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2024 Dec 6

- Exotic New Superconductors Delight and Confound

CONDENSED MATTER PHYSICS | VIEW ON WEBSITE

Exotic New Superconductors Delight and Confound

By Charlie Wood

December 6, 2024

Three new species of superconductivity were spotted this year, illustrating the myriad ways electrons can join together to form a frictionless quantum soup.

The new superconductors are all two-dimensional materials, honeycomb sheets of atoms that can be stacked and twisted to produce kaleidoscopic patterns and a vast range of behaviors.

Mark Belan/Quanta Magazine

Introduction

This year, superconductivity — the flow of electric current with zero resistance — was discovered in three distinct materials. Two instances stretch the textbook understanding of the phenomenon. The third shreds it completely. “It’s an extremely unusual form of superconductivity that a lot of people would have said is not possible,” said Ashvin Vishwanath, a physicist at Harvard University who was not involved in the discoveries.

Ever since 1911, when the Dutch scientist Heike Kamerlingh Onnes first saw electrical resistance vanish, superconductivity has captivated physicists. There’s the pure mystery of how it happens: The phenomenon requires electrons, which carry electrical current, to pair up. Electrons repel each other, so how can they be united?

Then there’s the technological promise: Already, superconductivity has enabled the development of MRI machines and powerful particle colliders. If physicists could fully understand how and when the phenomenon arises, perhaps they could engineer a wire that superconducts electricity under everyday conditions rather than exclusively at low temperatures, as is currently the case. World-altering technologies — lossless power grids, magnetically levitating vehicles — might follow.

The recent spate of discoveries has both compounded the mystery of superconductivity and heightened the optimism. “It seems to be, in materials, that superconductivity is everywhere,” said Matthew Yankowitz, a physicist at the University of Washington.

The discoveries stem from a recent revolution in materials science: All three new instances of superconductivity arise in devices assembled from flat sheets of atoms. These materials display unprecedented flexibility; at the touch of a button, physicists can switch them between conducting, insulating, and more exotic behaviors — a modern form of alchemy that has supercharged the hunt for superconductivity.

It now seems increasingly likely that diverse causes can give rise to the phenomenon. Just as birds, bees and dragonflies all fly using different wing structures, materials seem to pair electrons together in different ways. Even as researchers debate exactly what’s happening in the various two-dimensional materials in question, they anticipate that the growing zoo of superconductors will help them achieve a more universal view of the alluring phenomenon.

Pairing Electrons

The case of Kamerlingh Onnes’ observations (and superconductivity seen in other extremely cold metals) was finally cracked in 1957. John Bardeen, Leon Cooper and John Robert Schrieffer figured out that at low temperatures, a material’s jittery atomic lattice quiets down, so more delicate effects come through. Electrons gently tug on protons in the lattice, drawing them inward to create an excess of positive charge. That deformation, known as a phonon, can then draw in a second electron, forming a “Cooper pair.” Cooper pairs can all come together into a coherent quantum entity in a way that lone elections can’t. The resulting quantum soup slips frictionlessly in between the material’s atoms, which normally impede electric flow.

Bardeen, Cooper and Schrieffer’s theory of phonon-based superconductivity earned them the physics Nobel Prize in 1972. But it turned out not to be the whole story. In the 1980s, physicists found that copper-filled crystals called cuprates could superconduct at higher temperatures, where atomic jiggles wash out phonons. Other similar examples followed.

Heike Kamerlingh Onnes (left) stumbled upon superconductivity in 1911. An explanation for it eluded Albert Einstein and other luminaries until the 1950s, when John Bardeen, Leon Cooper and John Robert Schrieffer (right photo, left to right) determined that atomic vibrations known as phonons were at work.

From left: Chronicle/Alamy; AIP Emilio Segrè Visual Archives

Theorists brainstormed new ways of pairing electrons.

The higher-temperature superconductors seemed to have atoms arranged in a way that slows electrons down. And when electrons get the chance to mingle in a leisurely fashion, they collectively generate an ornate electric field that can make them do novel things, like form pairs rather than repel. Physicists now suspect that in cuprates, specifically, electrons hop between atoms in a particular way that favors pairing. But other “unconventional” superconductors are still quite mysterious.

Then, in 2018, a new superconductor opened physicists’ eyes wider.

Pablo Jarillo-Herrero, a physicist at the Massachusetts Institute of Technology, found that if you took a sheet of carbon atoms arranged in a honeycomb lattice — a 2D crystal called graphene — twisted it at precisely 1.1 degrees, and stacked it on top of another graphene sheet, the two layers could superconduct.

Researchers had already been dabbling with 2D materials and finding diverse behaviors. By applying electric fields, they could add electrons to the sheet or make the electrons feel almost as if the atomic grid were contracting. Twiddling these settings in a single 2D device could reproduce the behavior of thousands to millions of potential materials. Among those heaps of possibilities, Jarillo-Herrero had shown, was a new superconductor: “magic angle” graphene.

Then, a couple of years later, a group in California removed the magic angle, finding that three-layer, twist-free graphene devices could also superconduct.

Mark Belan/Quanta Magazine

Researchers are still discussing why electrons stick together in these cases. Phonons fit the data in some ways, but something new also seems responsible.

But what really thrilled physicists was the promise of a fresh way to investigate superconductivity in general. The customizable 2D devices had freed them from the drudgery of designing, growing and testing new crystals one by one. Researchers would now be able to quickly re-create the effects of many different atomic lattices in a single device and find out exactly what electrons are capable of.

The research strategy is now paying off. This year, physicists found the first instances of superconductivity in 2D materials other than graphene, along with a completely novel form of superconductivity in a new graphene system. The discoveries have established that the earlier graphene superconductors mark just the outskirts of a wild new jungle.

A Hint Vindicated

In 2020, the physicist Cory Dean and his team at Columbia University tried stacking sheets of a different 2D crystal — this one, a honeycomb arrangement of two types of atoms, called a transition metal dichalcogenide (TMD). When they twisted the sheets at 5 degrees, the resistance plunged toward zero but didn’t stay there. It was an inconclusive hint of superconductivity.

The tentative nature of the detection didn’t stop Liang Fu of MIT and Constantin Schrade of Louisiana State University from trying to explain it. They suspected that phonons weren’t the answer. Twisted materials are powerful because the twist changes what the electrons experience, imbuing the material with a kaleidoscopic “moiré” pattern. The moiré features large hexagonal cells that act like artificial atoms, hosting electrons. In this new environment, electrons move slowly enough for their collective electrical interactions to guide their behavior.

5W Infographics; Mark Belan/Quanta Magazine

But how were the electrons conspiring to form pairs? The Columbia group funneled electrons into the moiré. They observed that when there was one electron for each of the large cells in the moiré material, these electrons assumed an “antiferromagnetic” arrangement; their intrinsic magnetic fields tended to alternate between pointing up and down. Adding extra electrons to the moiré made the resistance drop to zero — Cooper pairs had formed. Fu and Schrade argued that the same electron-on-electron action was making both the antiferromagnetic state and the superconducting state possible. At one electron per cell, each electron can have a preferred location and magnetic orientation. But when additional electrons pile in, the magnetic arrangement becomes unstable, and the whole population starts to flow freely.

Cory Dean and his group at Columbia University spotted a flicker of superconductivity in a two-dimensional TMD material in 2020. This year, they confirmed the discovery.

Courtesy of Cory Dean

Scientific journals initially rejected Fu and Schrade’s paper describing these ideas because there wasn’t any hard evidence that TMDs can superconduct. Now there is. The Columbia group spent the last four years improving their ability to measure electrical resistance at low temperatures, and earlier this year they had a breakthrough. They assembled another two-sheet device with a 5-degree twist, cooled it down, and watched it superconduct — an observation soon to be published in Nature. “Lo and behold, we see that the state that we thought existed is appearing in exactly the right place,” Dean said. “It’s a little bit of vindication.”

Fu and Schrade’s theory — bolstered by the Columbia confirmation — has now been published, but it isn’t proved. One way to test it is to check whether the Cooper pairs can rotate, as the theory predicts. That’s an unusual feature, as electrons paired by phonons don’t orbit each other.

Adding electrons to an antiferromagnetic metal isn’t the only way to cook up superconductivity in TMDs. Shortly before the Columbia discovery, another group found an even more peculiar species of superconductivity in the very same material.

Jie Shan and Kin Fai Mak, an academic power couple who run a lab at Cornell University, had been searching for superconductivity in TMDs since Jarillo-Herrero’s blockbuster twisted-graphene discovery in 2018. They spent years mixing and matching five kinds of TMD crystals, trying out different twist angles and temperatures, and applying various electric-field strengths to the material — searching a massive haystack for a superconducting device.

When the needle finally appeared, it displayed a species of superconductivity that no one had seen coming. The Columbia team had started with an antiferromagnetic metal and added electrons. The Cornell group, however, started with an insulator and added nothing. Their moiré pattern — which resulted from a milder 3.5-degree twist — allowed electrons to slow down so much and interact so strongly that they all got stuck in place at precisely one electron per cell.

A team at Cornell University led by Kin Fai Mak (left) and Jie Shan recently discovered an unusual sort of superconductivity in a TMD device.

Sasha Maslov

Then the group made the device superconduct just by tweaking the strength of the applied electric field. That result, which the researchers reported in Nature in October, doesn’t neatly fit any popular theory of superconductivity.

“It really smells like something else is going on,” Vishwanath said.

The Most Exotic Beast Yet

Even as superconductivity has spread to the TMDs, graphene continues to astonish. Over the summer, a graphene device produced a mythical form of superconductivity.

“It is phenomenologically different from all other superconductors,” said Long Ju of MIT, leader of the group that found it. And that’s “comparing it to any superconductor that has been discovered since Kamerlingh Onnes in 1911.”

Twisting is too messy for Ju’s tastes; the moiré patterns tend to get disrupted by wrinkles in the sheets that make every device a little different. Instead, he studies a staircase-like arrangement of four graphene layers that can also slow electrons down. The challenge is to spot which graphene flakes naturally have this staircase arrangement — something Ju accomplishes with the aid of an infrared camera. “You don’t need to pick up four different layers and stack them,” Ju said. “Nature does it for you. You just need to have the right pair of eyes to see them.”

Last year, Ju’s group made a splash when they placed a five-layer graphene flake on an insulator at a twisted angle and observed a rare electron behavior that normally requires a strong magnetic field to induce. Theorists questioned whether the twist was essential, so he and his team went back to see what would happen when they took the twist out. “We found something that was more bizarre,” Ju said.

As they changed the strength of the electric field that they applied to the material, they found several settings where resistance vanished. In two cases, the superconductivity flickered, with resistance coming and going. Strangely, when they switched on a nearby magnet, the flickering stopped. Magnets normally kill superconductivity, but here, they strengthened it. “This existed only in the imagination of theorists,” Ju said.

Long Ju helped discover a truly unprecedented superconductor — one that grows stronger in the presence of magnetism.

Courtesy of Long Ju

Ju’s group suspects that their graphene staircases are creating the conditions for electrons to pair up and rotate. But they think that in their graphene devices, all pairs tend to rotate in the same direction — either clockwise or counterclockwise — and flickers appear when pairs aren’t all rotating uniformly. The magnetic field stamps out the flickers by pushing any wayward pairs to align with the overall gyre. A material with such a preferred internal direction is called “chiral,” but chirality has long been thought to preclude superconductivity, since it distinguishes leftward- and rightward-moving electrons in a way that should stop pairs from forming.

“People thought you would not get superconductivity in this setting,” Vishwanath said. “It really calls for something entirely new.”

In fact, it’s so unusual that other researchers are waiting for more experiments to verify it. “It’s probably still an evolving story,” Mak said. “It just needs additional data to fully confirm whether it’s a chiral superconductor or not.”

Theorists, meanwhile, have published new theories of how chiral superconductivity might happen. Fu and collaborators proposed the following recipe in September: You start with electrons arranged to form a repeating crystal — like in an insulator, except in this case the electron grid is free to float independently of the background atomic nuclei. Then the electron grid relaxes, and its ripples pair electrons the way phonons do. Fu stressed that this is just one possibility, noting, “We’re in uncharted territory.”

A True Understanding

While physicists can’t say for sure what’s pairing electrons in these 2D materials, they feel more confident that there are multiple ways to do it. Electrons organize into all sorts of materials, from insulators to magnetic metals to electronic crystals, and slight disturbances seem poised to tip many of these materials into superconducting electron pairs.

Related:

1. Will Better Superconductors Transform the World?

2. Physicists Puzzle Over Emergence of Strange Electron Aggregates

3. Physics Duo Finds Magic in Two Dimensions

Being able to directly see what happens when they add more electrons to a material or slightly weaken its electric field lets physicists quickly try out an unprecedented number of recipes and see which ones lead to superconductivity.

“The real promise,” Dean said, is that each of these devices is “a tunable lab in which we can make basically any other material.”

The experimentalists are amassing a treasure trove of data for theorists to explain. Mak and Shan hope that this abundance will let theorists predict ways to create superconductivity that experiments can confirm. That would demonstrate a true understanding of the phenomenon, which would mark both an academic achievement and a key step toward designing materials for revolutionary new technologies.

But for now, experimentalists are still the ones leading the way. “Everyone’s rushing as fast as they can,” Yankowitz said. “I can’t believe that we’re six years in and you can’t take a break.”

2024 Dec 5

- How Is Cell Death Essential to Life?

THE JOY OF WHY | VIEW ON WEBSITE

How Is Cell Death Essential to Life?

By Steven Strogatz

December 5, 2024

Cells in our bodies are constantly dying — and these countless tiny deaths are essential to human health and multicellular life itself. In this episode, co-host Steven Strogatz speaks with cellular biologist Shai Shaham about what makes a cell “alive” and the latest developments in understanding how and why cells die.

Peter Greenwood for Quanta Magazine

Introduction

Death might seem like a pure loss, the disappearance of what makes a living thing distinct from everything else on our planet. But zoom in closer, to the cellular level, and it takes on a different, more nuanced meaning. There is a challenge in simply defining what makes an individual cell alive or dead. Scientists today are working to understand the various ways and reasons that cells disappear, and what these processes mean to biological systems. In this episode, cellular biologist Shai Shaham talks to Steven Strogatz about the different forms of cell death, their roles in evolution and disease, and why the right kinds and patterns of cell death are essential to our development and well-being.

Listen on Apple Podcasts, Spotify,  TuneIn or your favorite podcasting app, or you can stream it from Quanta.

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Transcript

[Theme plays]

STEVE STROGATZ: In the second that it took you to hit play on this episode, a million cells in your body died. Some were programmed to expire in natural, regulated processes, such as apoptosis. Some terminated their own lives after infection, to stop viral invaders from spreading. Others suffered physical damage and went through necrosis, their membranes splitting open and their contents spilling out.

We know there are nearly a dozen different ways for our cells to kick the bucket. And learning how to control these processes can make all the difference in the world to a sick patient.

[Theme continues]

I’m Steve Strogatz, and this is “The Joy of Why,” a podcast from Quanta Magazine, where I take turns at the mic with my cohost, Janna Levin, exploring some of the biggest unanswered questions in math and science today.

In this episode, we ask cellular biologist Shai Shaham, how can the death of a cell help other cells around it? And how do these insights help us understand life itself? Shai is a professor at The Rockefeller University, where he studies programmed cell death during animal development and the complex role that glial cells play in the nervous system.

[Theme ends]

Shai, welcome to “The Joy of Why.”

Shai Shaham

SHAI SHAHAM: Thank you for having me, Steve.

STROGATZ: Thank you for joining us. I’m very curious to learn more about cell death. So I thought maybe we could start by talking about the lives of cells. What are the sorts of things that cells do that tell us they’re alive?

SHAHAM: So that’s actually a fairly complicated question. It really depends on the specific assay that you use to ask whether the cell is alive or not. So for example, if a cell is moving from one place to another, you might say the cell is alive. But if the cell is sitting and not going anywhere, you have to ask, what does it mean to be alive? Is it metabolizing food? Is it producing signals to other cells?

But others would say that these sorts of things can also be the hallmarks of cells that are just chemically active, but not performing any biological function. The whole field of cell death is plagued by this question of defining what a dead cell is. And, really, the best definition that at least I’ve been most comfortable with is if the cell is just completely gone, then I know it’s dead. Otherwise, it’s very difficult to say.

STROGATZ: It’s interesting that it’s so subtle. I think many of us think of cells as dividing. And I’m wondering, is that a crucial aspect of being alive? Does a cell have to divide to be considered alive?

SHAHAM: You would say certainly that if a cell is dividing, it is alive. The question is though, if it’s not dividing, is it not alive? And I think that the answer to that is really dependent on context. So, for example, you can have bacterial spores that survive for years without dividing. And then when the time is right, they emerge from the spore configuration that they’re in and start dividing and replicating themselves. And so for all of that period of time, which could be even decades, was the cell dead or alive?

The whole field of cell death is plagued by this question of defining what a dead cell is.

There was an example near and dear to my heart, since we work on C. elegans, which is a nematode worm. And there was a recent description of a nematode that was extracted from permafrost in Siberia where it froze about 40,000 years ago and was revived back in the lab. And so you ask yourself, was that whole organism alive or dead for 40,000 years?

STROGATZ: Unbelievable. That’s so interesting. I mean, we have this concept in ordinary language of suspended animation. The spores that you talked about, they’re waiting to come back to life, would be the common-sense way of saying it. But what are they when they’re in suspended animation? So that brings up this question of irreversibility.

SHAHAM: Yeah, absolutely, I mean, I think you’re struggling with something that we in the field struggle with a lot. At the end of the day, it all boils down to the assay. So let’s say that you had that spore that was sitting around for a hundred years waiting to start dividing. If you observed the spore, let’s say, at year 30, and decided to spend a few weeks looking at it, it would look dead, for all intents and purposes. And it’s only if you waited the full 100 years and then saw it emerging that you would say, ah, actually it was alive.

But if we have another assay where we’re looking at metabolism, or we’re looking at the ability to accumulate mutations in the genome, or the ability to signal to other cells. If the cell is doing stuff in terms of your assay, then you would consider it alive. But it’s a very operational definition. I don’t think there’s much point in involving the mystical here.

STROGATZ: It’s clean, isn’t it, to say that it’s sort of operationally alive relative to certain assays. That seems fairly clear cut. We could measure, is it metabolizing or not? Is it dividing or not? In trying to circumscribe life and death, let me bring in a few other categories of things to think about, like parts of a cell. Can parts of a cell die, or does it have to be in the nature of death that the whole cell has to die?

SHAHAM: So, certainly not. If you recall what I said earlier, I’m most comfortable defining a dead cell as a cell that’s just not there at all. And certainly, we have situations where parts of a cell disappear. And this can be either programmed events, which is supposed to happen, or it can be due to injury or some mishap.

There are cases in development where axons grow out of a neuron. So an axon, it’s a long thin process that comes out of a neuron whose job basically is to connect to other neurons to make our brain work. These axons, during a normal part of development, might decide to start retracting. And this retraction, in fact, is given the name “dying back.” So operationally here, the axon has no function and physically it’s actually disappearing. And so you would argue that part of the cell is actually dying.

STROGATZ: So, you mentioned something about programmed cell death, which is the area I want to start getting into with you next. For instance I read about something called necrosis. What happens if a cell becomes necrotic, or what is that kind of death?

I would say that people in the field often equate programmed cell death with apoptosis, but actually that’s not entirely accurate…. we know of basically three bona fide examples of genetically programmed cell death pathways.

SHAHAM: So let me distinguish between two kinds of cell death. So there’s a cell death, which is a consequence of a genetic program, which is present in the DNA, in the genes of a cell, which is dedicated to executing the demise of the cell. So this is a process which has been evolutionarily selected and which has been passed on from one generation of a cell to the next generation. And the job of this pathway is specifically to allow a cell to commit suicide.

Then there’s another category of cell death, which I would put in the category of what happens to a cell when you step on it. And there are myriad ways, as you can imagine, of hurting a cell in a non-natural way. Necrosis is one of those ways. It’s a very ill-defined term, but when people usually talk about it, they refer to an unregulated type of cell death that’s not encoded in our genes and involves swelling of the cell, often formation of membrane whorls or substructures within the cell that are abnormal, and eventually leakage of the content of the cell into the environment.

STROGATZ: And I suppose that provokes a reaction from the immune system?

SHAHAM: Yes, so the difference generally between the genetically programmed death events and the foot-stepping-on-the-cell type of events, is that the former are designed in a very clean way to not perturb the surrounding environment. In fact, they do everything they possibly can to minimize any damage to surrounding cells when they die.

The other type of death, though, often elicits harsh reactions, either from neighboring cells, or, if the animal has an immune system, from immune cells that try to cope with the damage that the exploding cell has unleashed on its environment.

STROGATZ: I mentioned this term “apoptosis” earlier, this genetically programmed style of death that’s relatively clean. Am I getting that right? That’s what we’re talking about now?

SHAHAM: I would say that people in the field often equate programmed cell death with apoptosis, but actually that’s not entirely accurate. Apoptosis is one form of programmed cell death. We’ve discovered one in our own lab, a different one called “linker cell–type death” or LCD. And there’s at least one other type of cell death that I know of, which has been studied by a colleague of mine in Drosophila melanogaster, the fruit fly. So we know of basically three bona fide examples of genetically programmed cell death pathways.

STROGATZ: Do you want to give us a picture of them? What should we visualize if a cell is undergoing any of those three?

There are examples where individual animals die as a way to better the entire collective.

SHAHAM: So “apoptosis,” that term was actually first coined by [John F.R.] Kerr and [Andrew] Wyllie in a paper in the early 1970s. It’s related to a Greek word, which has to do with the falling of leaves from the tree, to make the connection to some sort of a death process. And so it’s characterized by the condensation of chromatin, or of the DNA, inside the nucleus. It becomes very compact and it cannot carry out its functions because it is so compact.

In addition, the cell cytoplasm, so the bulk of the cell, seems to shrink. And often the organelles, like the mitochondria that are present in the cytoplasm, will rupture. But this happens generally fairly late in the process. Overall the whole thing happens very rapidly. It’s only if you sit there and count the number of cells over time that are undergoing this process that you realize how prevalent it is.

So overall you have a very compact demolition process, which gets rid of the cell and then these cells that have died on their surface have special signals that are known in the field as “eat me” signals, and they signal to neighboring cells or to specialized phagocytic cells to come and literally eat them up and degrade them. And so most programmed cell death follows that path. And apoptosis in particular has the features that I mentioned.

The linker cell–type death is in some sense almost like a mirror image of apoptosis. There’s very little chromatin condensation. In fact, the hallmark of this cell death is that there’s very open chromatin, and then organelles, rather than waiting till the end of the death process to exhibit defects, right from the beginning tend to swell. But, importantly, this type of cell death still presents “eat me” signals on its surface, and these cells are still cleared by either neighboring cells or specialized phagocytes that degrade it.

STROGATZ: I’m curious to hear a little more about this second one. Because number one, I never heard of it before. And number two, my first scientific paper in my own career was about applying math to the structure of the chromatin fiber. So when you mention linker, are you referring to the linker DNA between nucleosomes?

SHAHAM: Actually I’m not. This cell death, we actually discovered it in the nematode C. elegans. And it’s the death of a single cell in the male of the animal that’s called the “linker cell.” And the reason it’s called the linker cell is because it connects the developing male gonad to the exit channel, which will allow sperm to be released from the male during mating. And this cell basically stands as a plug in between the gonadal tube and the exit channel. And so the animal eliminates it using this novel linker cell–death program, and that allows these two tubes to fuse together so that sperm can exit.

And what we’ve discovered is that what you can see by electron microscopy, which allows you to view cells at very high magnification and with specific types of contrast, this type of cell death actually is not relegated only to this one cell in nematodes, but it’s also extremely prevalent in developing mammals and in humans. In fact, much of the cell death that happens in our nervous system has this shape.

How does a bacteria decide that it needs to die?

And in addition to the features that I mentioned, one other prominent feature that this cell death has is that the nuclear envelope acquires these indentations, or “crenellations,” as we call them, where it just looks very wavy. And this is really a hallmark of a lot of cell death that happens in human disease also. And so we’re very curious about the possibility that linker cell death might play a role in human disease, where, in the diseased state, you’re inappropriately activating this type of cell death when you’re not supposed to.

STROGATZ: I do want to come back to this question about cell death and its implications for human disease. But if it’s okay, I’d like to keep enumerating various pathways of cell death because there are a few that have to do with defensive functions. I’m thinking of cases where viruses or other pathogens are causing infections or other sorts of problems, and cell death is happening in response to attack.

SHAHAM: So many of these actually have a lot in common with apoptosis and the name signifies just the context. So, for example, “pyroptosis” is a type of apoptotic cell death that happens during an inflammatory response. And so the “pyro” is supposed to allude to the inflammation or this fiery kind of state. And the idea there, basically, is that you might have a situation where a cell is infected with a virus or a bacterium, and it’s to the benefit of the host organism that the cell off itself, so that the rest of the organism doesn’t get exposed to the bacterium or to the virus.

There’s many pathways that are dedicated towards eliminating cells that are infected besides what you might consider apoptotic-type cell death. For example, when a particular form of T-cell called a cytotoxic T-cell recognizes a cell that has been infected with a virus, it will release proteins called perforins whose name is exactly what they sound like, they basically make pores. And so they release these perforin proteins that make holes in the membranes of the target cell. And that will trigger either an apoptotic response or just leakage in general out of the cell. And eventually the cell just disintegrates and gets eaten by circulating phagocytes.

So this type of response is similar to the type of thing that happens in complement-mediated cell death, another type of reaction that our body has in response to a cell that has been invaded by a foreign organism. And often it’s a very complicated cascade of proteins that are circulating in the blood that will eventually lead to a coating of an infected cell with a certain type of protein, which is an “eat me” signal for phagocytes. So the cell itself is not destroyed from within, as in some of these other examples that we’ve been talking about, but it’s just marked as a bad seed, so that the phagocytes can come and take care of it.

In embryogenesis, all vertebrates have a very prominent cellular webbing that connects the digits. And in vertebrates like us, for example, there’s massive cell death that happens in that interdigital webbing that eliminates those cells. And that’s why we have well-separated digits.

STROGATZ: So the impression I’m getting from all of this discussion is that when cells either carry out these programs or allow themselves to be marked as “eat me” cells, it’s for the greater good. That this is to help other cells around them or other tissues. It feels like this is something that is multicellular. If you were a single cell, you wouldn’t have the same incentive to do this sort of thing. It’s in the context of being in a multicellular organism that these processes happen. Is that wrong?

SHAHAM: You’re on the right track. I wouldn’t necessarily restrict it to a multicellular organism. You just need to be in a situation where you have a conglomeration of cells that need each other in order to survive. So it’s true that in a multicellular organism, you need to exercise this principle of “I might need to die for the greater good,” but it’s also true in bacteria.

So for example, bacteria tend to form what are known as biofilms, basically sheets of many bacteria lined up next to each other. Under starvation conditions, when the biofilm doesn’t have enough food to feed everybody, a subset of the bacteria there decide to just destroy themselves and serve as nutrients for the other bacteria that are surviving. Often there’s wars between the bacteria and they will invoke killing mechanisms in your gut. So I think the principle that you hit on that you need to be in a multicellular environment is important, but it doesn’t necessarily have to be within a single organism.

STROGATZ: All right. So multicellularity broadly construed, then, not necessarily in a multicellular organism, but [in] multicellular life in its various forms, these issues come up.

SHAHAM: In the context of animals, there are examples where the general principles that we’ve found could be very meaningful. So one place to look, for example, are ants. So in an ant colony, it’s essentially what’s called a “superorganism,” where each ant plays an important role within the colony. And often, it’s true that ants have to die in order to generate an interesting structure that’s important for the survival of the colony or to even just provide nourishment. So there’s these wonderful movies that you can find on YouTube and on National Geographic where you can see ants forming a bridge so that other ants can travel across this bridge. And often those ants that are on the bridge will die. And their exoskeleton is what serves as the part of the bridge on which other ants march. So there are examples where individual animals die as a way to better the entire collective.

STROGATZ: That’s interesting. One other thing that I was wondering about, because you did mention C. elegans, the wonderful little worm, only about a millimeter long, that has taught us so much about biology, from development, genetics, behavior, neurobiology, aging. It’s incredible what we’ve learned from this little critter. And some of our listeners may not be familiar with this creature. Can you just tell us a little about C. elegans and also how it has helped us learn about processes involved in cell death and their significance?

SHAHAM: Sure. If you want to study cell death it would be really useful to know that at a given moment in time, at a given location within the animal, a cell is going to die. Because if you have that predictability, you are able to manipulate the system ahead of time to ask all sorts of questions. That predictability is absent in most model systems.

However, in nematodes, and specifically in the nematode C. elegans, this is precisely what we can do. So C. elegans has the remarkable property that the pattern of cell divisions from the fertilized egg all the way to the adult is entirely identical, except for a very small number of exceptions, between individuals of the species. And superimposed on this cell division pattern, is also a pattern of cell death which is exactly the same. The way we can demonstrate that the pattern is the same, is that we can give cells names in C. elegans. So we can say this cell is called Moe and this one is called Curly — but actually we give them much more boring names, like ASE or NSM or CEP sheath. Whereas in us, or in other vertebrates, you really can’t name cells and have them be the same cell in every animal. We can tell you with precision that the cell called Curly will die four hours and 20 minutes after the fertilized egg began dividing. And we can tell you for sure that it’s going to take 25 minutes for that death process to occur.

This detail was worked out in the late 1970s and early 1980s by two extraordinary scientists, Bob Horvitz and John Sulston. And they determined the entire pattern of cell divisions from the fertilized oocyte all the way to adulthood. And as they were watching these cell divisions unfold, they realized that there were cells that would eventually disappear. And those were the dying cells. And so we know that in, for example, a developing C. elegans hermaphrodite worm, 1,090 somatic cells precisely are generated. And of those exactly 131 cells will die, leaving the animal with a complement of 959 somatic cells. And based on this precision, we can now do all sorts of genetic studies and cell biological studies, where we can look at the same exact cell over and over and over again to try to understand what drives the cell death process. And really, I think this is the biggest advantage of using C. elegans to study cell death.

STROGATZ: So in case anyone is wondering, they’re not hard to capture, right? They’re just like, if you pick up a handful of dirt, there’s a lot of these C. elegans in there?

SHAHAM: So nematodes and C. elegans in particular is found all over the world. And in fact, when I started my laboratory at Rockefeller, the first thing that I decided to go and do was to see if I could isolate the Rockefeller version of C. elegans. So I went out and I got a bunch of dirt and I put it on petri plates that have agar, that’s how we grow the worms, and just waited for them to emerge. And indeed we found them. And I was very excited to find the Rockefeller isolate, only later to find out that Rockefeller actually imports its dirt from upstate New York. So in fact, they were not local C. elegans. They were upstate New York C. elegans.

Cell death is associated with virtually every disease state in humans.

STROGATZ: Country worms coming down to the city. So the story you’ve just told is so remarkable and amazing. The machine-like development of this creature from the time it’s fertilized oocyte to an adult. And then you mentioned that for a mouse or for us, it’s not as predictable. I’m sure some people must be wondering, aren’t they very special in the whole zoo of life? Convince us that studying this strange worm is really relevant to us.

SHAHAM: First, I should start out by saying that they are very special. So there is something that they do that other organisms don’t. And I think it’s important not to gloss over that. But in terms of the relatedness to other animals, you need look no further than the DNA of the animal and the genome. So the sequence of DNA nucleotides, which code for genes in our genome, are essentially the same in C. elegans as they are in us.

For example, the process of apoptosis is executed by a protein called a caspase. It’s a protein whose job is to cleave other proteins, and the protein is encoded by a gene, and this gene is pretty much the same gene in worms as it is in people. if you want to follow Nietzsche’s line of thought, “Man is worm.”

STROGATZ: I’m not familiar with that quote. Is that the real quote?

SHAHAM: It is. It’s in German, but this is the translation of it.

STROGATZ: Okay. I never thought of him as a cell biologist, but maybe he was on to something. We’ll be right back after this message.

[Break]

STROGATZ: Welcome back to “The Joy of Why.”

So, I wanted to explore a variety of laboratory systems for looking at cell death from, say, bacteria in a plate, to C. elegans, up to more complex organisms. So, what is the right scale for us to be studying these questions of cell death?

SHAHAM: I think it is important to look at all different scales. I guess the smallest scale is the cell itself and certainly there are examples of bacteria where cells die and those are very important to understand for health reasons, but also just as basic questions of curiosity. How does a bacteria decide that it needs to die? Working in bacteria is a wonderful system.

Working in a cell culture might also tell us a lot. So if we take cells from, let’s say, a human or from a mouse, and put them in culture and let them divide, and die within the culture, we might not learn about the context in which they’re executing the cell death, but we might be able to learn a lot about the molecules and about the signals that are involved in telling cells whether to die or not to die. And once we’ve established some principle in this simplified cell culture, we can then try to move our understanding into an organism where we could, for example, explore the role of a gene that we discovered in cell culture and see what effects it might have on the organism.

In an organismal level, there’re aspects of cell death that you can’t really explore in other settings, which has to do with collective phenomena of cell death. So not just a single cell dying, but aggregates of cells. And that’s probably most beautifully demonstrated in the field of developmental biology, and particularly the process of morphogenesis. So that is the process by which animals or any living organism that’s multicellular get their form, their shape. Rodin is famous for saying that he was trying to reveal the statue that was within the slab of stone that he’s carving. [Editor’s note: That may have been Michelangelo.] And it’s the same principle in terms of cell death. We have this mass of cells and in many cases, some of them die to be able to form a particular shape. And perhaps the most famous example is the development of the digits in vertebrates. So, in embryogenesis, all vertebrates have a very prominent cellular webbing that connects the digits. And in vertebrates like us, for example, there’s massive cell death that happens in that interdigital webbing that eliminates those cells. And that’s why we have well-separated digits.

Cancers are cells where somehow the programs that allow the body to eliminate these harmful cells have stopped doing this, and the cells are inappropriately surviving.

STROGATZ: So you’re talking about formation of fingers or toes here.

SHAHAM: Yes, exactly. But in the duck, for example, a lot of that cell death doesn’t take place, and that’s why they have webbed feet.

STROGATZ: That’s amazing. Not that they were growing the web, it’s that the other creatures were sculpting away their web. Aren’t there genetic variants? Or I think some of my relatives have said, look at my toes, I have webs between these toes.

SHAHAM: So those are probably vestigial structures that did not completely get eliminated during embryogenesis.

STROGATZ: Let’s move on to more of a human-centered point of view here about cell death. maybe related to healthcare issues, medical care. For instance, would knowing more about cell death help us reverse organ failure or anything else in which lots of cells in a tissue might be dying?

SHAHAM: So cell death is associated with virtually every disease state in humans. And broadly, you can categorize them into two kinds of problems. One group are diseases where there’s too much cell death going on, diseases like organ infarction. Like, for example, when you have a heart attack, cells in your heart will die, or in neurodegenerative conditions where cells in the brain will die and then you develop Alzheimer’s or Parkinson’s disease. And then there’s the opposite side of the spectrum, diseases where cells that should be dying are not dying. And that’s essentially what all cancers are. So cancers are cells where somehow the programs that allow the body to eliminate these harmful cells have stopped doing this, and the cells are inappropriately surviving.

And so really this, in principle, could touch every major disease. Now, this is not to say that cell death is the root cause of every disease. But certainly there are cases where if we could block the cell death from happening, it might at least give us a fighting chance to treat the cells that otherwise would be completely gone. In terms of utility, there’s been a number of drug studies looking at compounds that can either inhibit or promote cell death in various disease contexts. For example, in the clinic now, there are drugs whose job is to trigger cell death in specific tumor settings. And these drugs arose from our understanding of how cell death happens and the specific molecules involved.

STROGATZ: It makes me wonder with your earlier mention of markers on cell surfaces that say “eat me,” whether that can be used on cancer cells, maybe in a kind of cancer immunotherapy or something like that.

SHAHAM: At the moment, there isn’t anything that’s specifically in trials to look at these “eat me” signals. But what you can do is you can create your own “eat me” signals. So if you can discover something on the surface of a cancer cell that marks it uniquely from all other cells, because you only want to eliminate the cancer cell, you don’t want to get rid of all the other cells in your body. So if you can identify this you can generate a specific antibody which would trigger, for example, an apoptotic response in the cell to which it binds.

As long as there’s a question to be asked and a way that I can imagine to solve it, that will bring me into work every day.

And in fact there is really an incredible revolution afoot in the treatment of cancers using what’s known as immunotherapy. And this is precisely what this is based on. So the idea here is to allow the body to identify specific unique markers for tumor cells, generate an immune response towards those, and then immune cells will go to these cells and destroy them using a variety of different ways that we mentioned already in our conversation.

STROGATZ: We’ve been focusing a lot on what is known or what we’ve discovered in the past few decades about cell death. I wonder if you have a few questions that you’d love to see answered in your lifetime or where you think the great, exciting open areas might still lie in this field?

SHAHAM: Yeah, I think there’s an enormous amount for us to learn. So as you alluded [to] in the beginning of our conversation, a very commonly studied cell death process is called apoptosis. And we for many years thought that this process was sufficient to explain many of the types of cell death–related events that happen during the development of animals.

But work over the last couple of decades has demonstrated that you can completely eliminate this cell death program from the genome of an animal. And yet, the animal can still survive just fine. And so what that means is that there must be other ways to kill cells that are out there. Now, one way might be this linker cell–type death, which I mentioned, but it may not be the only way. There may be other ways. And so that whole black box of what other programs are out there is an incredibly fascinating direction that will definitely deserve our attention, particularly if we wish to make cell death an important angle of attack in disease.

There is another big question that we would like to understand. So I told you in C. elegans, we know precisely which cells are going to die at any given moment. We don’t know this in vertebrates. But we would love to be able to understand how, if you have two neighboring cells in a human, why one will undergo cell death and another will not. And we don’t at all understand that. So I think this becomes a much bigger question. It’s a question that has to do with how cells respond to their environment. And cell death in this case would just be a readout. But certainly still an incredibly fascinating question and wholly unanswered.

STROGATZ: Wonderful. Those are some great directions. Finally, you as an individual scientist in this great enterprise, is there something about your own research that particularly gives you joy?

SHAHAM: I love discovering stuff. I have always been interested in finding new things that no one has found out before. And in some sense, the specific details of what it is that I’m finding are not even that important. Because I think once you get into the details, everything seems interesting and exciting. As long as there’s a question to be asked and a way that I can imagine to solve it, that will bring me into work every day. And it still does.

STROGATZ: I know that feeling, and I sometimes will tell my own graduate students that — that it almost doesn’t matter what the question is, the process of discovery is so fulfilling, and everything becomes interesting once you start looking at it deeply enough.

SHAHAM: Absolutely. Rare, but fulfilling.

Science has proven over and over how discoveries that seemed unimportant and fringe at any moment turn out to be all the rage just a couple of decades later.

STROGATZ: But what about something that Francis Crick said one time, that it’s just as easy to work on an important problem as a trivial or uninteresting or unimportant problem. Do you ever think about that aspect, that you want to work on things that matter in some external sense?

SHAHAM: I’ve often thought of that quote in trying to decide what my next goal should be. But I will tell you that, in my opinion, I lack the hubris to decide what’s important and what’s not. And I think science has proven over and over how discoveries that seemed unimportant and fringe at any moment turn out to be all the rage just a couple of decades later. And this could be true in biology. This could be true in physics. This could be true in mathematics. And so I think that by narrowing myself to this particular scheme that Crick suggested, I might be excluding areas of discovery that could be even more exciting than what I can imagine. And I just think my imagination, good as it is, is just not good enough to be able to foretell the future like that.

[Theme plays]

STROGATZ: I’m getting a great deal of joy personally from that answer. The virtue of modesty, it may actually be a very practical thing for exactly the reason that you described, that we don’t really know. I could talk to you all day, Shai. This has been wonderful.

SHAHAM: Okay, Steve. I really enjoyed it.

STROGATZ: We’ve been speaking with cell biologist and neuroscientist Shai Shaham. Thanks so much for joining us here on “The Joy of Why.”

SHAIHAM: Thank you, Steve.

[Theme continues]

STROGATZ: Thanks for listening. If you’re enjoying “The Joy of Why” and you’re not already subscribed, hit the subscribe or follow button where you’re listening. You can also leave a review for the show — it helps people find this podcast.

“The Joy of Why” is a podcast from Quanta Magazine, an editorially independent publication supported by the Simons Foundation. Funding decisions by the Simons Foundation have no influence on the selection of topics, guests or other editorial decisions in this podcast or in Quanta Magazine.

Related:

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2. Cellular Self-Destruction May Be Ancient. But Why?

3. Most Life on Earth Is Dormant, After Pulling an ‘Emergency Brake’

4. All Life on Earth Today Descended From a Single Cell. Meet LUCA.

5. ‘Lava-Lamp’ Proteins May Help Cells Cheat Death

6. Biologists Rethink the Logic Behind Cells’ Molecular Signals

“The Joy of Why” is produced by PRX Productions; the production team is Caitlin Faulds, Livia Brock, Genevieve Sponsler and Merritt Jacob. The executive producer of PRX Productions is Jocelyn Gonzales. Morgan Church and Edwin Ochoa provided additional assistance.

From Quanta Magazine, John Rennie and Thomas Lin provided editorial guidance, with support from Matt Carlstrom, Samuel Velasco, Arleen Santana and Meghan Willcoxon. Samir Patel is Quanta’s editor in chief.

Our theme music is from APM Music. Julian Lin came up with the podcast name. The episode art is by Peter Greenwood and our logo is by Jaki King and Kristina Armitage. Special thanks to the Columbia Journalism School and Bert Odom-Reed at the Cornell Broadcast Studios.

I’m your host, Steve Strogatz. If you have any questions or comments for us, please email us at [email protected]. Thanks for listening.

2024 Dec 4

- The AI Pioneer With Provocative Plans for Humanity

Q&A | VIEW ON WEBSITE

The AI Pioneer With Provocative Plans for Humanity

By Susan D'Agostino

December 4, 2024

While some fret about technology’s social impacts, Raj Reddy still believes in the power of artificial intelligence to improve lives.

Raj Reddy is one of the founders of what we now call artificial intelligence. He still feels optimistic about its power to help people.

Elliott Cramer for Quanta Magazine

Introduction

Before he became a decorated pioneer of artificial intelligence, Raj Reddy grew up far from a computer lab. As a child in the 1940s, he lived in rural Katur, Andhra Pradesh, India. His one-room schoolhouse had no paper or pencils, so he learned to write letters in a plot of sand. On hot nights in a home with no electricity or running water, he and six siblings cooled off by dragging their mattresses outside.

“The sky was beautifully clear, and I could see all the stars,” said Reddy, who smiles easily. “People have asked, ‘Oh my God, were you that poor?’ But I never felt deprived at all.” On the advice of an astrologer, his father sent him to college, with tuition paid by his uncle. Reddy bought his first pair of shoes for the occasion.

Reddy’s first encounter with a computer came later, at the University of New South Wales in Australia, when he was pursuing his master’s degree in civil engineering. Immediately he put it to work solving integration problems, amazing a classmate in the process. “If you’re willing to let your mind wander,” he told the classmate, “you can come up with a solution.”

Reddy soon got a job at IBM, where he read a paper by John McCarthy, the computer scientist who coined the term “artificial intelligence.” It changed the trajectory of his life. “That’s what I want to work on,” Reddy thought to himself. In 1963, he started as McCarthy’s doctoral student in the newly formed Stanford Artificial Intelligence Lab. Reddy’s early research on computer speech recognition, human-computer interactions, and robotics — depicted in an early, homegrown documentary — launched a lifetime of revolutionary work in AI.

Reddy grew up in poverty in colonial India. He rose to become a professor at Carnegie Mellon University in 1969, a job he’s held ever since.

Elliott Cramer for Quanta Magazine

After earning the first doctorate in computer science at Stanford, Reddy joined the faculty of Carnegie Mellon University and later served as founding director of the institution’s Robotics Institute, informally known as the “Raj Mahal.” He eventually received the Turing Award for pioneering the design and construction of artificial intelligence systems and demonstrating the practical importance and potential commercial impact of AI technology.

In addition to more than 50 years — and counting — of research at Carnegie Mellon, Reddy has long been a vocal advocate of technology in service of society. In his home state in India, he helped found the Rajiv Gandhi University of Knowledge Technologies, which serves rural youth. He also often appears on high-profile stages around the world, such as the Association for Computing Machinery, where he recently spoke about user interfaces for those at the bottom of the economic pyramid. And in Hong Kong this year, he spoke about eliminating the literacy divide with AI.

Quanta caught up with Reddy in Germany at the Heidelberg Laureate Forum to discuss AI-enhanced productivity, forced altruism and government-mandated health monitoring. The interview has been condensed and edited for clarity.

Reddy argues that AI can be used benevolently to create a world with greater wealth and more resources, and that it’s our collective responsibility to make sure they’re distributed fairly.

Elliott Cramer for Quanta Magazine

You’ve been in computer science almost since the beginning. What was it like back then, nearly 60 years ago — did anyone understand what you did?

People were asking, “What is computer science?” There was a famous paper in which the authors made up a definition. They said, “Computer science is what we use computers to do.” It was like biologists saying, “We do biology.” [Laughs.]

I proposed a definition and submitted my paper, which was rejected promptly. [Laughs.] But I still think my definition is right. I said that engineering is a field that enhances the physical capabilities of the human being; computer science and AI are fields that enhance our mental capabilities. Anything you do with your mind, you can do faster, better, cheaper using computers. But I was a lowly grad student!

You’ve long highlighted these benefits for humanity, but how could that work practically?

With AI, everyone [could theoretically] do a day’s work in an hour. What will people do with that extra time? One possibility is that everyone will do 10 times more work in a day. If everybody does 10 times more work, then we’ll have a world in which we’ve created 10 times more wealth.

We could target the extra productivity to areas where there’s a major societal need. A lot of countries, cities and villages need food, water and electricity — even today. Can we have people displaced by AI work on manufacturing and installing solar cells to ensure there’s power in every village and every home? We need to set priorities and then say to the tech companies, “We need people in these areas. If you don’t need them, retrain them to work in these areas.”

To avoid future lockdowns, Reddy suggests governments monitor everyone’s health via mandatory smartwatches. “With appropriate actions, we could eliminate pandemic lockdowns,” he said. “Nobody says requiring a driver’s license is authoritarian.”

Elliott Cramer for Quanta Magazine

Tech companies are not usually known for their altruism. How would you make sure humanity is the focus, and not just profits?

[Governments] need to say that, for a period of 10 years, [workers disrupted or displaced by AI] must earn the same amount that they were earning before. Then, gradually, it can go down to 50%. It’s like pandemic-era employment assurance, except there’s a floor.

The companies might say, “Hey, this is a social policy, but I’m a capitalistic company. I can’t do that.” Then tax them more and use the money to repurpose workers in essential tasks. For example, they could teach sustainable agriculture to young people in Mali. Put the onus of repurposing workers to create more wealth on companies. That’s one answer.

There’s currently a lot of wealth in the world, unevenly distributed. How do you keep AI-enhanced productivity from only benefiting the wealthy?

The unequal distribution will always be there. But when you increase productivity and wealth by a factor of 10, there will be more money and opportunities for more people.

When I was growing up in my village, most people did not have shirts. They wore shorts and walked around semi-naked. Why? Because they didn’t have enough money to buy a shirt. Now if I go there, everyone is dressed very nicely. Where did that wealth come from? More money and more opportunity.

Reddy in his office at Carnegie Mellon.

Elliott Cramer for Quanta Magazine

Another criticism of AI today is how much energy it consumes. Isn’t that a problem?

This is a temporary phenomenon. Governments could easily say, “If you’re consuming more than a certain percentage of the national electric power generation, tough luck, you’re not gonna get any more power.” Then the companies would figure out how to optimize. Right now, the same databases are used over and over by everybody. There are many, many ways of looking at how to reduce computation. Deep learning in its full-blown glory works well, but you can’t consume all the power for optimal training. Good enough is good enough.

One specific use of AI you’ve championed is encouraging governments to eliminate future pandemic lockdowns by monitoring the health metrics of “everyone on the planet” via their smartwatches. How would that work?

In the long run, a visionary leader will say, “This is part of the digital infrastructure, fellas. You have to have a watch, and you have to give us access to your watch’s data. Here’s a group of eminent scientists who guarantee your data will be anonymized and not misused.” Anonymization technology exists now to largely protect privacy. Also, data is shared only by opting in.

Aren’t you worried about authoritarian governments taking on that role?

Nobody says requiring a driver’s license is authoritarian. Nobody says requiring a passport to enter a country is restricting global, free movement. Those are the laws. Every country has that. Even in the U.S., there are a set of states saying, “You cannot have an abortion.” It doesn’t matter why. There’s no free choice. That’s an authoritarian rule to me, but these are laws made by a democratic system.

With appropriate actions, we could eliminate pandemic lockdowns, which cause serious disruption to society. We need regulations saying that, if you want to move about or get on a bus or plane during a pandemic, you must have a clean passport on your watch.

“Engineering is a field that enhances the physical capabilities of the human being; computer science and AI are fields that enhance our mental capabilities,” Reddy said. “Anything you do with your mind, you can do faster, better, cheaper using computers.”

Elliott Cramer for Quanta Magazine

Do you expect to see such mandatory health-monitoring smartwatches in your lifetime?

It could happen if enough influential heads of state say, “There’s gonna be a pandemic in 10 to 20 years. We don’t want our people to die. We don’t want to lock you down. We want you to keep working so that the economy doesn’t take a hit. Therefore, this is going to be required.”

I’m planning to meet with political leaders in Qatar and the United Arab Emirates, where I’m convinced they might require everybody to wear a watch in the next pandemic. The cost of the watch could be $100 or less, but an individual would only pay $10 because the rest would be subsidized. Digital infrastructure, including a free smartwatch, should be publicly funded, just like roads, water, hospitals and libraries.

Isn’t this just a bit fantastical? Tech companies and governments have famously misused technology, especially among marginalized populations.

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Technology has always caused problems. When cars came in, nobody had a driver’s license. People drove around and killed. Finally, the government woke up and said, “No, you can’t drive a car without a driver’s license.”

Also, hundreds of years ago, you didn’t need a passport to go from country to country. All of these things evolve. You need permissions of various kinds.

The same thing should happen — will happen — with public health. When it will happen, I don’t know. Pandemics may only happen every 10 years, so people forget.

You’re known for the “full Raj,” in which you wrap an arm around someone when asking for help with ambitious AI goals. Will you deploy that for mandatory health monitoring?

The full Raj — I didn’t even know I did it! But yes, if I need somebody to do something, I would corral them and say, “Hey, let’s do this!”

2024 Dec 2

- Fish Have a Brain Microbiome. Could Humans Have One Too?

MICROBIOME | VIEW ON WEBSITE

Fish Have a Brain Microbiome. Could Humans Have One Too?

By Yasemin Saplakoglu

December 2, 2024

The discovery that other vertebrates have healthy, microbial brains is fueling the still controversial possibility that we might have them as well.

Scientists have discovered the strongest evidence yet that healthy vertebrates can have brain microbiomes.

Samuel Velasco/ Quanta Magazine

Introduction

Bacteria are in, around and all over us. They thrive in almost every corner of the planet, from deep-sea hydrothermal vents to high up in the clouds, to the crevices of your ears, mouth, nose and gut. But scientists have long assumed that bacteria can’t survive in the human brain. The powerful blood-brain barrier, the thinking goes, keeps the organ mostly free from outside invaders. But are we sure that a healthy human brain doesn’t have a microbiome of its own?

Over the last decade, initial studies have presented conflicting evidence. The idea has remained controversial, given the difficulty of obtaining healthy, uncontaminated human brain tissue that could be used to study possible microbial inhabitants.

Recently, a study published in Science Advances provided the strongest evidence yet that a brain microbiome can and does exist in healthy vertebrates — fish, specifically. Researchers at the University of New Mexico discovered communities of bacteria thriving in salmon and trout brains. Many of the microbial species have special adaptations that allow them to survive in brain tissue, as well as techniques to cross the protective blood-brain barrier.

Matthew Olm, a physiologist who studies the human microbiome at the University of Colorado, Boulder and was not involved with the study, is “inherently skeptical” of the idea that populations of microbes could live in the brain, he said. But he found the new research convincing. “This is concrete evidence that brain microbiomes do exist in vertebrates,” he said. “And so the idea that humans have a brain microbiome is not outlandish.”

While fish physiology is, in many ways, similar to humans’, there are some key differences. Still, “it certainly puts another weight on the scale to think about whether this is relevant to mammals and us,” said Christopher Link, who studies the molecular basis of neurodegenerative disease at the University of Colorado, Boulder and was also not involved in the work.

Irene Salinas, who studies fish immune systems at the University of New Mexico, probed the fish brain for microbes. Now she’s looking for them in mice brains, too.

Courtesy of Irene Salinas

The human gut microbiome plays a critical role in the body, communicating with the brain and maintaining the immune system through the gut-brain axis. So it isn’t totally far-fetched to suggest that microbes could play an even larger role in our neurobiology.

Fishing for Microbes

For years, Irene Salinas has been fascinated by a simple physiological fact: The distance between the nose and the brain is quite small. The evolutionary immunologist, who works at the University of New Mexico, studies mucosal immune systems in fish to better understand how human versions of these systems, such as our intestinal lining and nasal cavity, work. The nose, she knows, is loaded with bacteria, and they’re “really, really close” to the brain — mere millimeters from the olfactory bulb, which processes smell. Salinas has always had a hunch that bacteria might be leaking from the nose into the olfactory bulb. After years of curiosity, she decided to confront her suspicion in her favorite model organisms: fish.

Salinas and her team* started by extracting DNA from the olfactory bulbs of trout and salmon, some caught in the wild and some raised in her lab. They planned to look up the DNA sequences in a database to identify any microbial species.

These kinds of samples, however, are easily contaminated — by bacteria in the lab or from other parts of a fish’s body — which is why scientists have struggled to study this subject effectively. If they did find bacterial DNA in the olfactory bulb, they would have to convince themselves and other researchers that it truly originated in the brain.

Looking under the microscope, she captured an image of a bacterium frozen in time within the blood-brain barrier.

To cover their bases, Salinas’ team studied the fishes’ whole-body microbiomes, too. They sampled the rest of the fishes’ brains, guts and blood; they even drained blood from the many capillaries of the brain to make sure that any bacteria they discovered resided in the brain tissue itself.

“We had to go back and redo [the experiments] many, many times just to be sure,” Salinas said. The project took five years — but even in the early days it was clear that the fish brains weren’t barren.

As Salinas expected, the olfactory bulb hosted some bacteria. But she was shocked to see that the rest of the brain had even more. “I thought the other parts of the brain wouldn’t have bacteria,” she said. “But it turned out that my hypothesis was wrong.” The fish brains hosted so much that it took only a few minutes to locate bacterial cells under a microscope. As an additional step, her team confirmed that the microbes were actively living in the brain; they weren’t dormant or dead.

Olm was impressed by their thorough approach. Salinas and her team circled “the same question, from all these different ways, using all these different methods — all of which produced convincing data that there actually are living microbes in the salmon brain,” he said.

But if there are, how did they get there?

Invading the Fortress

Researchers have long been skeptical that the brain could have a microbiome because all vertebrates, including fish, have a blood-brain barrier. These blood vessels and surrounding brain cells are fortified to serve as gatekeepers that allow only some molecules in and out of the brain and keep invaders, especially larger ones like bacteria, out. So Salinas naturally wondered how the brains in her study had been colonized.

How the Brain Protects Itself From Blood-Borne Threats

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How the Brain Protects Itself From Blood-Borne Threats

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By comparing microbial DNA from the brain to that collected from other organs, her lab found a subset of species that didn’t appear elsewhere in the body. Salinas hypothesized that these species may have colonized the fish brains early in their development, before their blood-brain barriers had fully formed. “Early on, anything can go in; it’s a free-for-all,” she said.

But many of the microbial species were also found throughout the body. She suspects that most bacteria in the fishes’ brain microbiomes originated in their blood and guts, and continuously leak into the brain.

“After that first wave of colonization,” she said, “you need to have specific features to go in and out.”

Salinas was able to identify features that let bacteria make the crossing. Some could produce molecules, known as polyamines, that can open and close junctions, which are like little doors in the barrier that allow molecules to pass through. Others could produce molecules that help them evade the body’s immune response or compete with other bacteria.

Salinas even caught a bacterium in the act. Looking under the microscope, she captured an image of a bacterium frozen in time within the blood-brain barrier. “We literally caught it right in the middle of crossing,” she said.

It is possible that the microbes don’t live freely in the brain tissue but are engulfed by immune cells. That would be the “most boring interpretation of this paper,” Olm said, and would suggest that the fish have adapted to bacterial inhabitants by containing them.

However, if the bacteria are free-living, they could be involved in the body’s processes beyond the brain. It’s possible that the microbes actively regulate aspects of the creatures’ physiology, Salinas suggested, the way human gut microbiomes help regulate the digestive and immune systems.

Fish, of course, are not humans, but they allow a fair comparison, Salinas said. And her work suggests that if fish have microbes living in their brains, it’s possible we have them, too.

Biologists recently probed the brains of healthy salmonids, including rainbow trout (left) and Alaskan Chinook salmon (right), and discovered they were home to living microbes

Left: California Department of Fish and Wildlife Service. Right: U.S. Fish and Wildlife Service

Impenetrable or Not?

Bacteria have been found living in just about every human organ system, but to many scientists the brain is a step too far. The blood-brain barrier has traditionally been seen as “impenetrable,” said Janosch Heller, who studies the barrier at Dublin City University and was not involved in the new research. Plus, the brain has immune cells working overtime to zap any potentially harmful invaders. When microbes have been found in the human brain, they are are associated with active infections or typically linked to a breakdown in the barrier due to diseases such as Alzheimer’s.

This assumption was challenged in 2013, when scientists studying the neurological impacts of HIV/AIDS found genetic hints of bacteria in the brains of both sick and healthy people. The findings were the first to suggest that maybe humans could have a brain microbiome in the absence of disease.

It’s possible that the microbes actively regulate aspects of the creatures’ physiology.

“No one believed it 10 years ago,” Heller said. Follow-up studies — there haven’t been many — have been inconclusive. “It is very easy to trick yourself into thinking microbes are present because microbial DNA is essentially everywhere,” Olm said. “So it would take a lot of evidence to convince me that it does exist.”

The fish experiment did convince him, and other researchers, that a human brain microbiome is not impossible. What is nearly impossible, however, is confirming that without harming healthy people. To build a case, Link suggested repeating the fish experiment in rodents. “This protocol should be able to be adapted really easily to mouse brains,” Salinas said — and indeed her team has started looking into it. They have found early hints that microbes exist in the olfactory bulbs of healthy mice and, to a lesser extent, throughout the brain.

“There’s no reason, if fish have them, that you wouldn’t have them, or that mice wouldn’t have them,” Link said. If microbes have adapted to cross the fish blood-brain barrier and survive in the fish brain, they could do the same in our bodies. It’s unlikely they would be present at the same levels as they are in fish, he added, “but that doesn’t mean there’s none.”

Related:

1. Global Microbiome Study Gives New View of Shared Health Risks

2. In the Gut’s ‘Second Brain,’ Key Agents of Health Emerge

3. Should Evolution Treat Our Microbes as Part of Us?

4. Some Animals Have No Microbiome. Here’s What That Tells Us.

Even in small numbers, Link said, resident microbes could influence our brain metabolism and immune systems. If they are truly present, this would suggest an extra layer of neurological regulation that we didn’t know existed. We already know that microbes influence our neurobiology: Right now, microbes in your gut are modulating your brain activity through the gut-brain axis by producing metabolites that are sensed by enteric neurons winding through your digestive system.

It’s a fascinating, though unproved, proposition that bacteria in the brain are directly impacting our physiology. However, thanks to research like Salinas’, more scientists are open to the idea that healthy human brains might also be home to microbes.

“Why not?” Heller said. “I’m not shocked anymore that they are there.” The more interesting question, he said, is: “Are they all there for a reason, or are they there by mistake?”

* Update: December 5, 2024

Important contributions to the research were made by Amir Mani, the lead author of the paper.

2024 Nov 26

- Teen Mathematicians Tie Knots Through a Mind-Blowing Fractal

FRACTALS | VIEW ON WEBSITE

Teen Mathematicians Tie Knots Through a Mind-Blowing Fractal

By Gregory Barber

November 26, 2024

Three high schoolers and their mentor revisited a century-old theorem to prove that all knots can be found in a fractal called the Menger sponge.

The Menger sponge can be constructed by removing ever-smaller cubes from a starting cube.

Dave Whyte for Quanta Magazine

Introduction

In the fall of 2021, Malors Espinosa set out to devise a special type of math problem. As with any good research question, it would have to be thought-provoking, its solution nontrivial — something others would want to study. But an additional constraint stumped him. Malors, then a graduate student in mathematics at the University of Toronto, wanted high school students to be able to prove it.

For years, Malors had been running summer workshops for local high schoolers, teaching them about basic ideas in mathematical research and showing them how to write proofs. But a few of his students seemed ready to do more — to find out what it means to do math when there is no answer key. They just needed the right question to guide them.

Malors finally found one while reading a textbook about chaos. In its pages, he came across a familiar object: a fractal, or self-similar shape, called the Menger sponge, which has a simple but elegant construction. First divide a cube into what looks like a Rubik’s cube. Remove the cube in the very center, along with the center cube of each of the six faces. Then repeat this process for each of the 20 remaining cubes. And repeat. And repeat. You’ll quickly see why the resulting fractal is called a sponge: With each iteration, its pores multiply exponentially.

Mark Belan/Quanta Magazine

Ever since Karl Menger introduced his fractal sponge nearly a century ago, it has captured the imaginations of professional and amateur mathematicians alike. One reason: It looks cool. In 2014, hundreds of math enthusiasts participated in a global effort, called MegaMenger, to build finite, 200-pound versions of the sponge out of business cards. Because of its porous, foam-like structure, the sponge has also been used to model shock absorbers and exotic forms of space-time.

But most important, the fractal possesses various counterintuitive mathematical properties. Continue to pluck out ever smaller pieces, and what started off as a cube becomes something else entirely. After infinitely many iterations, the shape’s volume dwindles to zero, while its surface area grows infinitely large. Such is the weirdness of fractals: hovering somewhere between dimensions, occupying space without truly filling it.

Three high school students — Niko Voth (top right), Joshua Broden (bottom right) and Noah Nazareth (far left) — recently proved a new theorem about knots and fractals with the help of their mentor Malors, a mathematician at the University of Toronto.

Clockwise from left: Somja Injac, Christian Voth and Timur Khayrullin

When he first defined his sponge in 1926, Menger also proved that any conceivable curve — simple lines and circles, structures that look like trees or snowflakes, fractal dusts — can be deformed and then embedded somewhere on the sponge. They can be made to wind their way along the sponge’s convoluted contours without ever leaving its surface, hitting a hole, or intersecting themselves. The sponge, Menger wrote, was therefore a “universal curve.”

But this, Malors later realized, raised a new question. Menger had proved that you could find a circle in his sponge. But what about objects that were equivalent, in a certain sense, to the circle? Consider a mathematical knot: a string that’s been twisted and tied up, its ends then closed to form a loop. From the outside, it might look like a tangled mess. But an ant walking along it would eventually find itself back where it started, just as it would on a circle. In this way, every knot is equivalent, or “homeomorphic,” to a circle.

Every knot is “homeomorphic” to the circle, meaning that it’s possible to map the points from one to the other while satisfying a simple set of conditions.

Menger’s statement didn’t distinguish between homeomorphic curves. His proof only guaranteed, for instance, that the circle could be found in his sponge — not that all homeomorphic knots could be, their loops and tangles still intact. Malors wanted to prove that you could find every knot within the sponge.

It seemed like the right mashup to excite young mathematicians. They’d recently had fun learning about knots in his seminar. And who doesn’t love a fractal? The question was whether the problem would be approachable. “I really hoped there was an answer,” Malors said.

There was. After just a few months of weekly Zoom meetings with Malors, three of his high school students — Joshua Broden, Noah Nazareth and Niko Voth — were able to show that all knots can indeed be found inside the Menger sponge. Moreover, they found that the same can likely be said of another related fractal, too.

“It’s a clever way of putting things together,” said Radmila Sazdanovic, a topologist at North Carolina State University who was not involved in the work. In revisiting Menger’s century-old theorem, she added, Malors — who usually does research in the disparate field of number theory — had apparently asked a question that no one thought to ask before. “This is a very, very original idea,” she said.

A Different Way to See Knots

Broden, Nazareth and Voth had taken several of Malors’ summer workshops over the years. When he first taught them about knots in an earlier workshop, “it blew 14-year-old me’s mind,” said Voth.

But the Menger problem would be their first time moving beyond school workbooks with answer keys. “It was a little bit nerve-racking, because it was the first time I was doing something where truly nobody has the answer, not even Malors,” said Nazareth. Maybe there was no answer at all.

Their goal was essentially to thread a microscopic sewing needle through a cloud of dust — the material that remained of the sponge after many removals. They would have to stick the pin in the right places, tie the knotted tangles with immaculate precision, and never leave the sponge. If their thread ended up floating in the empty holes of the sponge for any knot, it was game over.

Not an easy task. But there was a way to simplify it. Knots can be depicted on a flat piece of paper as special diagrams called arc presentations. To create one, you start with information about how the strands of your knot pass in front of or behind each other. Then you apply a set of rules to translate this information into a series of points on a grid. Every row and column of the grid will contain exactly two points.

Connect these points with horizontal and vertical lines. Any time two segments cross paths, draw the vertical one in front of the horizontal one.

Every knot can be represented in this gridlike way. Even though an arc presentation can sometimes look more complicated than other ways of drawing the knot, it makes it easier for mathematicians to study some of the knot’s most important properties.

When the students considered the diagrams of crisscrossing lines, they were reminded of the faces of the Menger sponge. It would be straightforward enough to place the horizontal lines of an arc presentation on one face of the sponge and the vertical lines on its opposite face. The difficulty would be in figuring out how to connect the knot — how to stretch it back into three dimensions. At every one of the arc presentation’s corners, the two faces would need to be connected through the interior of the sponge without accidentally hitting a hole.

To make sure that this was always possible, the mathematicians turned to what’s known as the Cantor set, a one-dimensional analog of the Menger sponge. To construct the set, start with a line segment and divide it into thirds. Remove the middle third, then do the same to the remaining two segments, and so on, ad infinitum. You’ll be left with a scattering of points.

The team considered both a Menger sponge and a Cantor set that have undergone the same number of removal steps. At points on the sponge’s faces whose coordinates are both in the Cantor set, they realized, there shouldn’t be a hole. What’s more, there shouldn’t be holes anywhere directly behind those points either, thanks to the sponge’s repetitive design. A knot would therefore be free and clear to pass through without accidentally jumping off the material of the sponge.

All that was left, then, was for the students to show that they could always compress or stretch a given knot’s arc presentation so that all of its corners would line up with coordinates in the Cantor set. (Such compressing and stretching was allowed because it wouldn’t affect the arc presentation’s overall structure and, therefore, what knot it represents.)

To complete this final step, Broden, Nazareth and Voth took a shortcut. They proved that they could deform any arc presentation so that the points where its vertical and horizontal segments crossed were in the Cantor set. This automatically guaranteed that the larger number of corners would line up with the Cantor set, too. In other words, they could always embed a given knot in some iteration of the Menger sponge.

Now that they’d answered Malors’ original question, they wanted to push their result further. They’d already started to investigate whether all knots could also be embedded in a tetrahedral version of the Menger sponge:

“It was surprisingly annoying,” Broden said. Without the convenience of faces aligned directly opposite one another, their method for pushing knots through the fractal would no longer work.

Measured by Knots

It was at this stage, according to Malors, that the students learned the pain of math research — that a large part of the discipline involves struggling with the failure of a promising avenue of attack. “We’re facing math, and math has no mercy,” he said. “With math as presented to high schoolers, they’re usually protected from that.”

Malors, for his part, was convinced that a so-called trefoil knot couldn’t be found in the tetrahedron. During a Zoom call, the three students pushed back. They left the meeting, they recalled, feeling dispirited and frustrated. But they decided to stick to their instincts. A couple weeks later, to Malors’ surprise, they returned with a result: They had figured out a new way to map the trefoil knot’s arc presentation into the tetrahedron. They later proved that this could be done for all “pretzel” knots, the more general class of knots that the trefoil belongs to — although the question remains open for other kinds of knots.

Related:

1. Why Mathematicians Study Knots

2. How Complex Is a Knot? New Proof Reveals Ranking System That Works.

3. 3-D Fractals Offer Clues to Complex Systems

Malors conjectures that the students’ methods might offer a way to measure the complexity of fractals more broadly. Not all fractals are guaranteed to admit all kinds of knots. Perhaps their structure can be better understood based on what types of knots they can and cannot hold.

At the very least, the work could inspire new art, akin to the 2014 MegaMenger contest. “It would be lovely to see this constructed out of physical materials,” said Allison Moore, a knot theorist at Virginia Commonwealth University.

In the meantime, Broden, Nazareth and Voth have all graduated high school. Only Broden has decided to continue working on the tetrahedron problem — when he’s not busy with college coursework — but all three are considering math careers. “It feels meaningful that I’m trying to contribute to something bigger than myself, to the nature of truth,” Nazareth said. It all starts with asking the right question.

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2024 Nov 26

Teen Mathematicians Tie Knots Through a Mind-Blowing Fractal