Posts Tagged ‘cells’
“In the beginning there is the stem cell; it is the origin of an organism’s life”*…
C.H. Waddington’s powerful image of embryonic stem cells specializing on a rolling landscape has captivated biologists since the 1950s. As Philip Ball reports, experimental data is finally confirming– and complicating– his visionary ideas…
By the middle of the 20th century, it had begun to seem that biology was almost solved. Charles Darwin’s theory of evolution by natural selection explained how organisms change and adapt. The modern science of genetics showed how it works at the molecular scale. Genes governing the traits of organisms get passed down from parent to offspring, and random mutations create the variations from which natural selection picks the “fittest.” Natural selection and genetics fitted together in what the biologist Julian Huxley christened “the modern synthesis” in his 1942 book). Once it was shown in 1953 that the genes are encoded by DNA, the rest of biology looked like little more than piecing together details.
But not everyone was satisfied. The British biologist Conrad Hal Waddington), known to his friends and colleagues as Wad, thought this focus on genes was all very well. But it wasn’t clear to him, or anyone else, exactly how genes shape the forms and features of organisms — how they reliably generate all the different tissues of the body, in all the right places, during embryonic development. Around the same time that Huxley unveiled the modern synthesis, Waddington presented a novel picture of how this might unfold.
He visualized the developmental process as a landscape with hills and valleys that split every so often like those in a river network. At the very top of the highest hill he imagined a ball, which represented a population of cells in their earliest embryonic form — what we now call stem or pluripotent cells, which have the potential to become any cell type. The progression of the cells towards their fates — to become, say, skin cells, muscle cells, or nerve cells — is like the ball rolling downhill through the landscape.
When the ball reaches a branching point (bifurcation), the model’s “gravity” pulls it to one track or the other: In scientific terms, it must differentiate. Through a particular sequence of such branching decisions, Waddington argued, cells specialize into their mature types, or fates, each expressing a particular set of genes. The cells are restricted to a small number of well-defined states because they are “canalized,” in Waddington’s lexicon: trapped and channeled by the sides of the valley. In this way, a limited number of cell types reliably arise from the activity of an army of genes.
Waddington’s landscape has been “remarkably useful as a conceptual scaffold,” said James Briscoe, a developmental biologist at the Francis Crick Institute in London. “The core ideas — that development is progressive, that cell states are distinct, that bifurcations represent [cell] fate decisions, that canalization implies robustness — all survive.”
“There’s so much richness to some of the concepts Waddington was trying to share,” said Susanne Rafelski, a biochemist at the Institute for Stem Cell and Regenerative Medicine in Seattle.
But the concept was more of a visual metaphor than a representation of an actual biological process. Or so it seemed. In the past several years, researchers have mapped out the real topography of cell-state spaces — in effect, Waddington’s landscapes — from experimental data collected from many thousands of cells over the course of embryonic development. Those analyses are revealing that development is not a mere readout of a genetic program, but rather a dynamic process in which communities of cells build themselves, and the very landscape they navigate, by mutual negotiation and interaction, into an organism.
This cartography of development is now helping researchers understand how identical cells in the early embryo develop into the distinct tissues and cell types of a complex organism. This matters enormously for regenerative medicine and stem-cell engineering, Briscoe said: “If you understand the landscape topology and know where the bifurcations lie, you can in principle design methods that steer cell populations to desired states with precision, rather than by trial and error.”
Waddington’s metaphor, then, could be the key to understanding and reshaping possibilities for what cells, tissues, and embryos can be…
Read on: “How Does Life Unfold? A Landscape Metaphor Comes Into Its Own.” from @philipcball.bsky.social in @quantamagazine.org.
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As we appreciate adaptability, we might send healing birthday greetings to Robert Peter Gale; he was born on this date in 1945. A physician and medical researcher, he conducted important research into leukemia and other bone marrow disorders (e.g., aplastic anemia). Gale was a a pioneer in bone marrow transplantation and co-founded the International Bone Marrow Registry. But he is perhaps most widely known for his assistance to foreign governments in treating radiation victims – to the Soviet Union (1986) after the Chernobyl disaster and to Brazil (1987) following an accident in Goiania. As a specialist in bone marrow transplants, he volunteered to treat Chernobyl victims and was invited by Mikhail Gorbachev to travel with a group to Moscow immediately after the April 1986 accident. He performed bone marrow transplants on 13 Chernobyl victims (though many of the highly exposed Chernobyl survivors have since died from latent radiation effects).
“Memory resides not just in brains but in every cell”*…
As the redoubtable Claire L. Evans [and here] reports, a small but enthusiastic group of neuroscientists is exhuming overlooked experiments and performing new ones to explore whether cells record past experiences — fundamentally challenging our understanding of what memory is…
In 1983, the octogenarian geneticist Barbara McClintock stood at the lectern of the Karolinska Institute in Stockholm. She was famously publicity averse — nearly a hermit — but it’s customary for people to speak when they’re awarded a Nobel Prize, so she delivered a halting account of the experiments that had led to her discovery, in the early 1950s, of how DNA sequences can relocate across the genome. Near the end of the speech, blinking through wire-framed glasses, she changed the subject, asking: “What does a cell know of itself?”
McClintock had a reputation for eccentricity. Still, her question seemed more likely to come from a philosopher than a plant geneticist. She went on to describe lab experiments in which she had seen plant cells respond in a “thoughtful manner.” Faced with unexpected stress, they seemed to adjust in ways that were “beyond our present ability to fathom.” What does a cell know of itself? It would be the work of future biologists, she said, to find out.
Forty years later, McClintock’s question hasn’t lost its potency. Some of those future biologists are now hard at work unpacking what “knowing” might mean for a single cell, as they hunt for signs of basic cognitive phenomena — like the ability to remember and learn — in unicellular creatures and nonneural human cells alike. Science has long taken the view that a multicellular nervous system is a prerequisite for such abilities, but new research is revealing that single cells, too, keep a record of their experiences for what appear to be adaptive purposes.
In a provocative study published in Nature Communications late last year, the neuroscientist Nikolay Kukushkin and his mentor Thomas J. Carew at New York University showed that human kidney cells growing in a dish can “remember” patterns of chemical signals when they’re presented at regularly spaced intervals — a memory phenomenon common to all animals, but unseen outside the nervous system until now. Kukushkin is part of a small but enthusiastic cohort of researchers studying “aneural,” or brainless, forms of memory. What does a cell know of itself? So far, their research suggests that the answer to McClintock’s question might be: much more than you think…
[Evans explains the prevailing wisdom, outlines the experiments that have challenged it, and unpacks (at least some reasons for) resistance to the notion of cellular-scale memory, both sociological and semantic…]
… In neuroscience, [biochemist and neuroscientist Nikolay] Kukushkin writes, the most common definition of memory is that it’s what remains after experience to change future behavior. This is a behavioral definition; the only way to measure it is to observe that future behavior. Think of S. roeselii snapping back into its holdfast, or a lab rat freezing up at the sight of an electrified maze it’s tangled with before. In these cases, how an organism reacts is a clue that prior experience left a lingering trace.
But is a memory only a memory when it’s associated with an external behavior? “It seems like an arbitrary thing to decide,” Kukushkin said. “I understand why it was historically decided to be that, because [behavior] is the thing you can measure easily when you’re working with an animal. I think what happened is that behavior started as something that you could measure, and then it ended up being the definition of memory.”
Behavior tells us that a memory has formed but says nothing about why, how or where. Further, it’s constrained by scale. Take Aplysia californica, a muscular sea slug with enormous neurons (the largest is about the size of a letter on a U.S. penny). Neuroscientists love to conduct memory experiments on Aplysia because its physical responses are easy to measure — poke it and it flinches — and they map cleanly to the handful of sensory and motor neurons involved.
The sea slug, Kukushkin said, can complicate neuroscience’s behavioral bias. Say you shock its tail, triggering a defensive reflex. If you shock it again the next day and find that the defensive reflex is stronger than it was before, that’s behavioral evidence that the slug remembers its initial shock. Any neuroscientist would associate it with a memory.
But what if (apologies to the squeamish) you take that sea slug apart and leave only its immobile neurons? Unlike the intact creature, the neurons can’t retract, so there will be no visible response. Is the memory gone? Certainly not, but without external validation, a behavioral definition of memory breaks down. “We no longer call that a memory,” Kukushkin said. “We call that a mechanism for a memory, we call that synaptic change underlying memory, we call that an analogue of memory. But we don’t call that a memory, and I think that it’s arbitrary.”
Perhaps a definition of memory should extend beyond behavior to encompass more records of the past. A vaccination is a kind of memory. So is a scar, a child, a book. “If you make a footprint, it’s a memory,” Gershman said. An interpretation of memory as a physical event — as a mark made on the world, or on the self — would encompass the biochemical changes that occur within a cell. “Biological systems have evolved to harness those physical processes that retain information and use them for their own purposes,” [cognitive scientist Sam] Gershman said.
So, what does a cell know of itself? Perhaps a better version of Barbara McClintock’s question is: What can a cell remember? When it comes to survival, what a cell knows of itself isn’t as important as what it knows of the world: how it incorporates information about its experiences to determine when to bend, when to battle and when to make a break for it.
A cell preserves the information that preserves its existence. And in a sense, so do we. As today’s cellular memory researchers revisit abandoned experimental threads from the past, they too are discovering what memory owes to its context, how science’s sociological environment can determine which ideas are preserved and which are forgotten. It’s almost as though a field is waking up from a 50-year spell of amnesia. Fortunately, the memories are flooding back…
“What Can a Cell Remember?” from @theuniverse.bsky.social in @quantamagazine.bsky.social.
For more on the work that got Barbara McClintock onto the Nobel podium see here.
And, also apposite, a pair of cautionary historical examples of scientists who followed Jean-Baptiste Lamarck, who argued in the early 19th century that an organism can pass on to its offspring physical characteristics that the parent organism acquired through use or disuse during its lifetime– that’s to say that learning (a kind of memory) is heritable… and went astray: Lysenko and Kammerer [and here].
* James Gleick, The Information
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As we muse on memory (and note that one cannot remember– and learn from– what one cannot know), we might recall that it was on this date in 1735 that New York Weekly Journal publisher and writer John Peter Zenger was acquitted of seditious libel against the royal governor of New York, William Cosby, on the basis that what he had published was true.
In 1733, Zenger had begun printing The New York Weekly Journal, voicing opinions critical of the colonial governor. On November 17, 1734, on Cosby’s orders, the sheriff arrested Zenger. After a grand jury refused to indict him, the Attorney General Richard Bradley charged him with libel. Zenger’s lawyers, Andrew Hamilton and William Smith, Sr., successfully argued that truth is a defense against charges of libel… and Zenger became a symbol for freedom of the press.
“The past lives within the present, and our ancestors breathe through our children”*…
Indeed, that’s true all the way back. And as Jonathan Lambert explains, we now have more visibility on that distant past. The emerging understanding of our “last universal common ancestor” suggests it was a relatively complex organism living 4.2 billion years ago, a time long considered too harsh for life to flourish…
If you follow any path of ancestry back far enough, you’ll reach the same single point. Whether you begin with gorillas or ginkgo trees or bacteria that live deep in the bowels of the Earth — or yourself, for that matter — all roads lead to LUCA, the “last universal common ancestor.” This ancient, single-celled organism (or, possibly, population of single-celled organisms) was the progenitor of every varied form that makes a life for itself on our planet today.
LUCA does not represent the origin of life, the instance whereby some chemical alchemy snapped molecules into a form that allowed self-replication and all the mechanisms of evolution. Rather, it’s the moment when life as we know it took off. LUCA is the furthest point in evolutionary history that we can glimpse by working backward from what’s alive today. It’s the most recent ancestor shared by all modern life‚ our collective lineage traced back to a single ancient cellular population or organism.
“It’s not the first cell, it’s not the first microbe, it’s not the first anything, really,” said Greg Fournier, an evolutionary biologist at the Massachusetts Institute of Technology. “In a way, it is the end of the story of the origin of life.”
Still, understanding LUCA — whether it was simple or complex, and how quickly it emerged after life’s origin — could help answer some of our deepest questions about where we come from and whether we’re alone in the universe.
“[LUCA] tells our own story,” said Edmund Moody (opens a new tab), an evolutionary biologist at the University of Bristol. “It gives us a point from which we can look even further back.”
For half a century, biologists have focused on different kinds of physiological, genomic and fossil evidence to paint portraits of LUCA that sometimes clash dramatically. In 2024, Moody and a team of interdisciplinary researchers, including geologists, paleontologists, system modelers and phylogeneticists, combined their knowledge to build a probabilistic model that reconstructs modern life’s shared ancestor and estimates when it lived.
The analysis, published in Nature Ecology and Evolution in July, sketched a surprisingly complex picture of the cell. LUCA lived off hydrogen gas and carbon dioxide, boasted a genome as large as that of some modern bacteria, and already had a rudimentary immune system, according to the study. Its genomic complexity, the authors argue, suggests that LUCA was one of many lineages — the rest now extinct — living about 4.2 billion years ago, a turbulent time relatively early in Earth’s history and long thought too harsh for life to flourish.
The analysis reaches two conclusions that seem in conflict with each other, according to Aaron Goldman, who studies the molecular evolution of early life at Oberlin College and wasn’t involved in the new research. “The first is that LUCA was a complex cellular organism that likely lived in a complex ecological setting,” he said. “The second is that LUCA dates to a time that is pretty early in the history of Earth.” The results could mean that life evolved from a simple replicator into something resembling modern microbes remarkably quickly, he said. “That’s really exciting.”
“Our work suggests that those early steps of evolution weren’t hard; they’re pretty easy,” said co-author Phil Donoghue, an evolutionary biologist at the University of Bristol. “If you’re concerned with the origin of microbial-grade life, then that’s apparently very easy, and it should be quite common in the universe.”
Not all experts in the field agree, however. Some argue that a few hundred million years is not enough time for complex life to have evolved. The authors stress that their analysis is a first attempt to paint a fuller, admittedly fuzzy, picture of LUCA. “I fully expect and hope people prove us wrong in certain aspects,” said Moody, the paper’s lead author, especially if those new results offer a clearer view of the ancient ancestor of all life we know…
Eminently worth reading in full: “All Life on Earth Today Descended From a Single Cell. Meet LUCA,” from @evolambert in @QuantaMagazine.
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As we look back, we might send microscopic birthday greetings to Lewis Thomas; he was born on this date in 1913. A physician, poet, etymologist, essayist, administrator, educator, policy advisor, and researcher, he distinguished himself in medicine and microbiology both for his suggestion that an immunosurveillance mechanism protects us from the possible ravages of mutant cells (an idea later championed by Macfarlane Burnett) and for his proposal that viruses have played a major role in the evolution of species by their ability to move pieces of DNA from one individual or species to another.
But Lewis is more widely known for his writing, perhaps most especially for his first two books– The Lives of a Cell: Notes of a Biology Watcher (which won National Book Awards in two categories) and The Medusa and the Snail: More Notes of a Biology Watcher (which won another National Book Award)– which underscored the interconnectedness of life by sketching the ways that what is seen under the microscope is similar to the way human beings live.
“Every living thing is made of cells, and everything a living thing does is done by the cells that make it up”*…
And so, as Charudatta Navare explains, we need to be thoughtful about how we talk about them, as prevailing scientific narratives project human social hierarchies onto nature in misleading ways…
When you think about it, it is amazing that something as tiny as a living cell is capable of behaviour so complex. Consider the single-cell creature, the amoeba. It can sense its environment, move around, obtain its food, maintain its structure, and multiply. How does a cell know how to do all of this? Biology textbooks will tell you that each eukaryotic cell, which constitutes a range of organisms from humans to amoeba, contains a control centre within a structure called the nucleus. Genes present in the nucleus hold the ‘information’ necessary for the cell to function. And the nucleus, in turn, resides in a jelly-like fluid called the cytoplasm. Cytoplasm contains the cellular organelles, the ‘little organs’ in the cell; and these organelles, the narrative goes, carry out specific tasks based on instructions provided by the genes.
In short, the textbooks paint a picture of a cellular ‘assembly line’ where genes issue instructions for the manufacture of proteins that do the work of the body from day to day. This textbook description of the cell matches, almost word for word, a social institution. The picture of the cytoplasm and its organelles performing the work of ‘manufacturing’, ‘packaging’ and ‘shipping’ molecules according to ‘instructions’ from the genes eerily evokes the social hierarchy of executives ordering the manual labour of toiling masses. The only problem is that the cell is not a ‘factory’. It does not have a ‘control centre’. As the feminist scholar Emily Martin observes, the assumption of centralised control distorts our understanding of the cell.
A wealth of research in biology suggests that ‘control’ and ‘information’ are not restricted at the ‘top’ but present throughout the cell. The cellular organelles do not just form a linear ‘assembly line’ but interact with each other in complex ways. Nor is the cell obsessed with the economically significant work of ‘manufacturing’ that the metaphor of ‘factory’ would have us believe. Instead, much of the work that the cell does can be thought of as maintaining itself and taking ‘care’ of other cells.
Why, then, do the standard textbooks continue to portray the cell as a hierarchy? Why do they invoke a centralised authority to explain how each cell functions? And why is the imagery so industrially loaded?…
We need better metaphors to describe cellular life: “The cell is not a factory,” from @charudatta_n in @aeonmag.
* cytologist and author L.L. Larison Cudmore
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As we avoid anthropomorphism, we might recall that it was on this date in 1981 that the first patent for a life form (U.S. No. 4,259,444) was issued to Ananda Chakrabarty (who had done his research at GE). Chakrabarty had developed Pseudomonas bacterium (now called Burkholderia cepacia) which can be used to clean up toxic spills (as it can break down crude oil into simpler substances that can even become food for aquatic life)– an ability possessed by no naturally occurring bacteria.
The application had been originally denied by the patent office, on the grounds that under patent law at that time, living things were generally understood to not be patentable subject matter under 35 U.S.C. § 101.
Chakrabarty (and GE) appealed (to the Board of Patent Appeals and Interferences), lost, and appealed again ( the United States Court of Customs and Patent Appeals) and prevailed…. At which point, the Patent Office (led by director Sydney Diamond) appealed in civil court.
Ultimately, the Supreme Court ruled (5-4, Diamond v. Chakrabarty) in Chakrabarty’s favor. As Chief Justice Warren Burger wrote for the majority, life can be patented if they are the outcome of “human ingenuity and research” and not “nature’s handiwork”– a ruling that cleared the way for patents to be issued on genetically-engineered mice and other animals, seeds, and more.
“Without debatement further, more or less, / He should the bearers put to sudden death, / Not shriving time allow’d.”*…
“Cell suicide” is inherently self-destructive, and yet it’s an essential and productive process in complex organisms. How did cells evolve a process to end their own lives? As Veronique Greenwood reports, recent research suggests it first arose, first arose billions of years ago… but why?…
It can be hard to tell, at first, when a cell is on the verge of self-destruction.
It appears to be going about its usual business, transcribing genes and making proteins. The powerhouse organelles called mitochondria are dutifully churning out energy. But then a mitochondrion receives a signal, and its typically placid proteins join forces to form a death machine.
They slice through the cell with breathtaking thoroughness. In a matter of hours, all that the cell had built lies in ruins. A few bubbles of membrane are all that remains.
“It’s really amazing how fast, how organized it is,” said Aurora Nedelcu, an evolutionary biologist at the University of New Brunswick who has studied the process in algae.
Apoptosis, as this process is known, seems as unlikely as it is violent. And yet some cells undergo this devastating but predictable series of steps to kill themselves on purpose. When biologists first observed it, they were shocked to find self-induced death among living, striving organisms. And although it turned out that apoptosis is a vital creative force for many multicellular creatures, to a given cell it is utterly ruinous. How could a behavior that results in a cell’s sudden death evolve, let alone persist?…
The story in full: “Cellular Self-Destruction May Be Ancient. But Why?“, from @vero_greenwood in @QuantaMagazine.
* Shakespeare, Hamlet (Act 5, Scene 2)
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As we appreciate apoptosis, we might send healthy birthday greetings to Lillian Wald; she was born on this date in 1867. A nurse, humanitarian, political reformer, and author, she was instrumental in establishing a nationwide system of nurses in public schools. Known as “the Angel of Henry Street” (for her founding and running of the Henry Street Settlement in New York City), she directed the Henry Street Visiting Nurse Service, while at the same time tirelessly opposing political and social corruption. She helped initiate the revision of child labor laws, improved housing conditions in tenement districts, drove the enactment of pure food laws, championed and improved education for the mentally handicapped, and led the passage of enlightened immigration regulations.
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