Category Archives: Genetics

Making New Friends: The Genetics of Animal Domestication – lareviewofbooks

JUNE 18, 2017

THERES A SCENE in Antoine de Saint-Exuprys The Little Prince where the alien prince, fallen to Earth, comes across a fox. Come and play with me, he proposes to the fox, who replies, I cant play with you. Im not tamed. The prince, whos never heard the word tamed before, asks what it means. Its something thats too often neglected, the fox tells him. It means, to create ties. [] If you tame me, well need each other. Youll be the only boy in the world for me. Ill be the only fox in the world for you. [] [I]f you tame me, it will be as if the sun came to shine on my life. I shall know the sound of a step that will be different from all the others.

In 1952, nine years after Saint-Exuprys book was published, the Russian geneticist Dmitri Belyaev set out, like the Little Prince, to tame a fox or rather, foxes. His goal was to better understand how domesticated dogs evolved from the wolf, and he proposed to do this by domesticating the silver fox, the wolfs genetic cousin. By mimicking the wolfs transformation with a close relative, Belyaev thought, we could better understand one of the great mysteries of prehistory: the dogs route to domestication.

We know more about this process now than we did when Belyaev embarked on his research project decades ago. To his scientific peers, Belyaevs belief that he could replicate 10,000 years of evolution and breeding in a few decades with a species that had never been domesticated before, seemed entirely fanciful. But he turned out to be right: within a few years of starting his experiment, the foxes were already showing signs of domestication; within decades, they were on their way to becoming their own species. How to Tame a Fox (And Build a Dog) traces the history of Belyaevs experiment against the background of first the Soviet Union and then postCold War Russia. Its co-authored by the geneticist Lyudmila Trut, who joined Belyaevs team early on and has been the lead researcher of the fox domestication project since 1959, and the evolutionary biologist Lee Alan Dugatkin.

Domesticated animals exist in a peculiar gray area between the world of humanity and the rest of nature. From the Book of Genesis to the modern environmental movement, we tend to understand nature as something that we stand apart from and exert power over, whether to dominate or to protect. But cats, dogs, horses, and other domesticated creatures exist in a liminal space between these two worlds. As W. G. Sebald says of the dog, His left (domesticated) eye is attentively fixed on us; the right (wild) one has a little less light, strikes us as averted and alien.

Domestication is not simply the engineering of a change in animal behavior; it is a matter, as Dugatkin and Trut write in their opening pages, of constructing a brand new biological creature. Dogs, after all, are a separate species from wolves, and housecats are so different from their feline cousins that its not entirely clear from which species they were domesticated (though most biologists agree that it was probably the Middle Eastern wildcat). Domestication is not just a question of selectively breeding some traits at the expense of others; its about fundamentally changing the animal.

Across species, domesticated animals seem to share a number of traits that differentiate them from their wild counterparts. Most have shorter faces and curly and floppy tails, traits associated with delayed physiological development and remaining in a stage of perpetual adolescence; biologists refer to this as neoteny. Domestic animals also tend to develop different coloration patterns, and unlike their wild cousins, who mate only once a year, theyre fertile year round. Other traits are significant but harder to measure: a dog may not have the same apparent aptitude for solving puzzles as a wolf, but will display more social intelligence in its ability to manipulate human emotions.

The riddle of domestication has always been how to unravel this ball of traits, and learn how they came to be associated with one another. Were early domestic animals selected for their usefulness to humans (cats for pest control, dogs for security and hunting), and then socialized from there? Were their neotenic traits necessary for their domestication, as animals that remained juveniles were perhaps easier to train? Was the wolfs nature as a pack animal, and responsiveness to socialization and group identity, crucial to its taming? And what of the superficial aesthetic differences do they have any bearing on domestication? Farmers raising cows, after all, had nothing to gain from their cows having black-and-white spotted hides, Dugatkin and Trut note. Why would pig farmers have cared whether their pigs had curly tails?

Belyaevs hypothesis was that the single most important defining trait was comfort around human beings. Zebra and deer, for example, share many traits in common with horses but have long resisted any attempts at domestication. Zebra, under constant threat from predators, have developed a fierce defensiveness, whereas deer remain skittish and are universally nervous around humans. What separates both of these animals from their close genetic cousin the horse is the latters tolerance of humans. Early attempts to domesticate horses, DNA evidence suggests, were based on selecting for agreeableness and manipulating the horses innate fear response.

Among the numerous traits that identify domestic animals, then, Belyaev used as his sole criterion tolerance for human beings. Foxes tend to be either aggressive or skittish around humans; Belyaev and his team focused on those that seemed least defensive. These were bred together, and successive generations were likewise measured for their tolerance for humans, with the researchers hoping that eventually this quality could be bred in offspring.

Within three breeding seasons, the researchers were seeing results: Some of the pups of the foxes theyd selected were a little calmer than their parents, grandparents, and great-grandparents, Trut and Dugatkin write. They would still sneer and react aggressively sometimes when their keepers approached them, but at other times they seemed almost indifferent. Even more surprising, though, was how quickly these behavioral changes were accompanied by other differences. In a matter of years, hormones associated with stress decreased, while levels of serotonin (which decreases anxiety and elevates ones mood) increased. The foxes went from being merely indifferent around the researchers to actively soliciting their affection. Eventually, their tails would even wag at the sight of humans something no other animal besides a dog has been known to do.

Selecting for tameness also led to a series of physical changes: Belyaevs foxes had bushier tails, shorter faces, lighter fur. Which is to say: Traits that were not in any way selected for nonetheless began to assert themselves. At one point, the foxes began making a sound that at first confounded Trut and her team, until she realized that they appeared to be mimicking human laughter. As they ultimately concluded, the tame foxes were making this noise in order to attract human attention and prolong interaction with people. They were displaying the same kind of social intelligence that dogs do when they perform tricks for their masters.

The fox experiment bore out Belyaevs initial hypothesis about tolerance for humans as the key to domestication. These results suggest that many of the various other traits associated with domestication are in fact already latent in animals genetic codes; its just that, in the wild, these traits are inactive, rarely expressing themselves. Selective breeding can allow them to come to the fore relatively quickly. Shake up the fox genome by placing foxes in a new world where calm behavior toward humans is the ultimate currency, Dugatkin and Trut conclude, and youll get lots of other changes mottled fur, curly, wagging tails, and better social cognition as well.

The story of Belyaev and Truts decades-long experiment is fascinating, though in How to Tame a Foxs telling some important details get left out. In crafting a heartwarming story of how easy it was to create docile, loving pets, Dugatkin and Trut dont dwell on the fact that they were also trying to create exceptionally aggressive foxes to further test the hypothesis. Nor were they just breeding foxes: other species, including rats and beavers, were also bred for both aggressiveness and tameness. According to one anecdotal report of the project that isnt mentioned in the book, Soviet officials had planned to use the most aggressive beavers as a line of defense against a possible US invasion. One wonders what other strange tidbits might have come to light had the authors not chosen to selectively shape their narrative. As a result, the book itself feels much like its subjects: bred for tameness.

It might have been better had How to Tame a Fox not been co-written by one of the principal researchers, so as to introduce a modicum of objectivity and critical distance into the writing. At times the book reads like a third-person memoir: Pushinka [one of the foxes] lay by Lyudmilas feet while she worked at her desk, and she loved for Lyudmila to play with her and take her for walks around the area. A favorite game was when Lyudmila would hide a treat in her pocket and Pushinka would try to snatch it out. Such passages are often lovely and do help to convey the remarkable level of domestication the foxes had achieved in such a small span of years (and only the coldest hearted wont melt at the photos of the foxes themselves). But in a book that largely skimps on the scientific and philosophical implications of its narrative, they can feel a bit too sentimental. It is also odd to read passages that describe Trut as a woman of great warmth and an unassuming demeanor, whose formidable energy and determination made her a force to be reckoned with when she is also listed as a co-author of the book.

One thing How to Tame a Fox does reveal is the precariousness inherent in government-funded research, with lessons that go far beyond Soviet Russia. In the early 50s, when Belyaev began his project, the entire field of genetics was under assault in the USSR. A well-placed friend of Stalin, Trofim Lysenko, had promised that he could increase crop yields by freezing seeds before planting. Lysenkos claim was not only false, it ran counter to the prevailing understanding of crop genetics. Since Lysenko knew geneticists could unmask him as a fraud, he began a campaign to discredit the entire discipline, labeling them as saboteurs. Thus, when Belyaev first described his research program to Trut, he told her it could not appear to have anything to do with genetics; instead, it had to be described as an inquiry into fox physiology.

After Stalins death, Lysenkos stranglehold on the discipline loosened, and geneticists could once again work without fear of reprisal. But with the fall of the Soviet Union and the economic crash of the 1990s, research budgets were slashed, and the project nearly ended for lack of funds. Trut took to begging passersby for food to feed her starving animals; eventually she was forced to sell some of the domestic foxes for pets, and some in the control groups for fur. Only an internationally published paper on her results saved the project, triggering a fundraising campaign that kept the animals alive.

Belyaev died in 1986, but he had hoped to one day write a book himself, which he planned to call Man Is Making a New Friend. How to Tame a Fox (and Build a Dog) is not far off from what Belyaev envisioned: written for a general audience, it chronicles the story of a scientific gambit that was more successful that even its creators had dreamed. Its an inspiring reminder of how much we still dont know about the world, and how much can be learned by taking bold chances. Its also a cautionary tale about the risks of state-funded science that has nearly as much relevance to Trumps United States, where federal research budgets are in danger of being slashed right and left, as it does to Stalins Russia.

But Belyaevs experiment didnt just produce new knowledge; it also created a new species of animal, one thats become entirely dependent on humans, and its worth asking what the ethical and philosophical consequences of this might be. Some scientists believe that wolves actively participated in their own domestication; thousands of years ago, certain wolves may have made the calculation that, by sucking up to humans, they could live an easier life. These wolves gave up autonomy and freedom in exchange for food, shelter, and protection. The gamble ultimately paid off: there are now only about three hundred thousand wolves in the wild, and over half a billion dogs.

But a dogs life is not an easy one, especially without a human being to care for it. Many contemporary breeds lack the skills to fend for themselves, having depended on their masters for generations. Perhaps in the future wild foxes will go extinct, and the only foxes that remain will be the domesticated ones, the ones that have endeared themselves to humans to such a degree that even in times of strife and scarcity we will look out for them. But the precarious state of Belyaevs project may well signal another outcome, one in which these foxes, whove thrown their all in with their human protectors, may find a darker fate awaiting them. If the money to keep the program going dries up, and theres no market for them as pets, what then? In The Little Prince, Saint-Exuprys protagonist does indeed tame his new friend, but before he does the fox offers this warning: People have forgotten this truth. But you mustnt forget it. You become responsible for what youve tamed.

Colin Dickey is the author, most recently, of Ghostland: An American History in Haunted Places.

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Making New Friends: The Genetics of Animal Domestication - lareviewofbooks

Malky Mackay: we are fighting genetics and a Scottish diet – The Times (subscription)

Malky Mackay leaves no stone unturned in his efforts to improve the Scottish game. Graham Spiers reports

When Malky Mackay was making his way in football he studied for and received a Certificate of Applied Management from the Warwick Business School. It helped Mackay that he is, by nature, a voracious reader of books and a man who thirsts after knowledge.

Mackay once spent a day with the SAS because he wanted to understand the mechanics of key decision-making in pressured situations. I wanted to understand their team-work and leadership: who can handle a stressful situation under real pressure? he said. These guys are so good at what they do. And it is about life and death: if they dont get it right, if they dont have the right team-work, then thats it.

Last year Mackay travelled to America to spend time

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Malky Mackay: we are fighting genetics and a Scottish diet - The Times (subscription)

Episode 87: Virtual Reality, and the Politics of Genetics – The New Yorker

As scientists learn more about how genes affect everything from hair color to sexual orientation and mental health, were faced with moral and political questions about how we allow science to intervene in the genetic code. In this episode, Siddhartha Mukherjee, the author of the book The Gene: An Intimate History , talks with David Remnick about the intimate and global implications of modern genetic science, and speaks frankly about his own family history of mental illness. Plus, we visit the studio of a leading sound-effects artist, and a virtual-reality team struggles to make a V.R. experience that lives up to the hype. This episode originally aired on May 13, 2016.

Welcome to the thoughtsphere. Whats a thoughtsphere?

The physician and Pulitzer Prize-winning author examines the intimate and global implications of genetic science.

Virtual reality used to be the technology of the future. Now its here. How will artists use the young medium to tell stories?

Three weird things you need to check out: a random-film-clip generator, an Internet graveyard, and the Turkish Star Wars.

The sound of a guy getting beaten with a bat in Goodfellas was engineered by an ex-magician with a hideout in Jersey.

Two mothers meet on the playground, and things get weird.

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Episode 87: Virtual Reality, and the Politics of Genetics - The New Yorker

Genetics key to livestock disease relief – Iowa Farmer Today – Iowa Farmer Today

Ask people in the research business if they have a wish list, and many will answer in the affirmative.

There are always different things you want to see done, says Jim Reecy, an animal scientist and director of the Office of Biotechnology at Iowa State University.

Much of Reecys work involves genetically changing traits in cattle to better predict performance.

For example, researchers are working to find cattle that offer genetic resistance to respiratory ailments such as bovine respiratory disease (BRD). This trait would be similar to others producers have selected for years, such as birth and weaning weights.

There is a large consortium of universities working on this, and its very exciting, Reecy says. It would work just like any other EPD (expected progeny difference) that producers are already using to select genetics.

Heat tolerance is another trait being looked at under the microscope. Reecy says projects at the University of Missouri and the University of Florida could greatly influence genetic selection.

The project at Missouri is looking at hair coat shedding, and the other in Florida is looking at internal body temperatures, he says. This research would allow producers to select cattle that handle heat better.

At Iowa State, researchers are looking at what traits allow certain cattle to better respond to vaccinations used for respiratory disease.

Something like this will allow producers to cull off cattle that do not respond as well to vaccinations, Reecy says.

The top item on his wish list would be the elimination of communicable diseases like BVD (bovine virus diarrhea).

Something like this would be similar to the gene editing that led to de-horning, Reecy says. Something like that would change the industry.

Much of the work in the hog industry also involves genetics, says Dave Pyburn, a veterinarian and senior vice president for science and technology with the National Pork Board.

The most promising research, he says, comes from the University of Missouri where scientists have isolated the point where the PRRS virus enters a cell.

They have been able to remove that attachment point from the cell, Pyburn says. They also looked at pigs who were not affected. So, through natural selection or gene editing, we could get to the point where we have pigs that are resistant to PRRS.

This disease cost the industry $664 million last year, so this is very significant.

Pyburn says the technology could be available in five to 10 years.

Other areas receiving attention from researchers include biosecurity, animal welfare and pork quality.

We need to take our biosecurity research to the next level, Pyburn says. There are things we need to better understand, such as filtration systems in buildings. The key is to try and prevent the disease, and subsequently reducing the need for antibiotics.

He says animal welfare issues include different euthanasia methods and pain management.

More research is needed on teeth and tail clipping, as well as castration, Pyburn says. We need to look at analgesics that can be passed through the mammary glands to the baby pigs. So far, weve had to use too much analgesic to be effective, but I think we will figure it out.

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Genetics key to livestock disease relief - Iowa Farmer Today - Iowa Farmer Today

Scientists Find Genetic Mutation That Could Increase the Male Lifespan – Gizmodo

Jiroemon Kimura, the oldest man ever (Image: YouTube/Screenshot)

Professor S. Jay Olshansky once told Gizmodo, In the world of aging sciences, if you want to live a long life, choose long-lived parents. So genetic markers linked to longevity are interesting as hell. But if youve got the wrong genes, then the wrong moves might do you in.

A team of researchers from universities in the United States wanted to figure out the role of genetics in human lifespan, specifically relating to growth hormone. The researchers work shows two main things: first, that a mutation in mens DNA relating to growth hormone might lead to a longer lifespan. And secondly, that treating older people with growth hormone might be dangerous if they dont have the variation.

Gil Atzmon, the studys principal investigator from Albert Einstein College of Medicine and the University of Haifa in Israel, was most excited by how a slight change in DNA could have such a big impact. Delete a few base pairs, and you still have a functional protein that now makes people live longer, he said. I think this is phenomenal.

This is complex, so Im going to take it slow and possibly oversimplify things. Basically, theres one system in question, the IGF-1/GH axis. Each of these are genes that code for different molecules in your body.

Researchers have already had a hunch that IGF-1 can regulate height at the expense of longevity, like the case in dogs. More IGF-1 means taller but shorter lifespan and less IGF-1 means shorter but longer lifespan. This should make senseits akin to the way big dogs live shorter lives than small dogs.

The researchers studied 800 men and women from across four populations and found something surprising. Indeed, the IGF-1 levels were lower in the centenarians, but many of the men were also taller. The data showed the researchers that theres more than just IGF-1 at play.

Centenarian males were often missing a specific snippet of DNA in their GHR gene. These people seem to be more sensitive to growth hormone and grow taller. So, even though their IGF-1 levels were lower (they lived longer), they still grew taller from their special GH gene. The people with this mutation seemed to live ten years longer, on average.

And the study really was huge. The replication across the four different populations makes our result more accurate and globally translated.

Atzmon himself admitted that all this is pretty complex. But its definitely new, important evidence pointing to the role that this IGF-1/GH axis plays in simultaneously determining your height and your lifespan, explained Andrzej Bartke, Professor of Physiology and Internal Medicine at Southern Illinois University School of Medicine, in a conversation with Gizmodo.

But were not at some level of life-hacking clarity. Clearly more research is needed to understand exactly why this type of GH receptor favors extreme longevity, why the effect was seen only in men and why the results in people studied by these investigators differ from some of the previous findings in different groups of human subjects with the same type of receptors, said Bartke.

Theres a catch to all this. Their results seemed to show that folks who dont have the GH variation might actually be sensitive to growth hormone therapy. This is a stark reminder that administering growth hormone as an intervention to slow agingwhich is still being done in the anti-aging medicine industry is not warranted by the scientific literature, Olshansky told Gizmodo. In fact, could actually be harmful.

So, youre still going to die one day. But as to when, that answer probably doesnt reside in what you eat (or in young blood) nearly as much as it does in what your DNA looks like.

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Scientists Find Genetic Mutation That Could Increase the Male Lifespan - Gizmodo

Genetics in the Himalayas | Euronews – euronews

What are the mechanisms that allow us to adapt to extreme altitude and lack of oxygen? What role do genetics play?

Sherpa Everest is a pioneering project whose goal is to try to find the answers.

A team of scientists from Barcelona traveled to the Himalayas to join the expedition of mountaineer Ferran Latorre, who has just climbed Mount Everest, his 14th and final eight-thousander the name given to the worlds 14 mountain peaks that stand taller than 8,000 metres.

Its been a long and tough journey: This is my temporary home: the tent, here. You try to adapt things to your needs, but, of course, you spend many hours here alone and you miss your home, your house and the people. There are times when you feel a bit down, he says.

Latorre is one of the projects so-called guinea pigs. At a field hospital 5.400 metres high at Everest Base Camp, doctors working on the project take samples from 15 mountaineers from all over the world and 22 sherpas. As electricty is a rare commodity, the blood samples are kept cold in the icefall of the Khumbu glacier.

From there, they are flown by helicopter to Kathmandu. They will arrive in Barcelona in the coming weeks to be analyzed at the Hospital of Santa Creu i Sant Pau.

When we are exposed to extreme environmental situations, be it high altitudes or lack of oxygen, or hypoxia, our DNA sequence doesnt change, Jos Manuel Soria, head of Genomics at the Institute of Research of Sant Pau explains. What does change in these situations is how we regulate those genes, that is, the expression of those genes. And thats what we want to study.

Samples taken in the Himalayas will be compared with those of fifty patients suffering from respiratory conditions like asthma, chronic obstructive pulmonary disease (COPD) and chronic oxygen deficiency.

The aim of the project is to study how we adapt to oxygen deficiency at sea level, at Everest Base Camp and after trying to reach the summit, more than 8,000 meters high and then to compare it with people who live at Everest Base Camp year round, in an oxygen-poor environment, explains Oriol Sibila, a pneumologist at Sant Pau Hospital.

So who will benefit from this research?

In addition to people suffering from chronic respiratory disease, its hoped it will help people travelling to high altitudes and mountaineers like Ferran Latorre, who says hes not prepared to hang up his boots yet.

Well, the truth is that after finishing the 14 eight-thousanders, I have other plans like opening up a new route on an eight-thousander, which I have so far failed to do, he tells us. I also want to try climbing Mount Everests northern slope without oxygen. And then I want to climb Cerro Torre, the north face of the Eiger Those are all the things a mountaineer has to do before he can hang up his hiking boots.

Whether the goal is scientific, athletic or personal, its an invitation for everyone to pursue their own Everest.

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Genetics in the Himalayas | Euronews - euronews

Select Sires poised to acquire Accelerated Genetics – Eau Claire Country Today

What was more than likely an exciting time for Select Sires employees might have been a bit more of a somber occasion for Accelerated Genetics employees June 13 when it was announced that the boards of directors of the two artificial-insemination cooperatives had reached a decision to join forces.

Under the planned agreement, which will become effective on June 30 if Accelerated Genetics delegates vote in favor of the sale, Select Sires will acquire the assets of Accelerated Genetics, joining forces of the employees and independent sales representatives in each of their geographical member organizations.

Select Sires, Inc., with headquarters in Plain City, Ohio, has about 1,200 employees worldwide, while Accelerated Genetics, headquartered in Baraboo, has 250 employees plus another 180 independent contractors who work for the organization.

Shirley Kaltenbach, Select Sires director of communications, said the decision coincides with an already collaborative business relationship that began in 2001, where the two cooperatives share ownership of World Wide Sires, Ltd. World Wide Sires is the international marketing arm for both co-ops in Europe, Africa, Asia, the Middle East and Oceania.

Kaltenbach said although some people knew an acquisition might be in the works,there were a lot of people who were surprised by the June 13 announcement.

Over the past few weeks Ive gotten to know quite a few of the (Accelerated Genetics) employees, and they are good people, Kaltenbach said.It was a struggle for them the day they were told what was going on. These are people who might have worked 30 or 40 years and have been totally loyal to Accelerated Genetics.

While its exciting for us (at Select Sires), we needed to take a step back and think about those people and the tough day they were going to have learning that they might be at risk of being terminated or they were going to work with somebody they have competed with for years. Theyre great people and they have a genuine love for this industry.

Angie Lindloff, Accelerated Genetics vice president of marketing and communications, said it was no secret that Accelerated had been struggling financially in recent years.

From our standpoint we needed help, she said. We needed to partner with someone in the industry to make sure our customers will have the products and services they need. Sometimes in order to move forward, you have to join forces and utilize your resources together.

Kaltenbach and Lindloff said they didnt know how many employees might be displaced by the merger.

Lindloff said she hope(s) a lot of (Accelerated Genetics) team members will be offered positions moving forward.

Theyre trying to do the best for the majority of our employees, she said, to either repurpose them or find them a position.

Kaltenbach said Select Sires has nine member organizations including East Central Select Sires in Waupun and NorthStar Cooperative in Lansing, Mich., that together serve Wisconsin and each member organization will retain the number of Accelerated Genetics employees they need to serve their customers.

Short term, everything will stay the same, and (Accelerated Genetics) will operate as they normally do, Kaltenbach said. Itll probably remain like that until we get a long-term strategy in place. It has to evolve. Right now were trying to transition everything.

I can tell you that each person is valued and important and the goal is to make sound business decisions and take on as many as we can.

Lindloff said the acquisition has been in the works for several months, but only a few employees from each of the co-ops knew of the negotiations.

Its all been very confidential, she said. You have to protect the business and employees and sales representatives from their competitors. You have to keep mergers and acquisitions very quiet to do it correctly.

Lindloff said merging the two companies will give the larger cooperative more genetic strength and a bigger sire offering for our customers.

All of our customers will have access to all the good stuff offered by both companies, including the animal product line that both co-ops sell, she said.

Accelerated Genetics delegates are scheduled to vote on the proposed sale on June 22. If the vote is favorable, the deal will close on June 30.

Accelerated Genetics was formed as Vernon County Breeders in 1941. The cooperative consolidated with Trempealeau County Breeders Cooperative in 1947 and Tri-State Breeders was formed. The name was changed to Accelerated Genetics in January 1995.

The cooperative is led by a 10-member board of directors with dairy and beef farm members in Wisconsin, Minnesota, Iowa and Illinois.

Select Sires nine member cooperatives cover the U.S. The co-op was formed in 1965 when four farmer-owned co-ops joined forces to offer a wider variety of genetic options to their members and improve efficiencies. Select Sires is the largest artificial insemination organization in North America.

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Select Sires poised to acquire Accelerated Genetics - Eau Claire Country Today

Antonio Giraldez Named Chair of Genetics – Yale News

by Jill Max June 13, 2017

Antonio J. Giraldez, Ph.D., has been appointed chair of the Department of Genetics, effective June 1, 2017. Giraldez is professor of genetics and is affiliated with the Yale Cancer Center and the Yale Stem Cell Center. He was director of graduate studies for the Department of Genetics from 2012 to 2016.

Antonio is an outstanding investigator who has made major advances in our understanding of embryonic development. He is committed to continuing the outstanding academic tradition of the department, said Robert J. Alpern, M.D., dean and Ensign Professor of Medicine.

My goal is to continue our trajectory of basic science discovery and bring the research thats being done in our human genetics core closer to patients, so that we become a destination point for analyzing the genomes of thousands of patients.

Giraldezs research in developmental biology, genetics, genomics, and computational biology delves into deciphering the mechanisms by which a single-cell zygote transforms into a multicellular organism. Using zebrafish as a model system, his major contribution has been to contribute to our understanding of the maternal-to-zygote transitionwhat he terms embryonic pubertythe shift that occurs after the embryo interprets and destroys maternal instructions and activates the code contained in its own genome. He also found that the same stem cell factors that reprogram cells play a key role in activation of the genome after fertilization, a universal step in embryonic development that allows an early embryo to develop into different cell types.

Under his leadership, the Department of Genetics will continue to recruit outstanding faculty as it moves into a more quantitative approach to genetics and developmental biology and seeks to bring new understanding to the function of individual genes, as well as the organization of nuclear architecture into gene function. At the same time, Giraldez is excited about the central role genetics will play in our program in personalized medicine. He is eager to build upon Yales strengths in genomic analysis for clinical diagnosis and to leverage the knowledge gained from clinical data to propel basic science discoveries using model systems.

Last year, Giraldez was named as a Howard Hughes Medical Institute (HHMI) Faculty Scholar, an award that recognizes basic researchers who apply innovative approaches to biological problems that are relevant to human health. In 2014, he won the Vilcek Prize for Creative Promise in Biomedical Sciences. He was named as a Pew Scholar in Biomedical Sciences in 2008 and won the John Kendrew Young Investigator Award from the European Molecular Biology Laboratory in 2007. He has twice been a finalist for the Blavatnik National Award for Young Scientists.

Giraldez obtained his doctoral degree in developmental genetics from the European Molecular Biology Laboratory in Heidelberg, Germany and did postdoctoral training in developmental biology at the Skirball Institute of Biomolecular Medicine at New York University Langone Medical Center and Harvard University.

This article was submitted by John Dent Curtis on June 13, 2017.

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Antonio Giraldez Named Chair of Genetics - Yale News

Genetics, data affect direction of ag research – Iowa Farmer Today

AMES, Iowa Data is key when it comes to research. And the world is getting to be very good at collecting and analyzing data.

Thats a big bucket research area, says Joe Colletti, senior associate dean in the College of Agriculture at Iowa State University and associate director of the Iowa Agriculture and Home Economics Experiment Station.

Colletti says that while research is being done in a variety of areas, a couple of types stand out today. One of those is the collection, standardization and use of data by and for farmers.

Another area of great advance is predictive genomics, which has been a hot issue for some time. Phenomics is a big thing in the plant and animal sciences research fields, Colletti says. Scientists are looking at genomes and phenotypes as a way of better predicting what the offspring of any genetic cross will look like, not only one generation down the road but many generations down the road. That type of assessment could help speed and fine tune research for crops and for livestock.

That fits into the work of the commodity organizations. Rod Williamson, director of research and development for the Iowa Corn Growers Association, says that his organization is looking at research in several basic areas.

The ICGA emphasis is on non-food industrial products. One example is bioplastics which are already being made using other biological products but which could be made using corn. Right now, he says, plastic water bottles are often made using sugar cane from South America.

The process includes a number of steps. If researchers can reduce the number of steps involved and can do so using corn, it could open up new markets. If corn captured just 3 percent of that market it could mean use for 100 million bushels of corn.

Williamson says other research supported by the corn growers includes work on higher blends of ethanol in fuel. On the production side, he says nitrogen efficiency by plants through better genetics is a priority. And he says the genomic efforts cited by Colletti are also a priority.

Other commodity organizations are also emphasizing research. Scott Nelson, director of the on-farm network for the Iowa Soybean Association, cites several research priorities.

He says crop inoculants are one area of interest. Another is better weed control, especially of waterhemp and Palmer amaranth. Soybean cyst nematode remains a priority, as does corn rootworm. And variable rate technology and multiple-variety planting technology are also items he sees developing.

But one of the most exciting topics of discussion for many researchers is CRISPR/Cas9 technology. CRISPR/Cas9 is an RNA-guided genome editing tool that allows researchers to knock out genes or insert genes more easily into a cell line.

Colletti says the technology isnt aimed at adding genes from other plants or animals, but instead, works toward more exact advances in a crop or animals existing genes.

This is a technique that is being improved daily, hourly, he says. It is moving us in the right direction.

That more specific genetic work on the plant, combined with better data gathering and analysis due to improved computer technology, will lead plant genetic work forward at a faster pace than was possible in the past.

Nelson agrees, saying the technology will help companies to develop better plant varieties.

It could be revolutionary, he says.

Meanwhile, Colletti says soil is also getting more and more attention from researchers.

The work on cover crops and an increased emphasis on erosion control, water and soil quality will influence research. Scientists are starting to look at how cover crops and larger yields lead to changes in plant biomass. That in turn can influence planting and harvest conditions, as well as soil quality and weed and bug pressure.

It is now easier to gather mass amounts of data in the lab and in the field through unmanned aircraft systems imagery, aerial photography and analysis, as well as through other means. That massive increase in the volume, variety, velocity, voracity and value of data that can be gathered and the increased speed at which it can be analyzed will lead to more flexibility for farmers to make decisions quickly in the field.

This can lead to more just-in-time nutrient applications or weed and pest control, for example. It will lead to better crop genetics. And it will lead to more informed management decisions and achievement of private and public goals in the future, Colletti says.

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Genetics, data affect direction of ag research - Iowa Farmer Today

NewLink Genetics Is Still Undervalued, Despite The Disappointment From Navoximod – Seeking Alpha

NewLink Genetics (NASDAQ:NLNK) lost 40% of its value in a single day, as it surprisingly announced that Roche ([[OTCQX:RHHBY]], [[OTCQX:RHHBF]])/Genentech would return the rights on Navoximod, an IDO inhibitor, to the company. In this article, I will discuss what the reasons for this decision were and importantly why I believe that NewLink Genetics is highly undervalued at the current, all-time low, share price of $6.46 (Figure 1).

Figure 1. Common stock chart for NLNK. Source: Yahoo Finance

NewLink Genetics pipeline concentrates on the development of IDO (indoleamine-2, 3-dioxygenase) pathway inhibitors. IDO inhibitors, in general, are expected to boost the body's immune system to fight against cancer, similar to PD-1 and CTLA-4 pathway inhibitors.

NewLink was focused on two distinct IDO pathway inhibitors:

One is the already mentioned Navoximod, a direct inhibitor of IDO, which works very similar to Incyte's (NASDAQ: INCY) Epacadostat and Bristol-Myers Squibb's (NYSE: BMY) BMS-986205. Their most advanced drug is Indoximod, which is no direct blocker of IDO but rather mimics the effect of IDO inhibition.

Navoximod

In 2016 Roche/Genentech licensed all worldwide commercialization rights for Navoximod and paid NewLink Genetics $150 million upfront, with eligibility to $1 billion more if certain milestones are met.

Navoximod is currently tested in phase 1 trials in several solid cancers including non-small-cell lung cancer ("NSCLC"), renal cell cancer ("RCC"), urothelial bladder cancer ("UBC"), triple-negative breast cancer ("TNBC") in combination with Atezolizumab (the PD-L1 inhibitor from Genentech/Roche). In all these cohorts combined (separated data is not available yet) Navoximod + Atezolizumab showed a partial response in only 9% (4/45) of patients [1].

Epacadostat is tested in many different solid cancers in partnership with Merck's (NYSE: MRK) Keytruda. If the same patient cohorts of Epacadostat and Keytruda are pooled they achieve 27% (40/146 pooled; stratified in cancer types: 14/40 NSLC, 13/37 UBC, 9/30 RCC, 4/39 TNBC) [2][3]. Based on this data Roche/Genentech decided to return the rights for Navoximod to NewLink Genetics.

I think one of the reasons why Navoximod doesn't perform as well as Epacadostat could be rooted in their differential efficacies to inhibit IDO. This is read out by measuring the kynurenine levels in the blood (kynurenine is the product of an active IDO enzyme, so the greater the drop in kynurenine levels the better inhibited is IDO). Navoximod brings down blood kynurenine to 70% of the pre-treatment level. In comparison to that, Epacadostat achieves a 50% reduction and even better is BMS-986205, which manages to drop the kynurenine level to about 40% of pre-treatment levels [4][5]. This indicates that Navoximod is not such a potent IDO inhibitor than the ones of the competitors and thus might explain why Navoximod has less efficacy than Epacadostat.

Based on the disappointing preliminary results and especially with a competitor that is, first, much further in the development (multiple clinical phase 3 trials of Epacadostat + Keytruda will be started in 2017) and second, shows better efficacy, it is understandable that Roche/Genentech decided to not further develop Navoximod. I personally think it is unlikely that NewLink will continue to develop Navoximod unless they see potential in any of the single cancer types. My feeling is that in neither of the single cancer types Navoximod performed comparable to Epacadostat, otherwise Roche/Genentech wouldn't have returned the rights to the drug.

Indoximod

Indoximod is tested in combination with several different agents in phase 2 studies in melanoma, pancreatic cancer, breast cancer, metastatic castration-resistant prostate cancer (mCRPC) and glioblastoma.

Melanoma

Beginning of April 2017, NLNK released preliminary results of Indoximod in combination with Keytruda in advanced melanoma. The combination achieved a 59% objective response rate and 80% disease control rate (Table 1) [6]. Including patients with ocular melanoma, a very hard to treat patient population, the ORR is 52% and the DCR is 73%.

Treatment

Objective response rate

Disease control rate

Grade 3 adverse events

Epacadostat / Keytruda

n = 19

58%

74%

19%

Indoximod / Keytruda

n = 51

59%

80%

Nivolumab / Ipilimumab

n = 314

58%

71%

55%

Table 1. Objective response rates and adverse events in melanoma. For Indoximod/Keytruda only data from non-ocular patients are included. *Only incomplete data available

This news was followed by a 33% drop in NLNK's stock price, due to disappointment that the Indoximod/Keytruda combination was not much better than the 58% ORR and 74% DCR achieved with Epacadostat/Keytruda in treatment-naive advanced melanoma [7]. Another reason for the disappointment is the complete response rate of 26% for Epacadostat/Keytruda, compared to only 12% for Indoximod/Keytruda. Here it should be taken into account, however, that the presented data for Epacadostat consist of only 19 patients, whereas the data for Indoximod include 51 patients. So it is possible that the complete response rates of Epacadostat will drop once more patients are added.

I was positively surprised by how similar the two drugs performed, given that the mechanism of action differ quite significantly between Indoximod and Epacadostat and would rate it as a good sign that in melanoma Indoximod is able to perform similarly than Epacadostat.

The current, best-in-class, treatment option for metastatic melanoma is the combination of Nivolumab with Ipilimumab (PD-1 and CTLA-4 inhibitors from BMY), which achieves 58% ORR and 71% DCR (Table 1) [8].

The phase 3 trials of Indoximod and Epacadostat in melanoma will likely be benchmarked against this combination. The IDO inhibitor combinations seem to be unable to surpass anti-PD-1/CTLA-4 inhibition in terms of ORR or DCR. But then the rate of serious adverse events will come into play. Epacadostat/Keytruda has 19% of Grade 3 adverse events and although no concrete numbers are available for Indoximod/Keytruda, they are not higher than with Keytruda alone.

This means that both IDO inhibitors are exceptionally well tolerated and well below the 55% of Grade 3 adverse events observed with the anti-PD-1/CTLA-4 treatment. Therefore, there is a good chance that the IDO inhibitors will be approved based on the more manageable safety profile.

Acute myeloid leukemia

In acute myeloid leukemia, Indoximod is tested in combination with 7+3 chemotherapy. This combination leads to a complete remission in 83% of tumors (5 of 6 patients) with no evidence of minimal residual disease [9]. With 7+3 chemotherapy alone in young adults, complete remission can also be achieved in up to 75% of patients [10]. The big problem rather is that the relapse rate is very high and thus it will be critical for Indoximod to show prolonged relapse-free survival and overall survival.

Pancreatic cancer

In pancreatic cancer, the combination of Indoximod with chemotherapy achieved an ORR of 45% (14/31) vs. 23% for chemotherapy alone [11]. Pancreatic cancer is a notoriously hard to treat cancer type and many drugs failed to get approved. NewLink, for instance, also tried to get a drug approved for pancreatic cancer, called Algenpantucel-L. After promising objective response rates in a phase 2 study, the drug failed to enhance overall survival in a phase 3 trial. So I think that also for Indoximod it is important to remain patient and to wait whether the convincing ORR in pancreatic cancer can be transformed into a survival benefit.

Metastatic castration-resistant prostate cancer

Indoximod is combined with PROVENGE (a vaccine already approved for prostate cancer) for patients with mCRPC. The combination was able to enhance radiographic progression-free survival (rPFS) from 4.1 months in the placebo arm to 10.3 months in the treatment arm [12]. This compares to the rPFS of Enzalutamide, an androgen receptor inhibitor, which is 8.3 months [13]. In general, rPFS is highly associated with overall survival in mCRPC and so it is likely that Indoximod/PROVENGE will also enhance overall survival [14].

Glioblastoma

In addition to these trials, Indoximod is also tested in glioblastoma also in combination with chemotherapy and a 6-month progression free survival in 25% of patients compared to a historical rate of 15% [15].

Breast cancer

Recently a statement was released, that Indoximod plus chemotherapy failed to meet the primary end points of statistically different progression-free survival and overall survival in metastatic breast cancer [16].

The use of IDO inhibitors in breast cancer thus continues to disappoint, as also the combination of Epacadostat and Keytruda only achieved a 10% objective response rate in triple negative breast cancer [17].

Valuation and Conclusion

NewLink Genetics has a current market capitalization of $ 189 million. If cash of $ 75 million, expected at the end of 2017 and debt plus royalty obligations of $ 6.5 million are taking into account, the whole company is currently valued at $ 120.5 million.

Their most promising and also furthest developed indication for Indoximod is in melanoma. I think it was very important for NewLink to show comparable objective response rates, which, since they have a different mechanism of action, was far from certain. As estimated by Bhavneesh Sharma in his article, the current, risk-adjusted, peak revenue of Indoximod in melanoma alone is $ 106 million in 2024. This means the company is currently valued at little above the peak revenue of a single indication. They furthermore have promising first results in other indications as well, importantly in cancer types that Incyte is currently not pursuing or lagging behind.

Given the general high valuation of companies developing novel immunotherapies, NewLink Genetics market capitalization is extremely low. This was majorly caused by disappointment that Indoximod didn't surpass Epacadostat's objective response and complete response rates in melanoma and of course by Roche/Genentech returning their rights on Navoximod to the company.

At this price, NewLink Genetics to me seems to be an attractive takeover candidate for companies who want to quickly spice up their immune-oncology portfolio but are not willing to pay a high premium for it. Bristol-Myers Squibb, for instance, paid $ 800 million upfront (total deal volume is $ 1.25 billion) for Flexus Therapeutics, which developed a preclinical IDO inhibitor of in 2015 [18].

If NewLink Genetics is not bought up or they continue to develop Indoximod unpartnered, they will need to raise additional capital at some point until the end of 2018. Other risks include the failure of clinical trials or that their drugs do not get approved by the regulatory agencies.

Summing this up, I believe the current valuation of NewLink Genetics is very cheap and I fully expect their stock price to rise again, once investors have digested the disappointments of the last months and regain their faith in the company again.

Disclosure: I am/we are long NLNK.

I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

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NewLink Genetics Is Still Undervalued, Despite The Disappointment From Navoximod - Seeking Alpha