What Protects Elephants from Cancer?

Elephants and other large animals have a lower incidence of cancer than would be expected statistically, suggesting that they have evolved ways to protect themselves against the disease. A new study reveals how elephants do it: An old gene that was no longer functional was recycled from the vast “genome junkyard” to increase the sensitivity of elephant cells to DNA damage, enabling them to cull potentially cancerous cells early.

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

In multicellular animals, cells go through many cycles of growth and division. At each division, cells copy their entire genome, and inevitably a few mistakes creep in. Some of those mutations can lead to cancer. One might think that animals with larger bodies and longer lives would therefore have a greater risk of developing cancer. But that’s not what researchers see when they compare species across a wide range of body sizes: The incidence of cancer does not appear to correlate with the number of cells in an organism or its lifespan. In fact, researchers find that larger, longer-lived mammals have fewer cases of cancer. In the 1970s, the cancer epidemiologist Richard Peto, now a professor of medical statistics and epidemiology at the University of Oxford, articulated this surprising phenomenon, which has come to be known as Peto’s paradox.

The fact that larger animals like elephants do not have high rates of cancer suggests that they have evolved special cancer suppression mechanisms. In 2015, Joshua Schiffman at the University of Utah School of Medicine and Carlo Maley at Arizona State University headed a team of researchers who showed that the elephant genome has about 20 extra duplicates of p53, a canonical tumor suppressor gene. They went on to suggest that these extra copies of p53 could account, at least in part, for the elephants’ enhanced cancer suppression capabilities. Currently, Lisa M. Abegglen, a cell biologist at the Utah School of Medicine who contributed to the study, is leading a project to find out whether the copies of p53 have different functions.

Vincent Lynch, a geneticist at the University of Chicago, has shown that part of what enabled elephants to grow so big was that one of their pseudogenes—a broken duplicate of an ancestral gene—suddenly acquired a new function.

Courtesy of Vincent J. Lynch

Yet extra copies of p53 are not the elephants’ only source of protection. New work led by Vincent Lynch, a geneticist at the University of Chicago, shows that elephants and their smaller-bodied relatives (such as hyraxes, armadillos and aardvarks) also have duplicate copies of the LIF gene, which encodes for leukemia inhibitory factor. This signaling protein is normally involved in fertility and reproduction and also stimulates the growth of embryonic stem cells. Lynch presented his work at the Pan-American Society for Evolutionary Developmental Biology meeting in Calgary in August 2017, and it is currently posted on biorxiv.org.

Lynch found that the 11 duplicates of LIF differ from one another but are all incomplete: At a minimum they all lack the initial block of protein-encoding information as well as a promoter sequence to regulate the activity of the gene. These deficiencies suggested to Lynch that none of the duplicates should be able to perform the normal functions of a LIF gene, or even be expressed by cells.

The eminent biologist Richard Peto, now at the University of Oxford, pointed out in the 1970s that elephants and other large-bodied animals ought to be at great statistical risk for cancer.

Cathy Harwood

But when Lynch looked in cells, he found RNA transcripts from at least one of the duplicates, LIF6, which indicated that it must have a promoter sequence somewhere to turn it on. Indeed, a few thousand bases upstream of LIF6 in the genome, Lynch and his collaborators discovered a sequence of DNA that looked like a binding site for p53 protein. It suggested to them that p53 (but not any of the p53 duplicates) might be regulating the expression of LIF6. Subsequent experiments on elephant cells confirmed this hunch.

To discover what LIF6 was doing, the researchers blocked the gene’s activity and subjected the cells to DNA-damaging conditions. The result was that the cells became less likely to destroy themselves through a process called apoptosis (programmed cell death), which organisms often use as a kind of quality control system for eliminating defective tissue. LIF6 therefore seems to help eradicate potentially malignant cells. Further experiments indicated that LIF6 triggers cell death by creating leaks in the membranes around mitochondria, the vital energy-producing organelles of cells.

To find out more about the evolutionary history of LIF and its duplicates, Lynch found their counterparts in the genomes of closely related species: manatees, hyraxes and extinct mammoths and mastodons. His analysis suggested that the LIF gene was duplicated 17 times and lost 14 times during the evolution of the elephant’s lineage. Hyraxes and manatees have LIF duplicates, but the p53 duplicates appear only in living and extinct elephants, which suggests that the LIF duplications happened earlier in evolution.

Elephants are closely related to large animals such as manatees (left), but also to smaller ones like hyraxes (right), aardvarks and armadillos. Elephants only began to develop their immense size about 30 million years ago.

Jim P. Reid, USFWS / Bjørn Christian Tørrissen

Lynch found that most duplicates of the LIF gene are pseudogenes—old, mutated, useless copies of genes that survive in the genome by chance. The exception, however, is the LIF6 gene sequence, which unlike the others has not accumulated random mutations, implying that natural selection is preserving it.

“We think that LIF6 is a refunctionalized pseudogene,” Lynch said. That is, the elephant LIF6 re-evolved into a functional gene from a pseudogene ancestor. Because it came back from the dead and plays a role in cell death, Lynch called it a “zombie gene.”

Although manatees and hyraxes also have extra copies of LIF, only modern and extinct elephants have LIF6, which suggests that it evolved only after the elephants branched away from those related species. And when Lynch’s group dated the origin of LIF6 by molecular clock methods, they found that the pseudogene regained a function about 30 million years ago, when the fossil record indicates that elephants were evolving large body sizes.

Lucy Reading-Ikkanda/Quanta Magazine

“Refunctionalizing a pseudogene is not something that happens every day,” explained Stephen Stearns, an evolutionary biologist at Yale University, in an email to Quanta. Being able to show that it happened at roughly the same time that elephants evolved a large body, he wrote, “supports, but does not prove, that the refunctionalizing of the gene was a precondition for the evolution of large body size.”

Evolving protections against cancer would seem to be in the interest of all animals, so why don’t they all have a refunctionalized LIF6 gene? According to the researchers, it’s because this protection comes with risks. LIF6 suppresses cancer, but extra copies of LIF6 would kill the cell if they accidentally turned on. “There’s a bunch of toxic pseudogenes sitting there” in the genome, Lynch explained in an email. “If they get inappropriately expressed, it’s basically game over.”

There also appears to be a trade-off between cancer suppression mechanisms and fertility. A study published in 2009 suggested that LIF is critical for implantation of the embryo in the uterus. Because LIF activity is controlled by p53, LIF and p53 jointly regulate the efficiency of reproduction. When the same set of genes has two functions (such as reproduction and cancer suppression), it is possible that those functions will be in direct conflict—a phenomenon that geneticists call antagonistic pleiotropy.

The elephants may have solved the problem of antagonistic pleiotropy by duplicating p53 and LIF and splitting up those functions, according to Maley. “Some copies of p53 and LIF are doing what’s necessary for fertility, while other pairs of LIF and p53 are doing what’s necessary for cancer suppression,” he said. Maley speculated that the gene duplicates “allowed the elephants to get better at cancer suppression and still maintain their fertility, which would allow them to grow a larger body.” That hypothesis, however, still needs to be tested, he said.

Bats are not large animals, but some species live for decades. Scientists are investigating whether they have their own protective adaptations against cancer.

Ann Froschauer, USFWS

Evolving extra copies of p53 and LIF may have helped elephants overcome Peto’s paradox, but that can’t be the only solution: Other large animals like whales have only one copy of p53 and one version of LIF. Lynch and his team are currently exploring how whales and bats solve Peto’s paradox. Although not large-bodied, some bat species live up to 30 years, and the longer-lived ones might have evolved cancer suppression mechanisms that the shorter-lived ones lack.

Maley is also working on how whales solve Peto’s paradox. Even though whales don’t have extra copies of p53, he said, “we do think there has been a lot of selection and evolution on genes in the p53 pathway.” Maley believes that understanding how diverse large-bodied animals solve Peto’s paradox may have applications in human health. “That is the end goal,” he said. “The hope is that by seeing how evolution has found a way to prevent cancer, we could translate that into better cancer prevention in humans.”

“Every organism that evolved large body size probably has a different solution to Peto’s paradox,” Maley said. “There’s a bunch of discoveries that are just waiting for us out there in nature, where nature is showing us the way to prevent cancer.”

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

Employees Displaced by Automation Could Become Caregivers for Humans

Sooner or later on, the usa will face mounting work losings considering improvements in automation, artificial intelligence, and robotics. Automation has emerged being a larger danger to United states jobs than globalization or immigration combined. A 2015 report from Ball State University attributed 87 per cent of present production work losses to automation. In no time, the number of vehicle and taxi drivers, postal workers, and warehouse clerks will shrink. What’s going to the 60 per cent associated with the population that lacks a degree do? Just how will this vulnerable an element of the workforce find both earnings while the sense of function that work provides?

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Oren Etzioni (@etzioni) is CEO of this Allen Institute for synthetic Intelligence and teacher at Allen School of Computer Science at University of Washington.

Recognizing the enormous challenge of technological jobless, Bing recently announced it is donating $1 billion to nonprofits that try to assist workers adapt to the brand new economy. But the solutions proposed by computer researchers particularly MIT’s Daniela Rus (technical training) and endeavor capitalists including Marc Andreessen (new task creation) are unlikely ahead fast enough or even to be broad enough. Honestly, it is not practical to teach many coal miners to become data miners.

Some of Silicon Valley’s leading business owners are drifting the thought of a universal basic income (UBI) as being a solution for work loss, utilizing the loves of eBay creator Pierre Omidyar and Tesla’s Elon Musk supporting this method. But as MIT economists Erik Brynjolfsson and Andrew McAfee have actually pointed out, UBI does not do nearly as good a job as other policies to keep people engaged in the workforce and supplying the feeling of function that work offers. UBI is also not likely to garner the mandatory political help.

So what might help? There is a category of jobs today which critical to our society. Many of us will use the solutions of the workers, however these jobs are all-too-often held in low esteem with poor pay and minimal a better job prospects. Some are creating alleged social robots to simply take these jobs. Yet, they’re jobs we categorically cannot wish machines doing for all of us, though devices could potentially help humans.

I will be speaking of caregiving. This broad category includes companions to your senior, house wellness aides, child sitters, special requirements aides, and more. We should uplift this category become better compensated and better regarded, though available to those without higher education. Laurie Penny highlights that numerous traditionally male vocations have been in jeopardy from automation, yet caregiving jobs are traditionally feminine; nevertheless, that gender gap can alter when caregivers are uplifted and other choices are more limited.

There is no doubting that uplifting is likely to be costly, but so are UBI and several other proposed programs. The riches caused by increased automation should be provided more broadly and might be used to assist fund caregiving programs.

Instead of anticipating vehicle motorists and warehouse workers to rapidly re-train for them to take on tireless, increasingly capable devices, let’s perform for their individual strengths and produce possibilities for workers as companions and caregivers for our elders, our kids, and our special-needs populace. With this specific one action, culture can both produce jobs for the most vulnerable portions of our work force and increase the care and connection for many.

The main element skills because of this category of jobs are empathy additionally the ability to make a human being connection. Ab muscles concept of empathy is feeling somebody else’s feelings; a machine cannot do that as well as a person. Individuals thrive on genuine connections, perhaps not with machines, however with one another. You don’t want a robot looking after your infant; an ailing elder must be liked, become heard, fed, and sung to. This is one job category that people are—and continues to be—best at.

As culture many years, interest in caregivers will increase. Based on the UN, how many individuals aged 60 years and older has tripled since 1950, while the combined senior and geriatric populace is projected to achieve 2.1 billion by 2050.

Rising work for caregivers is element of a broader multi-decade shift inside our economy from agriculture and manufacturing to delivering solutions. A significant change to more caregiving may require us to re-consider some of our values—rather than buying fancier and more costly gadgets every year, can consumers spot more value on community, companionship, and connection?

Exactly what are the making this vision a real possibility? Society should discover a way to significantly increase the payment for caregivers that assistance elders and special-needs populations. Realistically, uplifting caregiving will demand federal government programs and capital. The expense of these programs can be defrayed by increased economic growth and productivity as a result of automation. The numerous employees who’re not enthusiastic about, or with the capacity of, technical work could as an alternative get training and certification in many different caregiving occupations. Although some will simply be companions, other people can obtain certification as teachers, nurses, and much more.

Caregiving is just a practical selection for numerous displaced workers, plus one which both humane and uniquely peoples.

WIRED advice publishes pieces compiled by outside contributors and represents a wide range of viewpoints. Read more opinions right here.

How Moneyball Tactics Built a Basketball Juggernaut

As a longtime partner at Kleiner Perkins Caufield & Byers, Joe Lacob had a reputation for backing high-risk, high-reward startups. But when he paid $450 million in 2010 for the Golden State Warriors—then valued at a measly $315 million and considered the worst team in the NBA—even die-hard fans scoffed.

Seven years later, the Warriors are two-time champs worth a reported $2.6 billion. In his new book, Betaball, Erik Malinowski (a former WIRED staffer) credits the slingshot turnaround not to Steph Curry’s swishing three-pointers but to Lacob’s application of Silicon Valley strategies to revitalize a sluggish team.

First off, Lacob used his newcomer status to build a thriving corporate culture. He paid a reported $1.6 million for a flashy, startup-style open office that encouraged collaboration. Then he set up an email account where fans could submit feedback—and actually get a response.

As the first in his family to go to college, Lacob was a firm believer in hiring based on potential, not experience. He appointed Phoenix Suns GM Steve Kerr as head coach and former sports agent Bob Myers as general manager. Neither had ever formally wielded an NBA clipboard, but their passion for the game swayed the new owners. On and off the court, Lacob emphasized character. He signed upstanding players like Andre Iguodala and Harrison Barnes, and he traded Monta Ellis, who had been sued by a staff member for sexual harassment. (The case was settled.) The message: zero tolerance for brilliant jerks.

Having spent decades investing in experimental technologies, Lacob was one of the first NBA execs to see potential in SportVU, a motion-capture camera system. Another company, MOCAP Analytics, used AI and machine learning to turn the raw SportVU data into play simulations. Like big-­data-obsessed startups, the War­riors began quantifying everything, from players’ sleep schedules to their shooting accuracy.

Coming from the land of nap rooms and Soylent, Lacob embraced Jobsian mindful­ness. His team experimented with meditation, sensory-deprivation pods, and electricity-transmitting headphones. Turns out ballers like butter coffee too.

Before pouring millions into a startup, investors set clear performance goals. Lacob’s target was ambitious: to win a championship within five years. His team clinched the title in four years, seven months. A Golden unicorn was born.


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