought over a lucrative invention that could further scientific research. Harvard fought for years for rights to the cancer-prone, genetically engineered oncomouse. Until the US Supreme Court took them away in 2013, Myriad Genetics held the rights to genes for breast cancer. In 1980, researchers at UC San Francisco and Stanford figured out how to make recombinant DNA in bacteria, and patented it. In that last case, university licensing offices negotiated ways to let people use the technology to do science and create businesses. But the time for that kind of sensible negotiation seems to have passed with Crispr. Its the only thing all parties really agree on: Too much is at stake.

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Why I Wont Get the Genetic Test for Breast Cancer

A few years ago, my mother called with an urgent request. She was agitated. She had just come from a meeting of her Jewish women’s group, where she had learned about BRCA1 and BRCA2, the so-called breast cancer genes. She wanted me to get tested. She insisted. I immediately said no.

BRCA1 and 2 are some of the most powerful cancer markers scientists have discoveredarchetypes of an ever expanding pool of potentially livesaving genetic tests. A mutation in one of those genes more than quadruples your risk of breast cancer to between 45 and 65 percent. For ovarian cancer, the risk hits 10 to 39 percent. Treatment is ruthless but effective: Cut away your breasts and ovaries to cut down your risk.

When I got that call from my mom, though, I shut her down. Because while BRCA is a powerful tool to estimate risk, it’s not a crystal ball. As with every mutation in our DNA, its effects vary depending on where exactly the gene is broken and on a family’s cancer history. It’s never You will get cancer. As a science journalist, I long ago internalized that uncertainty. And I didn’t want the results of one inscrutable test to propel me into irreversible surgery.

It took me more than a year to step back from that gut reaction. The science of genetics is constantly evolving, and I wasn’t sure exactly where I stoodand if I wasn’t sure, then what did that mean for the millions of people getting results from other, even more inscrutable tests?

I decided to dig into the science.

My mom’s group had good reason to talk about breast cancer: Ashkenazi Jews like us have a 2 to 3 percent chance of inheriting a BRCA mutation, 10 times higher than average. My mom also made sure to point out that two of my paternal relativesGreat-aunt Ann and my dad’s cousin Frandied of breast cancer.

I came armed with that information to the National Cancer Institute in Maryland, where senior researcher Mark Greene plugged it into an online BRCA risk-assessment toola first step for any woman wondering whether to get the genetic test. After building a family tree, a web of cancers and no cancers, the program calculated what I expected: My risk of having the mutation is small. Basically, you have two distant relatives with cancer, only one of whom is a young case, said Greene. That’s not the kind of pattern we typically associate with mutations in BRCA1 or 2. The data wasn’t screaming at me to get tested.

I left Greene’s office feeling relieved. Still, low risk isn’t no risk. When I talked to a half-dozen researchers and genetic counselors, nearly every one of them thought I should play it safe and get the test.

So let’s say I did. If I tested positive, the statistics would push me toward removing my breasts and ovaries. Data suggests that surgery can increase survival in people with confirmed BRCA mutations. Removing my ovaries would reduce my ovarian cancer risk by as much as 90 percent.

There’s a problem with those rates, though: They’re largely based on families with a history of breast and ovarian cancer. The rates might not apply to other women. Ann and Fran died of breast cancerbut I don’t know if it was BRCA-linked.

Every BRCA-positive woman has to weigh the strength of that survival data against the repercussions of surgery. I wouldn’t be able to have children. I’d lose sensation in my breastsa crucial part of my sexual enjoymentand possibly strength in my arms. Oophorectomy also kick-starts menopause: That can mean early bone weakening, cardiovascular disease, even dementia.

Not worth it for many women. Plan B isn’t bad: twice-yearly breast scans, which can prevent some breast cancer deaths in BRCA-positive patients.

But here’s where things get truly trickyand where the initial choice to test becomes fraught. Frequent mammograms and MRIs usually find something, even if the shadows on the screen may never become life-threatening. But patients tend to pounce on those shadows. After years of tests and biopsies, some women give in and remove their breasts.

The data backs that up: Humans just can’t manage fear. Barry Kramer, director of the NCI’s division on cancer prevention, explains that mastectomies have increased steeply in the past few decades as women find early signs of cancer. But there’s pretty strong evidence that there’s no difference in overall survival, Kramer says. Patients are petrified. Then they take drastic, potentially harmfuland sometimes unnecessaryaction.

Genetic tests could mislead patients in the same way. The torrent of information buried in the tightly packed twists of our chromosomes will become more and more powerful, but it will never provide simple answers.

It will always be monstrously hard to calculate cancer risk. It’s even harder to turn that risk into helpful preventive care while facing the fear of death. I spoke to a woman who decided, after much agonizing, to take the BRCA test and then remove her breasts and ovaries. She didn’t regret it.

But her decision isn’t mine. Knowing what I do about my family’s historyafter Ann and Fran, there’s no more breast or ovarian cancer in my familya positive test wouldn’t convince me to get surgery. It would just feel like hefting a sword, dangling it by a frayed thread above my head, and waiting for it to fall. I’m more scared of living like that than I am of cancer.

Cynthia Graber(@cagraber) is a science writer and cohost of the podcast Gastropod.

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The Mystery of How Cancer Cells Barrel Through Your Body

In 1995, while he was a graduate student at McGill University in Montreal, the biomedical scientist Peter Friedl saw something so startling it kept him awake for several nights. Coordinated groups of cancer cells he was growing in his advisers lab started moving through a network of fibers meant to mimic the spaces between cells in the human body.

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Original storyreprinted with permission from Quanta Magazine, an editorially independent division of theSimons Foundation whose mission is to enhance public understanding of science by covering research developments and trends in mathematics and the physical and life sciences

For more than a century, scientists had known that individual cancer cells can metastasize, leaving a tumor and migrating through the bloodstream and lymph system to distant parts of the body. But no one had seen what Friedl had caught in his microscope: a phalanx of cancer cells moving as one. It was so new and strange that at first he had trouble getting it published. It was rejected because the relevance [to metastasis] wasnt clear, he said. Friedl and his co-authors eventually published a short paper in the journal Cancer Research.

Two decades later, biologists have become increasingly convinced that mobile clusters of tumor cells, though rarer than individual circulating cells, are seeding manyperhaps mostof the deadly metastatic invasions that cause 90 percent of all cancer deaths. But it wasnt until 2013 that Friedl, now at Radboud University in the Netherlands, really felt that he understood what he and his colleagues were seeing. Things finally fell into place for him when he read a paper by Jeffrey Fredberg, a professor of bioengineering and physiology at Harvard University, which proposed that cells could be jammedpacked together so tightly that they become a unit, like coffee beans stuck in a hopper.

Fredbergs research focused on lung cells, but Friedl thought his own migrating cancer cells might also be jammed. I realized we had exactly the same thing, in 3-D and in motion, he said. That got me very excited, because it was an available concept that we could directly put onto our finding. He soon published one of the first papers applying the concept of jamming to experimental measurements of cancer cells.

Physicists have long provided doctors with tumor-fighting tools such as radiation and proton beams. But only recently has anyone seriously considered the notion that purely physical concepts might help us understand the basic biology of one of the worlds deadliest phenomena. In the past few years, physicists studying metastasis have generated surprisingly precise predictions of cell behavior. Though its early days, proponents are optimistic that phase transitions such as jamming will play an increasingly important role in the fight against cancer. Certainly in the physics community theres momentum, Fredberg said. If the physicists are on board with it, the biologists are going to have to. Cells obey the rules of physicstheres no choice.

The Jam Index

In the broadest sense, physical principles have been applied to cancer since long before physics existed as a discipline. The ancient Greek physician Hippocrates gave cancer its name when he referred to it as a crab, comparing the shape of a tumor and its surrounding veins to a carapace and legs.

But those solid tumors do not kill more than 8 million people annually. Once tumor cells strike out on their own and metastasize to new sites in the body, drugs and other therapies rarely do more than prolong a patients life for a few years.

Biologists often view cancer primarily as a genetic program gone wrong, with mutations and epigenetic changes producing cells that dont behave the way they should: Genes associated with cell division and growth may be turned up, and genes for programmed cell death may be turned down. To a small but growing number of physicists, however, the shape-shifting and behavior changes in cancer cells evoke not an errant genetic program but a phase transition.

The phase transitiona change in a materials internal organization between ordered and disordered statesis a bedrock concept in physics. Anyone who has watched ice melt or water boil has witnessed a phase transition. Physicists have also identified such transitions in magnets, crystals, flocking birds and even cells (and cellular components) placed in artificial environments.

But compared to a homogeneous material like water or a magnetor even a collection of identical cells in a dishcancer is a hot mess. Cancers vary widely depending on the individual and the organ they develop in. Even a single tumor comprises a mind-boggling jumble of cells with different shapes, sizes and protein compositions. Such complexities can make biologists wary of a general theoretical framework. But they dont daunt physicists. Biologists are more trained to look at complexity and differences, said the physicist Krastan Blagoev, who directs a National Science Foundation program that funds work on theoretical physics in living systems. Physicists try to look at whats common and extract behaviors from the commonness.

In a demonstration of this approach, the physicists Andrea Liu, now of the University of Pennsylvania, and Sidney Nagel of the University of Chicago published a brief commentary in Nature in 1998 about the process of jamming. They described familiar examples: traffic jams, piles of sand, and coffee beans stuck together in a grocery-store hopper. These are all individual items held together by an external force so that they resemble a solid. Liu and Nagel put forward the provocative suggestion that jamming could be a previously unrecognized phase transition, a notion that physicists, after more than a decade of debate, have now accepted.

Though not the first mention of jamming in the scientific literature, Liu and Nagels paper set off what Fredberg calls a deluge among physicists. (The paper has been cited more than 1,400 times.) Fredberg realized that cells in lung tissue, which he had spent much of his career studying, are closely packed in a similar way to coffee beans and sand. In 2009 he and colleagues published the first paper suggesting that jamming could hold cells in tissues in place, and that an unjamming transition could mobilize some of those cells, a possibility that could have implications for asthma and other diseases.

Lucy Reading-Ikkanda for Quanta Magazine

The paper appeared amid a growing recognition of the importance of mechanics, and not just genetics, in directing cell behavior, Fredberg said. People had always thought that the mechanical implications were at the most downstream end of the causal cascade, and at the most upstream end are genetic and epigenetic factors, he said. Then people discovered that physical forces and mechanical events actually can be upstream of genetic eventsthat cells are very aware of their mechanical microenvironments.

Lisa Manning, a physicist at Syracuse University, read Fredbergs paper and decided to put his idea into action. She and colleagues used a two-dimensional model of cells that are connected along edges and at vertices, filling all space. The model yielded an order parametera measurable number that quantifies a materials internal orderthat they called the shape index. The shape index relates the perimeter of a two-dimensional slice of the cell and its total surface area. We made what I would consider a ridiculously strict prediction: When that number is equal to 3.81 or below, the tissue is a solid, and when that number is above 3.81, that tissue is a fluid, Manning said. I asked Jeff Fredberg to go look at this, and he did, and it worked perfectly.

Fredberg saw that lung cells with a shape index above 3.81 started to mobilize and squeeze past each other. Mannings prediction came out of pure theory, pure thought, he said. Its really an astounding validation of a physical theory. A program officer with the Physical Sciences in Oncology program at the National Cancer Institute learned about the results and encouraged Fredberg to do a similar analysis using cancer cells. The program has given him funding to look for signatures of jamming in breast-cancer cells.

Meanwhile, Josef Ks, a physicist at Leipzig University in Germany, wondered if jamming could help explain puzzling behavior in cancer cells. He knew from his own studies and those of others that breast and cervical tumors, while mostly stiff, also contain soft, mobile cells that stream into the surrounding environment. If an unjamming transition was fluidizing these cancer cells, Ks immediately envisioned a potential response: Perhaps an analysis of biopsies based on measurements of tumor cells state of jamming, rather than a nearly century-old visual inspection procedure, could determine whether a tumor is about to metastasize.

Ks is now using a laser-based tool to look for signatures of jamming in tumors, and he hopes to have results later this year. In a separate study that is just beginning, he is working with Manning and her colleagues at Syracuse to look for phase transitions not just in cancer cells themselves, but also in the matrix of fibers that surrounds tumors.

More speculatively, Ks thinks the idea could also yield new avenues for therapies that are gentler than the shock-and-awe approach clinicians typically use to subdue a tumor. If you can jam a whole tumor, then you have a benign tumorthat I believe, he said. If you find something which basically jams cancer cells efficiently and buys you another 20 years, that might be better than very disruptive chemotherapies. Yet Ks is quick to clarify that he is not sure how a clinician would induce jamming.

Castaway Cooperators

Beyond the clinic, jamming could help resolve a growing conceptual debate in cancer biology, proponents say. Oncologists have suspected for several decades that metastasis usually requires a transition between sticky epithelial cells, which make up the bulk of solid tumors, and thinner, more mobile mesenchymal cells that are often found circulating solo in cancer patients bloodstreams. As more and more studies deliver results showing activity similar to that of Friedls migrating cell clusters, however, researchers have begun to question whether go-it-alone mesenchymal cells, which Friedl calls lonely riders, could really be the main culprits behind the metastatic disease that kills millions.

Some believe jamming could help get oncology out of this conceptual jam. A phase transition between jammed and unjammed states could fluidize and mobilize tumor cells as a group, without requiring them to transform from one cell type to a drastically different one, Friedl said. This could allow metastasizing cells to cooperate with one another, potentially giving them an advantage in colonizing a new site.

The key to developing this idea is to allow for a range of intermediate cell states between two extremes. In the past, theories for how cancer might behave mechanically have either been theories for solids or theories for fluids, Manning said. Now we need to take into account the fact that theyre right on the edge.

Hints of intermediate states between epithelial and mesenchymal are also emerging from physics research not motivated by phase-transition concepts. Herbert Levine, a biophysicist at Rice University, and his late colleague Eshel Ben-Jacob of Tel Aviv University recently created a model of metastasis based on concepts borrowed from nonlinear dynamics. It predicts the existence of clusters of circulating cells that have traits of both epithelial and mesenchymal cells. Cancer biologists have never seen such transitional cell states, but some are now seeking them in lab studies. We wouldnt have thought about it on our own, said Kenneth Pienta, a prostate cancer specialist at Johns Hopkins University. We have been directly affected by theoretical physics.

Biologys Phase Transition

Models of cell jamming, while useful, remain imperfect. For example, Mannings models have been confined to two dimensions until now, even though tumors are three-dimensional. Manning is currently working on a 3-D version of her model of cellular motility. So far it seems to predict a fluid-to-solid transition similar to that of the 2-D model, she said.

In addition, cells are not as simple as coffee beans. Cells in a tumor or tissue can change their own mechanical properties in often complex ways, using genetic programs and other feedback loops, and if jamming is to provide a solid conceptual foundation for aspects of cancer, it will need to account for this ability. Cells are not passive, said Valerie Weaver, the director of the Center for Bioengineering and Tissue Regeneration at the University of California, San Francisco. Cells are responding.

Weaver also said that the predictions made by jamming models resemble what biologists call extrusion, a process by which dead epithelial cells are squeezed out of crowded tissuethe disfunction of which has recently been implicated in certain types of cancer. Manning believes that cell jamming likely provides an overarching mechanical explanation for many of the cell behaviors involved in cancer, including extrusion.

Space-filling tissue models like the one Manning uses, which produce the jamming behavior, also have trouble accounting for all the details of how cells interact with their neighbors and with their environment, Levine said. He has taken a different approach, modeling some of the differences in the ways cells can react when theyre being crowded by other cells. Jamming will take you some distance, he said, adding, I think we will get stuck if we just limit ourselves to thinking of these physics transitions.

Manning acknowledges that jamming alone cannot describe everything going on in cancer, but at least in certain types of cancer, it may play an important role, she said. The message were not trying to put out there is that mechanics is the only game in town, she said. In some instances we might do a better job than traditional biochemical markers [in determining whether a particular cancer is dangerous]; in some cases we might not. But for something like cancer we want to have all hands on deck.

With this in mind, physicists have suggested other novel approaches to understanding cancer. A number of physicists, including Ricard Sol of Pompeu Fabra University in Barcelona, Jack Tuszynski of the University of Alberta, and Salvatore Torquato of Princeton University, have published theory papers suggesting ways that phase transitions could help explain aspects of cancer, and how experimentalists could test such predictions.

Others, however, feel that phase transitions may not be the right tool. Robert Austin, a biological physicist at Princeton University, cautions that phase transitions can be surprisingly complex. Even for a seemingly elementary case such as freezing water, physicists have yet to compute exactly when a transition will occur, he notesand cancer is far more complicated than water.

And from a practical point of view, all the theory papers in the world wont make a difference if physicists cannot get biologists and clinicians interested in their ideas. Jamming is a hot topic in physics, but most biologists have not yet heard of it, Fredberg said. The two communities can talk to each other at physics-and-cancer workshops during meetings hosted by the American Physical Society, the American Association for Cancer Research or the National Cancer Institute. But language and culture gaps remain. I can come up with some phase diagrams, but in the end you have to translate it into a language which is relevant to oncologists, Ks said.

Those gaps will narrow if jamming and phase transition theory continue to successfully explain what researchers see in cells and tissues, Fredberg said. If theres really increasing evidence that the way cells move collectively revolves around jamming, its just a matter of time until that works its way into the biological literature.

And that, Friedl said, will give biologists a powerful new conceptual tool. The challenge, but also the fascination, comes from identifying how living biology hijacks the physical principle and brings it to life and reinvents it using molecular strategies of cells.

Original story reprinted with permission from Quanta Magazine, an editorially independent publication of the Simons Foundation whose mission is to enhance public understanding of science by covering research developments and trends in mathematics and the physical and life sciences.

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DNA database brings scientists closer to pinpointing genes for disease

Analysis of more than 60,000 peoples DNA will help scientists to determine whether genetic mutations seen in patients are in fact behind their disease

Scientists say they are closer to pinning down the genetic causes of inherited diseases ranging from muscular dystrophy to certain types of heart disease after analysing the DNA of more than 60,000 people.

Researchers have discovered more than 3,000 genes in which certain mutations are likely to play a role in disease, as well as more than 160 genetic mutations that have previously been linked to inherited conditions – but are in fact harmless.

The findings will help to pin down whether genetic mutations seen in a patient are likely to be behind their disease.

Researchers and clinicians need to be able to determine which DNA changes are important [in their patients], said Dr Jane Gibson from the University of Southampton, who was not involved in the study. Has a particular change been seen before in healthy individuals? This helps to prioritise the [genetic] changes and narrow down the likely cause of disease in their own patient.

The new research is based on regions of DNA that encode information needed to make proteins regions that account for just under 2% of the entire human genome.

Those protein coding regions contain the vast majority of the [genetic] variants that are known to cause severe rare diseases like muscular dystrophy, said Daniel MacArthur, senior author of the research from the Broad Institute of MIT and Harvard. So focusing on those regions really gives us a lot of bang for our buck in terms of understanding the genetic causes of severe diseases.

The research is the fruit of an international collaboration, dubbed Exac, which pulled together data from around the world to produce the largest ever catalogue of variations in protein-coding regions of DNA, boasting data from 60,706 individuals.

Among their findings, the scientists discovered almost 7.5million genetic variants in the database. More than half of those are seen only once in 60,000 people – thats an incredibly rare frequency, said MacArthur, adding that most of the mutations identified have never been seen before.

As well as highlighting the high degree of variation among humans, the finding has important implications. These extremely rare variants are the ones that are most likely to be involved in very severe diseases like cystic fibrosis or muscular dystrophy, he said.

The research also revealed that there are 3,230 genes which have fewer genetic variations that would inactivate the gene than expected, meaning that many of these genes are likely to be involved in essential processes in the cell. That, the scientists add, means that disruptive genetic mutations in these genes are likely to have adverse effects – although such impacts are at present unknown for more than 70% of these genes. We know of some of the genes in the list already where gene disruptions cause very severe childhood onset diseases, said MacArthur.

The team were also able to overturn a number of links previously made between particular genetic mutations and a host of disorders, finding more than 160 genetic variants that had erroneously been linked to inherited conditions.

Surprising findings like these allow us to get a better understanding of how the human genome works and how different changes might or might not affect our health, said Gibson.

While the Exac database has been freely available for use in clinical settings since late 2014, the new research, published in the journal Nature, marks the first analysis of the data.

By using the database to work out how common a patients genetic variant is, and comparing it to how common the patients disease is, researchers hope to be able to screen for disease-causing mutations.

If [a particular genetic variant occurs in] one in every 6,000 people, it cannot be a fully causal variant for a disease that [affects] one in 100,000, said MacArthur.

Ewan Birney, co-director of the European Bioinformatics Institute in Cambridge says the Exac database is extremely important. Previously there would be a sense that if you had breast cancer, and you had a rare mutation in [genes known as] BRCA1 or BRCA2, then perhaps that rare mutation was the reason you got breast cancer, he said. We can now say for many of those variants, it is rare but it is not so rare and so it probably doesnt cause breast cancer.

In a separate study by researchers from the Royal Brompton Hospital and the University of Oxford, scientists describe how they used the Exac database to whittle down the number of genetic mutations linked to cardiomyopathy – diseases of the heart muscle that affect one in 500 people in the UK and are the most common cause of sudden death in young people who are otherwise in good health.

Published in the journal Genetics in Medicine, the researchers reveal how they compared genetic information from almost 8,000 patients to genetic variations found in the Exac database. The team found 40 of the 48 genes previously linked to one form of cardiomyopathy – and a third of the genes linked to another form – were unlikely to cause the disease.

As well as increasing the accuracy of diagnosis, the findings are expected to be valuable for testing family members of those who have been diagnosed with an inherited disease. When a mutation is identified you can cascade it around the family and you can say to other family members you are also at risk, said Birney.

While the Exac database includes genetic information from individuals of many different ancestries, including Latino, African and East Asian, there are other populations, including those of Central Asian ancestry that are missing from the dataset.

For Europeans now we have this database that really helps to screen out what ends up being benign mutations, said Birney. We need that now for all populations.

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