Category Archives: Human Genetics

June 7, 2017 by Claire Conway Zev Gartner is growing breast organoids with precise ratios of normal and tumor cells (shown at left) to understand how cell-cell interactions contribute to tumor growth. Credit: Photo by Elisabeth Fall, Cell Image by Gartner Lab

Ophir Klein is growing teeth, which is just slightly less odd than what Jeffrey Bush is growing tissues that make up the face. Jason Pomerantz is growing muscle; Sarah Knox is growing salivary glands; and Edward Hsiao is printing 3-D bone using a machine that looks about as complex as a clock radio.

Together, these members of the UC San Francisco faculty are cultivating organs of the craniofacial complex the skull and face which too often go terribly wrong during fetal development. Deformities of these bones or soft tissues, the most common of birth defects, can cut life short by blocking the airway or circulation. Or they can disfigure a face so profoundly that a child struggles to see, hear, or talk. Perhaps most painful of all, such deformities render children physically other, potentially leading to a lifetime of corrective surgeries and social isolation.

As director of the UCSF Program in Craniofacial Biology, Klein orchestrates a multisite research endeavor to translate basic science findings in tissue regeneration into improved treatments for these kids. Using stem cells from patients with craniofacial deformities, Klein, Bush, Pomerantz, Knox, Hsiao, and their colleagues are growing tiny functioning segments of organs, called organoids, to figure out exactly when and how in fetal development such design flaws occur.

They are among scientists across UCSF who are cultivating cellular systems such as miniature brains and breasts from patient cells. They serve as dioramas of disease models derived from human cells either displacing or complementing the mouse models that have served science well, though inexactly, for many years. The effort is one of the most obvious and viable payoffs to date from stem cell science. With these organoids, physicians and scientists can not only trace the pathways of normal and abnormal development, but also test drugs and other treatments for their effectiveness in humans. Organoids are also one tiny step toward the ultimate goal of generating complete organs, as a way to circumvent rejection issues and save the lives of those who now die waiting for transplants.

As the reservoirs of human development, stem cells take it upon themselves to tirelessly renew and differentiate into the myriad cell types required to build out a body from an embryo. In creating an organoid, typical construction metaphors do not apply. There are no building blocks to nail, stack, or solder and no job-site supervisor barking orders. "That's not how biology works," says Zev Gartner, PhD, an associate professor of pharmaceutical chemistry.

"It is a self-organizing process," he explains, a process that starts in the womb with embryonic stem cells (ESCs) or, in the case of organoids, induced pluripotent stem cells (iPSCs). iPSCs are mature cells that are stripped back to their earliest stage of development using a process devised by UCSF Professor of Anatomy Shinya Yamanaka, MD, PhD, who won a Nobel Prize for discovering the process. To make organoids, iPSCs are put through a series of solutions, then added to a gel that mimics the squishy 3-D cellular matrix of the embryo. The gel provides the right conditions for them to get to work.

"Take an organ like the lung. Its basic functional units are a tube and a sac, and outside that sac are capillaries that allow gas exchange. Hundreds of millions of tubes and sacs make a lung," explains Gartner. "You can make the little sacs and the tubes in a dish as an organoid model. But we don't know how to drive the self-organization of those units into much more complex, elaborate, highly ramified structures." The fundamental limitation of organoids is that they lack the vasculature that brings nutrient-laden blood to fuel the evolution of the larger structure.

Gartner notes that people who work with stem cells tend to focus on either regenerative medicine or disease modeling. Those interested in disease make models of tissues so that they can understand how diseases work, while those interested in regenerative medicine try to make models of healthy tissue that could be transplanted. Gartner straddles both camps. He grows breast organoids. "The mammary gland is great because we can simultaneously think about these two phenomena as two sides of the same coin," he says. "One is regenerative medicine through self-organization, and the other is understanding the progression of breast cancer through a breakdown in self-organization."

So there's potentially a triple payoff in stem cell science: By deducing how a breast forms itself, Gartner might figure out how to grow the entire organ. By tracing how cancer throws a wrench in the works, he may be able to target ways to stop that process. And by growing a human organ in a dish, he avoids making cross-species assumptions or putting animals or humans at risk in testing potential drugs to cure breast cancer, greatly accelerating the push toward a cure.

Regenerate

On Klein's team, Jeffrey Bush, PhD, an assistant professor of cell and tissue biology, looks at organoids through the lens of disease.

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The organoids he grows model craniofrontonasal syndrome a birth defect that is caused by a mutation in a single gene and that dramatically impacts the shape of the face and head. He knows from studies reproducing craniofrontonasal syndrome in mice that the first place something goes wrong is in a cell type called the neuroectoderm. To create an organoid to study this, he obtained skin cells from Pomerantz, an associate professor of surgery, who has patients with the syndrome who were willing to donate tissue samples. Such collaborations between basic scientists and clinicians are key to bringing research out of the lab and into patient care.

"We studied this simple system to see how this mutation affected the organization of these cells," says Bush. His group has filmed cells as they rush about to self-organize when they're mixed together. In those films, he explains, "you can see that the mutated cells, which are dyed red, segregate from the normal cells, which are green they are like oil and water." In other words, the mutated cells completely disrupt the behavior of all the cells. By contrast, in the films of cells without the mutation, all the cells circulate easily among one another, like fish in an aquarium. This understanding has allowed Bush to begin to think about a drug that blocks this separation. He has several promising candidates that his team will test in pregnant mice. "Right now," he says, "there isn't a single drug that we can use for any kind of structural birth defects. If we could show that a medication blocks the effects of this mutation, it would serve as proof of principle that something besides surgery can be done. But we would have to know that it was safe for mother and child and that we could catch it early enough."

Reconstruct

Jason Pomerantz, MD, a plastic surgeon, falls into the regeneration camp. His clinical work is typified by a recent eight-hour operation on a 17-year-old boy with Crouzon syndrome, a severely disfiguring condition affecting every organ in the craniofacial structure muscle, bone, and skin. "My patient is excited for the outcome, but not about the process," says Pomerantz, surgical director of the UCSF Craniofacial Center. For three months, the patient will wear a large metal frame on his head with wires that will pull the bones in his face forward. Prior to the surgery, the boy's face was nearly concave, collapsed inward at the nose.

Yet bone is not all Pomerantz needs to work with to restructure a face. The subtle bends, creases, and curves of expression that make a face one's own are the work of tiny muscles. "Right now we can move a big muscle say, from the thigh to the face so that people can smile," he says. "But we can't reconstruct the fine ones that enable people to move their eyebrows up or move the eyeballs around. That requires little muscles. This is where we can make headway with stem cell biology.

"We have actually made a humanized organ in an animal," he continues, pointing to a picture of a mouse on his wall. Pomerantz is now considering incubating small human muscles in animals for use in his patients' faces. In a recent project, he inserted stem cells from human muscles into a mouse whose own muscle stem cells had been incapacitated. He then perturbed the muscle to stimulate regeneration. As the muscle healed, the cells created new muscle tissue, which the mouse's nerves innervated to make a functioning muscle. It's exactly the size of the muscles Pomerantz needs for full articulation of expression and function in a human face or hand.

Create

Muscles are part of a vast and intricate system strewn throughout the body. Teeth, on the other hand, are islands unto themselves. "Teeth intrigue me from a regeneration perspective," says Ophir Klein, MD, PhD, chair of the Division of Craniofacial Anomalies, the Hillblom Professor of Craniofacial Anomalies, the Epstein Professor of Human Genetics, and a resident alumnus. "They are discrete organs all the parts are there." More intriguing still is the fact that many rodents have the ability to grow their front teeth continuously. Elephants and walruses also have ever-growing tusks, and even some primates lemurs can regrow their teeth.

A tooth can be regenerated in parts. Stem cells can be used to grow the root, and then a crown can be added to complete the tooth. To generate a whole organ at once, Klein's colleagues are planning to partner with bioengineers who can produce a biocompatible material that could serve as a framing device to jump-start the creation of dentin, one of the hard components of a tooth. If they start with the right cells, then the scaffolding will give the cells the shape information they need to create the right design. But even that isn't Klein's endgame. "In my lab, we're interested in figuring out why humans can't regrow teeth," he says. "In studying species that can, we hope to unlock the regenerative potential in our own cells that might be turned off."

Klein's work to generate teeth is inspired by his patients with ectodermal dysplasia, a congenital disorder characterized by lack of sweat glands, hair, or teeth. Being able to generate the roots of teeth would be remarkable for these patients, since the rest can be done with a crown. Right now, they must be fitted with dentures.

Klein is also taking another tack to help these patients. "We completed a clinical trial of a drug that basically goosed up the development of the organs when they weren't forming properly," he says. The drug a protein developed by Swiss collaborators of Klein's, based on studies of embryonic mice, who develop these organs in early- to mid-gestation was given to infants with the disorder right after birth. The trial was unsuccessful. Now, scientists in Germany are running a trial of the same drug, giving it instead to mothers carrying babies with this genetic disorder. The scientists will try to gauge what the best timing is for delivering the drug.

"What's great about this drug is that it doesn't seem to have any effects on any other organs besides teeth, hair, and sweat glands," says Klein. "Drugs for other conditions are far riskier, because they affect pathways that are important in the development of many organs."

Maintain

Sarah Knox, PhD, an assistant professor of cell and tissue biology, is using stem cells to figure out how to regenerate salivary glands compromised by radiation treatments for head and neck cancers or by craniofacial deformities. Her focus is on how the environment contributes to the activation and maintenance of the gland. The salivary gland, like all organs, is continuously replenishing the supply of cells and tissues it needs to function. Knox's research shows that the gland takes directional cues from nearby nerve cells not only to remain functional, but also to continuously replace itself. Her organoids are made of cells from a patient and nerve cells (ganglia) from a fetal mouse. "We are trying to explore the relationship between the stem cells and the nerves," she says. "How do the nerves know the tissue is there? How do the nerves provide instruction and feedback? Individual cells die off and new cells have to replace them. Organoids are giving us insight as to where those new cells are coming from and how we keep repopulating [them] all our lives."

As head of the UCSF Program in Craniofacial Biology which is based in the School of Dentistry and the Division of Genetics in the School of Medicine Klein stands at one of science's most compelling crossroads: regenerative medicine and genetics. Far in the future, both fields have potential that seem like science fiction today. We live in a world where people die waiting for organ transplants. What if we could pull these organoids from their petri dish and supply them with the fuel they need to become full-blown organs? Such a feat would necessitate either a host embryo perhaps from a pig, because pigs have organs the size of human organs or some other biological foundation. Some scientists are hoping to jump-start organ development with "scaffolding," or cells engineered to speed the developmental process. Others are zeroing in on the genome, particularly in kids with craniofacial anomalies caused by just one mutation, like craniofrontonasal syndrome; for example, a tool called CRISPR could allow scientists to splice that gene out and replace it with a normal gene. But the tool has yet to be used in humans, let alone a human fetus.

Ethical questions pepper either route. At their best, stem cells regenerate tissues; at their worst, they go rogue and grow into a tumor. "Yet with gene editing tools like CRISPR, you literally have the potential to change the species," says Klein. And in both scenarios, the cells can act with unforeseen off-target effects. Klein and his colleagues are in continual discussion about the repercussions of their work with the director of UCSF Bioethics, Barbara Koenig, RN, PhD '88. "Gene therapy is an example of an exciting new treatment that cured one serious pediatric illness severe combined immunodeficiency syndrome (SCID) but the genes unwittingly led to the development of leukemia," explains Koenig. "Genetic and stem cell interventions must be painstakingly studied before application. And, once they are ready, who will regulate them? There are many questions yet to be answered. The challenges are most extreme when we talk about modifying an egg or sperm cell, where the changes are passed on to the next generation."

So Klein and his colleagues proceed with caution, curiosity, and awe. "The next decade will be an incredibly exciting time," says Klein. "With continual advances in human genetics and developmental and cell biology, we hope to be able to make drugs and use genetic tools to appreciably change the lives of our patients."

The Bone Printer

Bone grows like a runaway train in Edward Hsiao's patients with fibrodysplasia ossificans progressiva (FOP). The slightest bump or injury can set off a spurt of bone growth that can fuse their vertebrae, lock their joints, or even freeze up their rib cages, leaving them unable to breathe.

No one, to date, has successfully engineered bone. Hsiao, MD, PhD, is hoping to spark the process with the help of a 3-D printer from Organovo, a firm that specializes in bioprinting technology. From iPSCs, he can make many of the essential ingredients of bone, including mesenchymal stem cells, endothelial cells, and macrophages. "We are putting cells into the equivalent of an ink. Then we will print the structures with the ink, let the ink dissolve, and leave the cells," explains Hsiao. "The hope is that the cells can then recapitulate the normal developmental process."

If the approach is successful, Hsiao hopes to use the resulting models to test drugs and other treatments to halt or prevent bone deformities. Down the line, his progress also stands to transform bone and joint replacements. Through his work with FOP, he's uncovered one mechanism that drives rapid bone growth. "In these patients, we know that mature bone formation can happen in as quickly as two weeks, so it is possible to grow bone in an adult. We need to understand how to modulate that," says Hsiao. "Someday, my dream would be to be able to identify the cells we need, give someone a drug that induces the right genes and recruits the right cells to the correct site, and have the cells rebuild the joint from scratch."

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Francis Collins to Stay On as Director of National Institutes of Health Wall Street Journal (subscription) ... noted geneticist who once headed the government's Human Genome project and served previously as director of the National Human Genome Research Institute, is 67 years old. He had previously been a professor of internal medicine and human genetics ... Genetics Authority to Continue as Director of US Health InstituteU.S. News & World Report Trump says he's keeping Francis Collins as NIH directorCBS News all 31 news articles »

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Francis Collins to Stay On as Director of National Institutes of Health - Wall Street Journal (subscription)

After millions of years of evolution, our species has, like an aging rock band, settled into a comfortable, familiar groove: Your classic bipedal, theory-of-mind-having Homo sapiens. Then, there is another class of human. This class of human has spectacular powers, such as mind control or the ability to manipulate electromagnetic waves, and exists mostly in big-budget global superhero franchises, like X-Men (or in mid-budget Ben Stiller-starring cult classics from 1999, like Mystery Men).

These characters arent generally celebrated for their realismbut are they really so implausible? Is it so hard to believe that, in some late-career burst of creativity, human beings might finally get it together and start evolving some wings, or night vision, or whatever?

For the latest installment of Giz Asks,we asked evolutionary biologists, academics, and futurists if it is at all possible that people with superhuman abilities are living amongst us, or one day will, and which of these abilities are the most scientifically plausible. They let us know that while mutant-humans probably arent evolving alongside us, there are certain scenarios (a move to Mars, say, or wide-scale climate-related devastation) which might bring about humans with radically different genetics in the distant future. Or, via genetic modification, in the next few months.

Scott Solomon is a biologist, professor, and writer; author of Future Humans: Inside the Science of Our Continuing Evolution; he currently teaches ecology, evolutionary biology, and scientific communication as a Professor in the Practice at Rice University in Houston, Texas.

Its unlikely that natural selection is currently operating to give people telepathy or mind control. And its fair to say that traits which defy the laws of gravity, like flight, are unlikely to ever evolve in humans. But one thing thats being developed now is technology that allows us to make changes to our DNA, through the use of CRISPR/Cas 9 which is a way of editing genomesincluding, in principle, the human genome. That is setting up a scenario in which, in the near future, it might be possible to make changes to humans and other organisms in very specific, deliberate ways... if were talking about traits that are at least physically possible.

For example, humans are able to see within a certain range of lightwe so call it the visible light spectrum, because thats what we can see. But insects in some cases can see light that is invisible to humansultraviolet light, as an example. So that means that its physically possible for an organism to see UV light, we just dont have the ability to do that, because our photoreceptor cells in our eyes arent attuned to those wavelengths of light. So if we knew all of the genetics that allow an insect to see light in the ultraviolet spectrum then at least in theory it might be possible to alter our own genes to allow humans to see light in the UV range as well.

And likewise some organisms can detect heat in the infrared spectrumfor example some species of snakes, or some insects. So again if we understood the genetics of that, then at least in theory we could manipulate our own genes in order to allow us to do that. Whether or not we should do that is a whole other question. But history seems to suggest that when humans develop the ability to use a particular type of technology, we tend to use it.

For a new species of human to evolve [naturally], there needs to be some sort of reproductive barrier. There would need to be something keeping this other type of human from mating with us. The current trend, on earth, for humans, is for populations to be coming together and mixing their genes... But if you send some people to Mars, and they start adapting to conditions therewhether through natural selection, or deliberately editing genes to try to make it easier for them to live on other planetsthat might lead us down a path where you have a new species evolving.

Living and boning in spaceparticularly on Marshas fascinated our degenerate species for decades.

Professor, Department of Biology, University of Washington; author of multiple books, most recently A New History of Life: The radical new discoveries about the origins and evolution of life on Earth, with Joe Kirschvink

Its all about super-soldiers. This is what the holy grail is going to be: getting that better military creature. Nothing is more efficient than biological structureno silicon, no metal. A soldier whos much harder to bleed to death, or a soldier that doesnt need to drink as much water, or doesnt need to eat for five or six days, or doesnt need to sleepany one of these things would be an enormous advantage in warfare. [With CRISPR/Cas 9] you can put a new gene into an organism, or you can tweak a gene and turn it on where it had been turned off, or turn it off where it had been turned on. The most important genes are regulatory genestheyre like generals that control hundreds of other genes, and so just by messing with one of them you could change entire swaths of what an organism looks like or how it behaves.

At the same time it turns out that there is a means of causing change that is not Darwinian. Lamarck is always ridiculed in evolution classeshes the guy that said that the reason giraffes have long necks is that giraffes would stretch their necks every day, and stretch and stretch and stretch, and all that stretching led them to produce babies with longer necks. Ha, ha, ha.

But in terms of behavior, it turns out that he wasnt as wrong as we think. Were finding more and more that, for instance, people who have gone through combat, or women who have been abusedwhen you have these horrendous episodes in life, it causes permanent change, which is then passed on to your kids. These are actual genetic shifts that are taking place within people. Its called epigenetics, and that too can cause huge evolutionary change.

On a larger scale, the amount of stress that Americans are going through now, because of Trumpthere is going to be an evolutionary consequence.

President of the World Futures Studies Federation, Adjunct Professor at the Institute for Sustainable Futures (University of Technology, Sydney) and author of The Future: A Very Short Introduction & Postformal Education: A Philosophy for Complex Futures.

Todays transhumanists claim that the only way for humans to have superhuman powers is through technological, biological, or genetic enhancement. The more extreme views of human-machine interface include cyborgs; Ray Kurzweils singularity the idea that human functioning can be technologically advanced exponentially until convergence; and Elon Musks neural lace, which merges the human brain with AI. All these ideas are still in the realm of science fiction, yet they are attracting hundreds of millions of dollars in funding.

Ironically, the idea of human beings evolving superhuman powers is not new. Friedrich Nietzsche wrote in 1883 about the bermensch translated as: Superman, Ultrahuman or Higher-Person. His ideas integrated Darwins biological evolution with the German Idealists writings on evolution of consciousness. Like Nietzsche, French philosopher Henri Bergson wrote in 1907 about the Superman arising out of the human being, in much the same way that humans have arisen from animals. In 1950, Teilhard de Chardin wrote about the Ultra-human or Trans-human, but his transhumanism was humanistic and spiritual, not high-tech.

Australian-based member of the Evolution, Complexity and Cognition group at the Free University of Brussels, author of The Evolutionary Manifesto and Evolutions arrow: the direction of evolution and the future of humanity.

A few random genetic mutations are incapable of producing new, highly complex capacities such as winged flight. It is as unlikely as it would be for a random earthquake in a medieval village to re-arrange everything to produce a modern city. This is because gene-based evolution proceeds largely through blind trial and error. The great majority of mutations will be harmful. Complex new adaptations can be discovered only through the accumulation of small advances over many, many generations. Billions of individuals must die as failed experiments in order to produce anything by trial and error that is complex and adaptive. In contrast, we can use our intelligent minds to narrow down the search and then try out targeted possibilities in our minds. It is a lot more efficient and acceptable to try out changes in our minds rather than by producing vast numbers of mutant individuals, nearly all of whom would die as failed experiments. As the great philosopher Karl Popper put it, our hypotheses die in our stead.

It is also highly implausible that super powers could be enabled by changes within the bodies of humans. The current laws of physics and chemistry do not seem to allow for mechanisms in flesh and blood that could enable, for example, individuals on different continents to communicate as effectively as they can be using smart phones. Certainly the typical super powers possessed by mutants depicted in movies seem inconsistent with the known laws of nature. At present they are the stuff of science fiction and are likely to always remain so.

PhD student, Ecology, Penn State University

I would say flight, mind control, telepathy [are the least plausible superpowers]. Im not even sure how mind control and telepathy could occur (although you could say mind control if you have particularly charismatic people paired with heavily suggestible people). Flight would require us reshaping our body beyond just getting wings. Wed need much better chest/back muscles, and, I believe, a shifting in our center of gravity, which would be long-coming and difficult. Night vision might be the easiest, though it also wont be easy or quick to come, just because our long ago ancestors were nocturnal.

Could a new kind of superhuman conceivably evolve alongside regular humans? If this new kind of super-mutated human is still the same species as us regular people, then I would think its more likely that the mutation is caused by a recessive gene (think your little n to a big N), and if theyre still breeding with us regular humans, youd end up with fewer pure mutants (nn), more carriers (Nn), and regular people (NN). Whether they live alongside us depends on the scenario.

Either way, this would take a ton of time, so I guess your best chance of having mutants and regular humans living together at the same time would be having mutants be the same species as humans, but something happens with a gene that causes phenotypic differences and can be carried.

Professor of Science Communication, School of Mathematics & Physical Sciences, University of Hull

Some superpowers are always going to stay firmly in the range of the fantastical; to quote Star Trek: you cant change the laws of physics. So speedsters such as The Flash and Quicksilver are never going to be able to consume enough food to power their supersonic runs. Similarly Johnny Storms ability to (reversibly) turn into superheated plasma must stay firmly in the realm of fantasy, it needs just too much energy.

However there are plenty of examples of superpowers in nature, so we know that these are at least biologically possible. Kestrel may have some version of telescopic vision, which is achieved by just packing more light sensitive cells into the retina. Bats have echo location, like that used by Matt Murdoch (as Daredevil). Plenty of animals have what we might call supervision because of their ability to see in UV. Then theres Magneto, who can sense and manipulate electro-magnetic fields. This isnt so far away from the abilities of electric eels, and even the humble pigeon can sense magnetic fields.

Assistant Professor, University of Saskatchewan

Theres tons of evidence in the fossil record that [new kinds of humans have evolved alongside regular humans] in the past, so I see no reason why that couldnt happen in the future.

We used to the think that there was a linear trajectory from our fossil ancestors to contemporary modern humans, but the more fossils that are discovered, the more evidence we have to suggest that there was not just an ancestral branch or tree, but more of an ancestral bush of fossil species which went off in various directions and then for whatever reasonwe still dont knowwent extinct. Were the only living relative around today, but we have lost different species that existed and lived next to each other in time, though not necessarily in space.

In terms of superpowers that we might evolve, or that I would like to seeit would build on what we already do. One side of the coin is that were incredibly gifted at killing each other.

The flipside of that is that were also incredibly good at taking care of each other, and that is the reason why I think weve thrived as a species, because were social, and we work together, and we cooperate. So as we enter into this really tense and tenuous part of our history, when were in the Anthropocene, and the climate is changing, Id really like to see us as a species, and globally as a community, develop our superpowers to go above our current level of empathy and compassion and imagination and ingenuity and really take them to heroic, comic book levels of innovation and policy-making and invention. We need to become our own heroes.

Do you have a burning question for Giz Asks? Email us at tipbox@gizmodo.com.

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Can Superhuman Mutants Be Living Among Us? - Gizmodo

Instead of asking, Whats your sign? you should be asking a potential mate, Whats your genetic HLA blueprint?

It wasnt the dog in his profile picture or the kissy face emoji she sent you that attracted you to "the one" it was science.

via GIPHY

Humans have their own unique human leukocyte antigen (HLA) complex. HLA helps the immune system figure out which are its own cells and which are viruses and bacteria.

A study published in Nature studied attraction patterns in 254 couples and found that a partner with a different HLA pattern "correlates with sexuality and enhances the desire to procreate."

Opposites attract.

The study concluded that couples with differing HLA complexes found the scent of their partner even more appealing, but whether its genetics or just being enamored with the person, isnt clear.

via GIPHY

Men and women of various cultures seek out perfumes which highlight their body odour in the most desirable way, the study authors wrote. The famous novel Perfume by Patrick Suskind describes a perfume made of body odours that drives people into ecstasy and makes them forget civilized behaviour. However, recent research indicates that the olfactory match between people, rather than a universally irresistible smell, might be the key to olfactory attraction.

You and me baby ain't nothin' but mammals, so let's do it like they do on the Discovery Channel.

This olfactory attraction has evolutionary benefits, too.

Researchers found that if two animals with different major histocompatibility complexes (MHC) the equivalent of humans HLA mated, their baby would have an extremely strong immune system.

Study authors concluded: Attraction is a miracle to most of us and only some of the many factors mediating mate choice involve odours. However, within the world of human olfaction, there seems to be no perfect mate but a perfect partner and this depends on HLA match.

And if the Bloodhound Gangs 1999 hit is stuck in your head, youre welcome.

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Sexual attraction is all in your genes, baby - Metro US

The first genetic variants to be associated with female urinary incontinence have been identified.

Researchers based in the UK and Poland carried out a genome-wide association study using data from 8,997 people and then confirmed their findings in a cohort of 4,069.

The team detected five genetic loci associated with stress and urgency incontinence, including two that were replicated in the second cohort.

One of these was located near the gene encoding endothelin 1, which is involved in muscle contraction in the bladder. This genetic variant was strongly associated with urgency urinary incontinence, a sudden and uncontrollable need to urinate that affects around 5% of women.

Another genetic variant linked to urinary incontinence in both cohorts was identified near a gene called MARCO, which is involved in immune function.

Although stress and urinary incontinence have been shown to be heritable, no genetic variants had previously been associated with the conditions.

The findings indicate that drugs targeting the endothelin pathway could be effective in urgency incontinence, such as those already used for treating pulmonary hypertension and Raynauds syndrome, the researchers say.

The identification of genetic variants could also lead to screening women for risk of developing the condition to help improve the advice given to them during pregnancy and inform the choice of delivery, the team suggests.

Clearly this will need further debate and an analysis, not just of the cost to healthcare systems, but also of the benefit to women who may be spared the distress of urinary incontinence, says researcher Rufus Cartwright at Imperial College London, who presented the findings[1] at the European Society of Human Genetics Annual Conference in Copenhagen.

Citation: The Pharmaceutical Journal, PJ May 2017 online, online | DOI: 10.1211/PJ.2017.20202869

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Researchers find genetic link to female urinary incontinence - The Pharmaceutical Journal

About one in 200,000 people are affected by a severe group of skin disorders known as the ichthyoses (ik-thee-oh-sees), which feature dry, scaly, or thickened skin. Although treatment with topical medications can help, there is no cure. To better understand the cause of such skin disorders, a Yale-led research team studies the genes of individuals affected by the conditions.

Mutations underlying most types of ichthyosis have been identified, but roughly 15% of cases have unexplained origins, said associate professor of dermatology and senior author Dr. Keith Choate. To uncover potential new causes, the research team initially sequenced patients exomes (the protein-coding portions of the genome). They identified mutations in the gene KDSR that prevent the skin from producing ceramides fat molecules that seal the skin and protect it from water loss. Ceramides are naturally generated by the body, and are also a component of many commonly used moisturizers and cosmetics.

Interestingly, each of the study subjects has a KDSR mutation that might have been missed by standard analysis methods. Three of them have a silent substitution that usually would be considered harmless, but this particular mutation was demonstrated by the team to disrupt splicing the assembly of gene copies that are translated into proteins.

Additionally, while some subjects had observable mutations in both copies of the gene (one inherited from each parent), two subjects initially seemed to show only one mutation, said Dr. Lynn Boyden of the Yale Department of Genetics. This led us to look more closely, said Boyden, the lead author on the study.

The researchers noticed that both subjects shared a common benign variation in the KDSR gene. It appeared too frequently in the population to be disease-causing, but too rare to be a coincidental observation, and was a clue that these individuals likely also shared another KDSR mutation, one that contributed to disease but wasnt revealed by exome sequencing.

Sequencing of the entire genome of one of the subjects validated this hypothesis, exposing a large inversion that swapped the beginning of the KDSR gene with an unrelated sequence, and thereby disrupted the genes expression. Researchers often save money by sequencing only exomes, which are ~1% the size of genomes, but this is an example of the kinds of mutations that can be missed. This underscores the importance of comprehensively investigating unsolved genetic diseases, Boyden said.

The researchers also found that a commonly used acne medication, isotretinoin (Accutane), counteracts the effect of the mutations, allowing the skin to employ a different biological pathway to produce ceramides and to prevent the skin condition. In both patients whove utilized it, the medication has cured the disease, Choate said.

In addition to identifying effective treatment of a rare and disfiguring condition with an existing medication, the study results also highlight the central role of ceramides in skin health, and their value as common ingredients in many moisturizers and other cosmetic products, said the researchers.

Read the full paper, Mutations in KDSR cause recessive progressive symmetric erythrokeratoderma, in the American Journal of Human Genetics.

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Yale study finds cause of and cure for genetic skin disorder - Yale News

New York Times

How a Galpagos Bird Lost the Ability to Fly New York Times Alejandro Burga, who analyzed the DNA of these and other cormorants with his colleagues, is a researcher in the lab of Leonid Kruglyak, the chairman of human genetics at U.C.L.A.'s medical school. He said he and Dr. Kruglyak were discussing how they ... How the Galapagos cormorant lost its ability to flyUCLA Newsroom Galapagos bird's evolution could aid study of bone diseaseTimes LIVE all 6 news articles »

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How a Galpagos Bird Lost the Ability to Fly - New York Times

A new genetic study of male ancestry shows there were periods in human prehistory when just a few elite men controlled reproduction.

For example, one man about 190,000 years ago was the ancestor of 1,200 living men from 26 groups around the world whose genes were analyzed for the new study.

Would the world have been different if it had been another man who had fathered much of the human race?

Another finding of the study is that one man who lived in Europe about 4,000 years ago is the ancestor of half of Western European men, [study leader] Dr. [Chris] Tyler-Smith toldThe Telegraph. In Europe there was huge population expansion in just a few generations, he told The Telegraph. Genetics cant tell us why it happened but we know that a tiny number of elite males were controlling reproduction and dominating the population. Half of the Western European population is descended from just one man.

Nearly a year agoscientists reportedin the journalNaturethat the majority of European men are descended from just a handful of Bronze Age male ancestors.

The GLP aggregated and excerpted this blog/article to reflect the diversity of news, opinion, and analysis. Read full, original post:Just a Few Men Controlled Reproduction in Prehistory and Dominate World Genetics Today

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Studs: Most men trace their genetics back to a few early human prolific 'elite males' - Genetic Literacy Project

Researchers are working to determine why the aortic valve doesnt form correctly in patients with the most common congenital heart defect: bicuspid aortic valve.

In a new Nature Communications study, the Michigan Medicine-led group found two genetic variants associated with the condition.

Bicuspid aortic valve is moderately heritable, yet experts are still figuring out which part of our DNA code explains why some BAV patients inherit the disease.

Weve completed the first successful genomewide study of bicuspid aortic valve, by studying subjects at U-Ms Frankel Cardiovascular Center, says first author Bo Yang, M.D., Ph.D., a Michigan Medicine cardiac surgeon. We are using state-of-the-art technology of induced stem cell and gene editing to dissect the genomic region we found to be associated with BAV. Its a great collaboration that will accelerate our scientific understanding of this disease.

BAV patients have aortic valves with only two leaflets, rather than three, limiting the valves function as the heart pumps oxygen-rich blood toward the aorta to enrich the body. The condition is associated with various complications, including a narrowed valve (aortic stenosis), a leaky valve (aortic insufficiency or regurgitation), an infection of the valve or an aortic aneurysm.

"This finding gives us a great head start toward understanding the mechanism of how a genetic change outside the protein-coding part of the genome can lead to disease."Cristen Willer, Ph.D.

A great head start

The researchers performed genomewide association scans of 466 BAV cases from the Frankel Cardiovascular Center and 4,660 controls from the Michigan Genomics Initiative, with replication on 1,326 cases and 8,103 controls from collaborators at other leading institutions. They also reprogrammed the matured white blood cells to change them back into immortal cells (stem cells) and changed the genetic code of those cells to study the function of the variants they identified through the genomewide association study.

The team reports two genetic variants, both affecting a key cardiac transcription factor called GATA4, reached or nearly reached genomewide significance in BAV. GATA4 is a protein important to cardiovascular development in the womb, and GATA4 mutations have been associated with other cardiovascular defects.

One of the regions we identify actually changes the protein coded by the gene, and the other likely changes expression levels of GATA4 during valve formation, says senior author Cristen Willer, Ph.D., professor of internal medicine, human genetics and computational medicine and bioinformatics. Because most genetic variants associated with human disease are in the 99 percent of the genome that doesnt code for proteins, this finding gives us a great head start toward understanding the mechanism of how a genetic change outside the protein-coding part of the genome can lead to disease.

Specifically, the authors point to a disruption during the endothelial-mesenchymal transition, which is a critical step in the development of the aortic valve. Willer and Yang say this study, with support from the Frankel CVC and the Bob and Ann Aikens Aortic Program, adds new knowledge about the mechanism of BAV formation. They plan to continue to study the biological effect of both variants associated BAV in cells and animal models.

Reference

Yang, B., Zhou, W., Jiao, J., Nielsen, J. B., Mathis, M. R., Heydarpour, M., ... & Fritsche, L. (2017). Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve. Nature Communications, 8, 15481.

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2 Gene Variants Linked to Most Common Congenital Heart Defect - Technology Networks

PHILADELPHIAA new strategyan injectable antibodyfor lowering blood lipids and thereby potentially preventing coronary artery disease and other conditions caused by the build-up of fats, cholesterol, and other substances on the artery walls, is supported by findings from two new studies from researchers in the Perelman School of Medicine at the University of Pennsylvania.

The new approach targets a protein called ANGPTL3, a regulator of enzymes that clear triglycerides and other fat molecules from the blood. Research in recent years has hinted that inherited mutations in the ANGPTL3 gene that disable its function can decrease triglyceride, LDL cholesterol, and HDL cholesterol levels.

As reported in a paper published May 24 online in the New England Journal of Medicine, researchers from Penn Medicine, Regeneron Pharmaceuticals, and a group of international collaborators studied ANGPTL3 in both humans and mice. They found that blocking ANGPTL3 activity with an investigative injectable antibody, known as evinacumab, reduced triglycerides by up to 76 percent and lowered LDL cholesterol 23 percent in human study participants, and largely reversed signs of atherosclerosis in a mouse models.

Researchers also included a human genetics study of approximately 188,000 people, which found that carriers of mutations that disable ANGPTL3 had nearly 40 percent fewer incidents of coronary artery disease as compared to those with fully functioning ANGPTL3.

In the clinic, I treat many patients with very high triglycerides, but our current medications arent lowering triglycerides enough in many cases. Im delighted at the prospect of a new treatment thats a lot more potent, all the more because it lowers LDL at the same time, said study co-author Richard L. Dunbar, MD, assistant professor of cardiovascular medicine and member of Penns Division of Translational Medicine and Human Genetics. Its very reassuring to see that people with this genetic defect actually seem to be protected from heart disease. I think that really bodes well for a therapeutic thats targeting the ANGPTL3 pathway.

In a separate study, published in the March issue of the Journal of the American College of Cardiology (JACC) researchers from Penn Medicine, Harvard Medical School, Washington University in St. Louis, and nine other institutions, who also studied humans and mice, reported on a similar set of findings. Among these was the discovery from another large population sample that carriers of ANGPTL3-inactivating mutations had a 34 percent lower rate of coronary artery disease compared to non-carriers.

We used different lines of evidence to show that ANGPTL3 deficiency is associated with a reduced risk of coronary artery disease, said study co-author Kiran Musunuru, MD, PhD, MPH, an associate professor of Cardiovascular Medicine at Penn. But ultimately we were able to identify that fact that carriers of this genetic mutation did in fact experience a benefitwith little other health risk.

The trial of research on ANGPTL3 as a potential target for atherosclerosis prevention began over a decade ago when scientists reported on two cases of familial hypolipidemia, a rare inherited condition involving abnormally low blood levels of cholesterol and triglycerides. Most cases of familial hypolipidemia are linked to other gene mutations that cause liver and digestive problems, but in members of this American family with the condition, Musunuru found mutations in the gene for ANGPTL3, and no associated health problems.

In the NEJM study from Dunbar and colleagues, the antibody had similar effects in an initial clinical trial in 83 people, lowering the blood levels of triglycerides measured after fasting by about 75 percent at the highest dose, and lowering LDL cholesterol by about 30 percent.

Statins and other drugs are already widely used to lower LDL cholesterol, but there are fewer options for lowering triglycerides. For treating high triglyceride levels theres really nothing out there thats quite this potent, so thats where I expect this new approach to have its greatest therapeutic benefit, Dunbar said.

Hypertriglyceridemia, a condition in which fasting triglyceride levels are greater than 150 mg/dL, is estimated to affect at least tens of millions of American adults. It is associated with coronary artery disease and other forms of atherosclerosis, and can lead to potentially fatal inflammation of the pancreas.

In principle, the strategy of targeting ANGPTL3 could have an even broader use in treating atherosclerosis in the general population. The researchers found that in a mouse model of atherosclerosis, treatment with evinacumab reduced the area of atherosclerotic lesions by 39 percent.

The population study findings, including those from the JACC study, suggest that even the partial inactivation of ANGPTL3carriers typically have one mutant copy of the gene and one working copymay be powerfully protective against coronary artery disease, which has long been one of the leading causes of death in developed countries. In the JACC study, for example, carriers of inactivating ANGPTL3 mutations had only a 17 percent reduction in triglycerides on average. But that modest reduction was associated with a 34 percent reduction in coronary artery disease risk. Moreover, Musunuru and his colleagues found that the people in their sample with the lowest blood levels of ANGPTL3 had a 35 percent lower rate of heart attacks compared to those with the highest ANGPTL3 levels.

Dunbar noted that the population study findings probably have lain to rest a lingering concern about targeting ANGPTL3, namely its effect in lowering not just LDL and triglycerides but also the so-called good cholesterol, known as HDL cholesterol. If lowering HDL were a major concern, then I dont think we would have seen the evidence of overall benefit that we did in this study, he said.

The two studies together suggest that single copies of inactivating ANGPTL3 mutations are found in roughly one of every 250 people of European descent, whereas people with mutations in both copies of the geneas in the family studied by Musunuru and colleaguesare much rarer.

According to Dunbar, the next logical step would be to take evinacumab into larger clinical trials to study its safety, effectiveness, and optimal dosing. The effect of even a single dose lasts for several months, and its plausible that with multiple doses we would see an even deeper and more sustained effect, he said.

Additional Penn authors on the NEJM study include Scott Damrauer, MD, Aeron Small, and Daniel J. Rader MD, and the Journal of the American College of Cardiology study include Xiao Wang, PhD, Daniel J. Rader, MD, and Danish Saleheen, MBBS, PhD.

Funding sources for the studies detailed in this press release included grants from the National Heart, Lung, and Blood Institute (NHLBI) (R01HL131961), (K08HL114642), (R01HL118744), (R01HL127564), and (R21HL120781) and Regeneron Pharmaceuticals.

Editors Note: Dunbar has received grant support from and consulted for Regeneron Pharmaceuticals, Inc.

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Genetic Mutation Studies Help Validate New Strategy for Reducing ... - Lab Manager Magazine