These secret battles between your body’s cells might just save your life

喀秋莎 2019-10-16 4338

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    Yasuyaki Fujita has seen first-hand what happens when cells stop being polite and start getting real. He caught a glimpse of this harsh microscopic world when he switched on a cancer-causing gene called Ras in a few kidney cells in a dish. He expected to see the cancerous cells expanding and forming the beginnings of tumours among their neighbours. Instead, the neat, orderly neighbours armed themselves with filament proteins and started “poking, poking, poking”, says Fujita, a cancer biologist at Hokkaido University in Sapporo, Japan. “The transformed cells were eliminated from the society of normal cells,” he says, literally pushed out by the cells next door.

    In the past two decades, an explosion of similar discoveries has revealed squabbles, fights and all-out wars playing out on the cellular level. Known as cell competition, it works a bit like natural selection between species, in that fitter cells win out over their less-fit neighbours. The phenomenon can act as quality control during an organism’s development, as a defence against precancerous cells and as a key part of maintaining organs such as the skin, intestine and heart. Cells use a variety of ways to eliminate their rivals, from kicking them out of a tissue to inducing cell suicide or even engulfing them and cannibalizing their components. The observations reveal that the development and maintenance of tissues are much more chaotic processes than previously thought. “This is a radical departure from development as a preprogrammed set of rules that run like clockwork,” says Thomas Zwaka, a stem-cell biologist at the Icahn School of Medicine at Mount Sinai in New York City.

    But questions abound as to how individual cells recognize and act on weaknesses in their neighbours. Labs have been diligently hunting for — and squabbling over — the potential markers for fitness and how they trigger competitive behaviours. These mechanisms could allow scientists to rein in the process or to help it along, which might lead to better methods for fighting cancer and combating disease and ageing using regenerative medicine.

 “Cell competition is on the global scientific map,” says Eugenia Piddini, a cell biologist at the University of Bristol, UK, who likens the buzz around this idea to the excitement that helped propel modern cancer immunotherapies. The better scientists understand competition, she says, the more likely it is that they will be able to use it therapeutically.

History repeats

    During a blizzard that dumped more than 30 centimetres of snow this past February, biologists from about a dozen disciplines convened at a hotel at Lake Tahoe, California, for the first major meeting devoted to cell competition.

“It was a zoo of researchers,” says co-organizer Zwaka, and included biologists who study flatworms that can regenerate their whole body from a single cell, geneticists attempting to make interspecies chimaeras of mouse, monkey and rabbit embryos, and a keynote speaker who spoke about the terrible battles and cooperative campaigns waged in bacterial communities.

The snowbound attendees, about 150 in all, debated how and why cells size up their competition. And they celebrated the discovery that gave birth to the field.


    How secret conversations inside cells are transforming biology

    In 1973, two PhD students, Ginés Morata and Pedro Ripoll were perfecting a way to track the various cell populations in a fruit-fly larva that would eventually develop into a wing. Working at the Spanish National Research Council’s Biological Research Center in Madrid, they introduced a mutation called Minute into a few select cells in the larva and left the rest of the cells unaltered.

    Knowing that Minute cells grow slower than their unaltered neighbours, the scientists expected to find some smaller cells amid the wild-type counterparts. “Instead, we found that the cells disappeared,” says Morata, now a developmental biologist at the Autonomous University of Madrid in Spain.

    On their own, Minute cells can develop into a fly that is normal — except for the short, thin bristles on their bodies that give the mutation its name. But when mixed with wild-type cells in the larva, the cells simply vanished. “Minute cells were not able to compete with the more vigorous, metabolically active wild-type cells,” says Morata. They described the activity as cell competition. “It was a very surprising and interesting observation,” Morata says. But lacking the molecular tools to follow cell fates more closely, he and his colleagues let the finding simmer.

    Twenty-six years later, postdocs Laura Johnston and Peter Gallant observed nearly the same phenomenon. Working with Bruce Edgar and Robert Eisenman, respectively, at the Fred Hutchinson Cancer Center in Seattle, Washington, they were studying a mutation in another fly gene, Drosophila Myc (dMyc), that also slows cell growth.

“There was a eureka moment when Peter and I realized that these dMyc mutant cells would disappear,” says Johnston, now a developmental biologist at Columbia University Medical Center in New York City. They eventually showed that the mutant cells were forced to initiate a form of programmed cell death called apoptosis. “It was very clear that this was a competitive situation,” Johnston says. 

    Their 1999 paper ignited interest among scientists, including Morata. He jumped back into the fray with Eduardo Moreno, and they took advantage of modern molecular tools to repeat the Minute experiments. “The field blossomed from there,” says Johnston.

    Myc acts as a master controller of cell growth, and Minute encodes a key component needed for synthesizing proteins — so it’s not surprising that reduced expression of those proteins makes cells less fit. But Johnston’s next finding took people by surprise. She showed that cells with an extra copy of normal dMyc outcompeted wild-type cells. These fitter-than-wild-type cells came to be called “supercompetitors”.

    Johnston’s discovery of supercompetition emphasized that cell competition is about the relative fitness of a group of cells, says Zwaka. If one cell is falling behind, the entire group of neighbours could decide it has to go. But on the flipside, they can also sense that certain cells are better and should survive.

    Cell competition wasn’t simply about getting rid of defects; it was about survival of the fittest, with the less-fit ‘loser’ cells dying and the ‘winners’ proliferating. Importantly, competition was seen only when there was a mixture of genetically different cells, a phenomenon known as mosaicism. In this way, cell competition acts like a quality-control system, booting out undesirable cells during development.

Vying for viability

    Fujita’s observation of the kicked-out kidney cells was one of the first hints that mammalian cells compete, too. Soon after that work was published, researchers started to observe competition forcing out mutated cells from various other tissue types such as skin, muscle and gut.

    The next most obvious place to look for competing cells was the mammalian embryo. In 2013, Zwaka’s team, and two other laboratories, probed mouse embryos at the earliest stage of development — those that have progressed just beyond a ball of cells. Zwaka’s group made mouse embryonic stem cells (ESCs) with a supercompetitor mutation that lowered expression of p53, an important quality-control protein that normally puts the brakes on cell division. When these cells were put into a mouse embryo, they quickly took over and developed into a normal mouse5. Similarly, Miguel Torres’s lab at the National Center for Cardiovascular Research in Madrid showed that supercompetition could be induced in an early mouse embryo using slight overexpression of the mouse Myc gene.

    By artificially creating losers or winners, researchers could force cell competition into play. But Torres’s team, led by then-postdoc Cristina Clavería, also made the striking observation that Myc expression varied naturally in mouse ESCs. Cells in the embryo with approximately half the amount of the protein compared with their neighbours were dying by apoptosis. This was one of the first studies that strongly pointed to naturally arising cell competition.

Sculpting tissues

    The phenomenon also comes into play later on in embryonic development. In a study published this year, postdoc Stephanie Ellis at Elaine Fuch’s lab in Rockefeller University in New York City, looked at mouse skin. During development, its surface area expands by a factor of 30 over the course of about a week. The cells within proliferate wildly — first as a single layer and later as multiple layers.

    Ellis injected mouse embryos with a concoction that turns cells into genetic losers. She targeted a few cells present when the embryonic skin is a single layer thick, and added a marker gene that made them glow red. Then she used time-lapse imaging to watch their grim fates: the skin cells popped out from the surface layer, broke up and disappeared. Later, she noticed the winner cells engulfing and clearing the losers’ corpses.

    Repeating the experiment at the multilayer stage, Ellis no longer saw the less-fit skin cells perishing or being engulfed. Instead, the loser cells tended to differentiate and migrate into the outer layers of skin — where they acted as a barrier for a short time before being shed. The winner cells were more likely to remain behind in the bottom layer as stem cells.

This made sense. “Killing a cell is energetically expensive,” says Ellis. A developing tissue, she says, might decide: “Why not just remove losers through differentiation?” Emi Nishimura’s lab at the Tokyo Medical and Dental University in Japan, found that competing stem cells in the ageing tail skin of adult mice used the same pattern of asymmetrical divisions to eliminate stem cells with lower levels of a key structural collagen protein

This made sense. “Killing a cell is energetically expensive,” says Ellis. A developing tissue, she says, might decide: “Why not just remove losers through differentiation?” Emi Nishimura’s lab at the Tokyo Medical and Dental University in Japan, found that competing stem cells in the ageing tail skin of adult mice used the same pattern of asymmetrical divisions to eliminate stem cells with lower levels of a key structural collagen protein.

These experiments could provide guidance for scientists looking to harness stem cells to rejuvenate ageing tissues and organs. Cell competition could either help or hurt such therapies: stem cells might outcompete older, less-fit cells, or they might encounter a hostile neighbourhood when transplanted into tissue. Understanding whether and how cell competition happens in adult tissue could help settle this matter.

Piddini admits that she was a little obsessed with the idea, and her group was part of a wave of researchers that proved cell competition does take place in adult organisms. To test the idea, she says, the team “genetically sprinkled” a mutated copy of RPS3, a gene functionally related to Minute, into some cells in the intestine of adult flies. Cells with the mutant copy were outcompeted by their wild-type counterparts. It didn’t matter whether the losers were the stem cells that maintain the gut or differentiated cells: all eventually perished.

Cristina Villa del Campo, a senior postdoc in the Torres lab, tested for adult competition in the mouse heart by introducing winner cardiac cells at eight to ten weeks of age. Over the course of one year, she tracked the numbers of winner cells and wild-type losers and saw the loser population decline by about 40%.

“It was a slow replacement in the adult,” says Villa del Campo. “But even highly differentiated functional adult cells can sense the less-fit heart cells and eliminate them.”

Unanswered questions

    Even with so many examples of cell competition playing out in different conditions, the field still faces a torrent of unanswered questions. One big puzzle is how cells in a group sense fitness. “Maybe cells are recognizing chemical differences, or physical differences, or differences in cell-membrane composition,” says Fujita, who adds that labs have found evidence for all three.

His filament-poking kidney-cell experiments suggest that cell–cell contact is needed. Others have seen chemical-fitness signals that seem to be short-range, travelling up to eight cell diameters. Exactly which molecules are responsible for this signalling — either secreted chemicals or physical tags — is the subject of intense debate and investigation.


    The secret social lives of viruses

    Both Johnston and Zwaka have turned up signals associated with immune surveillance. Johnston’s group identified molecules that typically call immune cells to swarm in and engulf foreign invaders and that were driving death in losers11. Normal cells express low levels of these death signals at all times. But in a competitive mix, winners flooded their loser neighbours with the signal, which pushed them to kill themselves.

    Zwaka proposes that cells might assess each other’s health by sniffing out the general signals or debris that cells shed. It’s akin to smelling the steaks that your neighbour is grilling for dinner and concluding that they must be doing well.

    Or it could be as simple as seeing which flag your neighbour is flying. Moreno heads his own group now at the Champalimaud Centre for the Unknown in Lisbon, Portugal, which discovered a membrane-spanning protein called Flower. In humans, the protein can take four forms, each displaying its own characteristic structure on the outer cell surface. Two signal ‘I’m a winner’ and the other two signal ‘I’m a loser’ to nearby cells, says Moreno.

    Some human cancer cells fly the Flower-winner signals, which might enhance their survival. Experiments in Moreno’s lab showed that silencing the winning flags on tumours slowed the cells’ growth and made them susceptible to chemotherapy.

    Some researchers, however, dispute the importance of the Flower tags. Moreno acknowledges that they are not present in all cell-competition situations.

    Healthy competition

    Cracking the mechanics of competition will be key if researchers want to use it to improve cell-based cancer or regenerative therapies.

    There are tantalizing hints that cell competition might already protect against cancer. Findings made in the past few years reveal that human skin, oesophageal and lung cells show high levels of mosaicism. Approximately one-quarter of skin cells, for example, harbour many precancerous mutations that only rarely turn into tumours.

    It is unclear what gives cancerous cells the advantage when tumours do form. If researchers can learn how to subdue supercompetitors or blunt cancer cells’ ability to compete, they might be able to turn that against cancer.

    Conversely, stem cells might need to gain a competitive edge if they are to replace aged or diseased tissue for an organ makeover. Villa del Campo says that clinicians are already considering how to enhance patient-derived cardiac stem cells to efficiently replace cells that have been damaged by heart attacks or disease.

    What started as modest observations in minuscule fruit-fly larvae has exposed the primal cellular battles that could usher in a new era of cell-based medicine. The process has scientists buzzing, but it remains mysterious.

“Cell competition might be a general process to remove any undesirable cell that should not be there,” says Morata, after returning from a one-day meeting in Lausanne, Switzerland devoted to competition in September.

Now , he’s thrilled that work he essentially shelved more than 40 years ago is gaining new life and that the competition is heating up. “It’s really exciting.”

Nature 574, 310-312 (2019)


我在上班,别发骚图了。
最新回复 (6)
  • 联盟X 2019-10-16
    0 2
    傻了(洋文超差)
    匡扶汉室!
  • longwang12345 2019-10-19
    0 3
    你以为本站人均英文专八吗
    这个人很懒,什么也没有留下!
  • 3080 2019-11-24
    2 4
    Yasuyaki Fujita亲眼目睹了当细胞停止礼貌并开始变得真实时会发生什么。当他在一个培养皿中打开一个叫做Ras的致癌基因时,他瞥见了这个严酷的微观世界。他希望看到癌细胞扩散,并在邻近的细胞中形成肿瘤。日本札幌北海道大学的癌症生物学家藤田说,这些整洁有序的邻居们用长丝蛋白武装自己,开始“戳、戳、戳”。“转化的细胞从正常细胞的社会中被淘汰了,”他说,实际上是被隔壁的细胞排挤了出去。



    在过去的20年里,类似的发现层出不穷,揭示了细胞水平上的争吵、争斗和全面战争。这就是所谓的细胞竞争,有点像物种间的自然选择,更健康的细胞胜过不那么健康的细胞。这种现象可以作为生物体发育过程中的质量控制,作为对癌前细胞的防御,以及作为维持皮肤、肠道和心脏等器官的关键部分。细胞用各种各样的方法来消灭它们的对手,从把它们踢出组织到诱导细胞自杀,甚至吞噬它们并分解它们的成分。观察结果表明,组织的发育和维持比以前认为的要混乱得多。纽约市西奈山伊坎医学院的干细胞生物学家Thomas Zwaka说:“这是对一套预先设定好的规则的根本性背离,这些规则就像时钟一样运行。”



    但是,关于单个细胞如何识别周围细胞的弱点并对其采取行动的问题比比皆是。实验室一直在努力寻找——并争论——健康的潜在标记,以及它们是如何引发竞争行为的。这些机制可以让科学家控制这一过程,或者帮助它向前发展,这可能会导致更好的方法来对抗癌症,用再生医学来对抗疾病和衰老。



    “细胞竞争在全球科学地图上,”英国布里斯托尔大学(University of Bristol)的细胞生物学家尤金尼亚·皮迪尼(Eugenia Piddini)说。她说,科学家越了解竞争,他们就越有可能将其用于治疗。



    历史重演



    今年2月,一场暴风雪带来了30多厘米的降雪,来自大约12个学科的生物学家聚集在加州塔霍湖的一家酒店里,召开了第一次专门讨论细胞竞争的大型会议。



    说:“这是一个动物园的研究组织者Zwaka,包括生物学家研究扁虫,可以从一个细胞再生他们的全身,遗传学家试图使跨物种嵌合体小鼠,猴子和兔子的胚胎,和一位主讲人谈到了可怕的战斗和合作活动进行细菌社区。



    被雪困住的与会者总共约有150人,他们讨论了细胞如何以及为什么要衡量它们的竞争力。他们庆祝这一领域的发现。







    细胞内的秘密对话是如何改变生物学的



    1973年,两位博士生,希内斯·莫拉塔和佩德罗·里波尔,正在完善一种追踪果蝇幼虫中各种细胞群的方法,这些幼虫最终会发育成翅膀。他们在西班牙国家研究委员会位于马德里的生物研究中心工作,他们将一种名为“分钟”的突变基因注入到幼虫体内的几个精选细胞中,而其余细胞则保持不变。



    科学家们知道微小细胞的生长速度比未改变的相邻细胞要慢,因此他们希望能在野生型细胞中找到更小的细胞。“相反,我们发现细胞消失了,”莫拉塔说,她现在是西班牙马德里自治大学的发育生物学家。



    在它们自己身上,微小的细胞可以发育成正常的苍蝇——除了它们身上短而薄的刚毛,它们身上的这种突变因此得名。但当与幼虫中的野生型细胞混合时,这些细胞就消失了。“微小细胞无法与更活跃、代谢活跃的野生型细胞竞争,”莫拉塔说。他们把这种活动称为细胞竞争。“这是一个非常令人惊讶和有趣的观察结果,”莫拉塔说。但由于缺乏更密切地跟踪细胞命运的分子工具,他和他的同事让这一发现慢慢酝酿。



    26年后,博士后劳拉·约翰斯顿和彼得·格兰特观察到几乎相同的现象。他们分别与布鲁斯·埃德加(Bruce Edgar)和罗伯特·艾森曼(Robert Eisenman)在华盛顿州西雅图的弗雷德·哈金森癌症中心(Fred Hutchinson Cancer Center)合作,研究另一种果蝇基因——果蝇Myc (Drosophila Myc, dMyc)的突变。
  • rollnut 2019-11-24
    0 5
    wtf what is it?
    这个人什么也没有
  • 南在七月 2020-1-28
    0 6
    。。。还在高中的我表示无奈
    这个人很懒,什么也没有留下!
  • 喀秋莎 2020-1-29
    0 7
    南在七月 。。。还在高中的我表示无奈
    可以当阅读理解练习。
    我在上班,别发骚图了。
    • ACG里世界
      8
          
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