Day: 02/08/2023

The Cause of Depression Is Probably Not What You Think

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Depression has often been blamed on low levels of serotonin in the brain. That answer is insufficient, but alternatives are coming into view and changing our understanding of the disease.

A sad woman stands under an umbrella that is decorated with images of brains, molecules and DNA. Rain falls on her under the umbrella but the day is otherwise clear.

Introduction

People often think they know what causes chronic depression. Surveys indicate that more than 80% of the public blames a “chemical imbalance” in the brain. That idea is widespread in pop psychology and cited in research papers and medical textbooks. Listening to Prozac, a book that describes the life-changing value of treating depression with medications that aim to correct this imbalance, spent months on the New York Times bestseller list.

The unbalanced brain chemical in question is serotonin, an important neurotransmitter with fabled “feel-good” effects. Serotonin helps regulate systems in the brain that control everything from body temperature and sleep to sex drive and hunger. For decades, it has also been touted as the pharmaceutical MVP for fighting depression. Widely prescribed medications like Prozac (fluoxetine) are designed to treat chronic depression by raising serotonin levels.

Yet the causes of depression go far beyond serotonin deficiency. Clinical studies have repeatedly concluded that the role of serotonin in depression has been overstated. Indeed, the entire premise of the chemical-imbalance theory may be wrong, despite the relief that Prozac seems to bring to many patients.

If you were still of the opinion that it was simply a chemical imbalance of serotonin, then yeah, it’s pretty damning.

Taylor Braund, Black Dog Institute

A literature review that appeared in Molecular Psychiatry in July was the latest and perhaps loudest death knell for the serotonin hypothesis, at least in its simplest form. An international team of scientists led by Joanna Moncrieff of University College London screened 361 papers from six areas of research and carefully evaluated 17 of them. They found no convincing evidence that lower levels of serotonin caused or were even associated with depression. People with depression didn’t reliably seem to have less serotonin activity than people without the disorder. Experiments in which researchers artificially lowered the serotonin levels of volunteers didn’t consistently cause depression. Genetic studies also seemed to rule out any connection between genes affecting serotonin levels and depression, even when the researchers tried to consider stress as a possible cofactor.

“If you were still of the opinion that it was simply a chemical imbalance of serotonin, then yeah, it’s pretty damning,” said Taylor Braund, a clinical neuroscientist and postdoctoral research fellow at the Black Dog Institute in Australia who was not involved in the new study. (“The black dog” was Winston Churchill’s term for his own dark moods, which some historians speculate were depression.)

The realization that serotonin deficits by themselves probably don’t cause depression has left scientists wondering what does. The evidence suggests that there may not be a simple answer. In fact, it’s leading neuropsychiatric researchers to rethink what depression might be.

Treating the Wrong Disease

The focus on serotonin in depression began with a tuberculosis drug. In the 1950s, doctors started prescribing iproniazid, a compound developed to target lung-dwelling Mycobacterium tuberculosis bacteria. The drug wasn’t particularly good for treating tuberculosis infections — but it did bless some patients with an unexpected and pleasant side effect. “Their lung function and everything wasn’t getting much better, but their mood tended to improve,” said Gerard Sanacora, a clinical psychiatrist and the director of the depression research program at Yale University.

Joanna Moncrieff of University College London standing in her home.
To evaluate the evidence that imbalances of serotonin cause depression, the psychiatric researcher Joanna Moncrieff of University College London organized a review that looked at hundreds of papers in six areas of research.Courtesy of Joanna Moncrieff

Perplexed by this outcome, researchers began studying how iproniazid and related drugs worked in the brains of rats and rabbits. They discovered that the drugs blocked the animals’ body from absorbing compounds called amines — which include serotonin, a chemical that carries messages between nerve cells in the brain.

Several prominent psychologists, among them the late clinicians Alec Coppen and Joseph Schildkraut, seized on the idea that depression could be caused by a chronic deficiency of serotonin in the brain. The serotonin hypothesis of depression went on to inform decades of drug development and neuroscientific research. During the late 1980s, it led to the introduction of selective serotonin reuptake inhibitor (SSRI) drugs, like Prozac. (The drugs raise levels of serotonin activity by slowing down the neurotransmitter’s absorption by neurons.) Today, the serotonin hypothesis is still the explanation most often given to patients with depression when they’re prescribed SSRIs.

But doubts about the serotonin model were circulating by the mid-1990s. Some researchers noticed that SSRIs often fell short of expectations and didn’t improve significantly on the performance of older drugs like lithium. “The studies didn’t really stack up,” Moncrieff said.

An illustration of how SSRI drugs affect serotonin in neural synapses.
Merrill Sherman/Quanta Magazine

By the early 2000s, few experts believed that depression is caused solely by lack of serotonin, but no one ever attempted a comprehensive evaluation of the evidence. That eventually prompted Moncrieff to organize such a study, “so that we could get a view as to whether this theory was supported or not,” she said.

She and her colleagues found that it wasn’t, but the serotonin hypothesis still has adherents. Last October — just a few months after their review appeared — a paper published online in Biological Psychiatry claimed to offer a concrete validation of the serotonin theory. Other researchers remain skeptical, however, because the study looked at only 17 volunteers. Moncrieff dismissed the results as statistically insignificant.

A Different Chemical Imbalance

Although serotonin levels don’t seem to be the primary driver of depression, SSRIs show a modest improvement over placebos in clinical trials. But the mechanism behind that improvement remains elusive. “Just because aspirin relieves a headache, [it] doesn’t mean that aspirin deficits in the body are causing headaches,” said John Krystal, a neuropharmacologist and chair of the psychiatry department at Yale University. “Fully understanding how SSRIs produce clinical change is still a work in progress.”

Speculation about the source of that benefit has spawned alternative theories about the origins of depression.

Despite the “selective” in their name, some SSRIs change the relative concentrations of chemicals other than serotonin. Some clinical psychiatrists believe that one of the other compounds may be the true force inducing or relieving depression. For example, SSRIs increase the circulating levels of the amino acid tryptophan, a serotonin precursor which helps regulate sleep cycles. Over the last 15 years or so, this chemical has emerged as a strong candidate in its own right for staving off depression. “There’s quite good evidence from tryptophan depletion studies,” said Michael Browning, a clinical psychiatrist at the University of Oxford.

John Krystal standing in front of a laboratory at Yale University.
John Krystal, the chair of the psychiatry department at Yale University, called the effort to understand the clinical effects of SSRI drugs “a work in progress.”Nicole Mele

A number of tryptophan depletion studies found that about two-thirds of people who have recently recovered from a depressive episode will relapse when given diets artificially low in tryptophan. People with a family history of depression also appear vulnerable to tryptophan depletion. And tryptophan has a secondary effect of raising serotonin levels in the brain.

Recent evidence also suggests that both tryptophan and serotonin may contribute to the regulation of bacteria and other microbes growing in the gut, and chemical signals from these microbiota could affect mood. While the exact mechanisms linking the brain and gut are still poorly understood, the connection seems to influence how the brain develops. However, because most tryptophan depletion studies so far have been small, the matter is far from settled.

Other neurotransmitters like glutamate, which plays an essential role in memory formation, and GABA, which inhibits cells from sending messages to one another, may be involved in depression as well, according to Browning. It’s possible that SSRIs work by tweaking the amounts of these compounds in the brain.

Moncrieff sees the hunt for other chemical imbalances at the root of depression as akin to rebranding rather than a truly novel line of research. “I would suggest that they are still subscribing to something like the serotonin hypothesis,” she said — the idea that antidepressants work by reversing some chemical abnormality in the brain. She thinks instead that serotonin has such widespread effects in the brain that we may have trouble disentangling their direct antidepressant effect from other changes in our emotions or sensations that temporarily override feelings of anxiety and despair.

Genetic Answers

Not all theories of depression hinge on neurotransmitter deficiencies. Some look for culprits at the genetic level.

When the first roughly complete draft sequence of the human genome was announced in 2003, it was widely hailed as the foundation of a new era in medicine. In the two decades since then, researchers have identified genes that underlie a huge spectrum of disorders, including about 200 genes that have been linked to a risk of depression. (Several hundred more genes have been identified as possibly raising the risk.)

Just because aspirin relieves a headache, [it] doesn’t mean that aspirin deficits in the body are causing headaches.

John Krystal, Yale University

“It’s really important that people understand that there is a genetics of depression,” Krystal said. “Until very recently, only psychological and environmental factors were considered.”

Our knowledge of the genetics, however, is incomplete. Krystal noted that studies of twins suggest that genetics may account for 40% of the risk of depression. Yet the currently identified genes seem to explain only about 5%.

Moreover, simply having the genes for depression doesn’t necessarily guarantee that someone will become depressed. The genes also need to be activated in some way, by either internal or external conditions.

“There’s a false distinction that is sometimes drawn between environmental factors and genetic factors,” said Srijan Sen, a neuroscientist at the University of Michigan. “For most common traits of interest, both genetic and environmental factors play a critical role.”

Sen’s lab studies the genetic basis of depression by mapping subjects’ genomes and carefully observing how individuals with different genetic profiles respond to changes in their environment. (Recently, they have looked at stress brought on by the Covid-19 pandemic.) Different genetic variations can affect whether individuals respond to certain types of stress, such as sleep deprivation, physical or emotional abuse, and lack of social contact, by becoming depressed.

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A cross section of human brain that shows the distinct “gray matter” and “white matter” areas.
Research suggests that in the brains of people with chronic depression, the “white matter” areas that are rich in nerve fibers have fewer connections. The cause for this difference is uncertain, however.Ralph T. Hutchins/Science Source

Introduction

Environmental influences like stress can also sometimes give rise to “epigenetic” changes to a genome that affect subsequent gene expression. For example, Sen’s laboratory studies epigenetic changes in the caps on the ends of chromosomes, known as telomeres, which affect cell division. Other labs look at changes in chemical tags called methylation groups that can turn genes on or off. Epigenetic changes can sometimes even be passed down through generations. “The effects of the environment are just as biological as the effects of genes,” Sen said. “Just the source is different.”

Studies of these genes may someday help identify the form of treatment a patient would respond to best. Some genes may predispose an individual to better results from cognitive behavioral therapy, while other patients might fare better with an SSRI or therapeutic ketamine. However, it’s far too early to say which genes respond to which treatment, Sen said.

A Product of Neural Wiring

Differences in a person’s genes may predispose them to depression; so, too, may differences in the neural wiring and structure of their brain. Numerous studies have shown that individuals differ in how the neurons in their brains interconnect to form functional pathways, and that those pathways influence mental health.

Jonathan Repple and Susanne Meinert of Goethe University sitting in front of a desk and a computer monitor displaying brain mapping data.
Jonathan Repple and Susanne Meinert of Goethe University and their colleagues are exploring why chronically depressed people have fewer connections in their brains. Possible explanations include neuroplasticity and inflammation.Roberto Schirdewahn; WWU/R

Introduction

In a recent conference presentation, a team led by Jonathan Repple, a psychiatry researcher at Goethe University in Frankfurt, Germany, described how they scanned the brains of acutely depressed volunteers and found that they differed structurally from those of a non-depressed control group. For example, people experiencing depression showed fewer connections within the “white matter” of the nerve fibers in their brains. (However, there is no white-matter threshold for poor mental health: Repple notes that you can’t diagnose depression by scanning someone’s brain.)

After the depressed group underwent six weeks of treatment, Repple’s team ran another round of brain scans. This time, they found that the general level of neural connectivity in the depressed patients’ brains had increased as their symptoms lessened. To get the increase, it didn’t seem to matter what kind of treatment the patients received, so long as their mood improved.

A possible explanation for this change is the phenomenon of neuroplasticity. “Neuroplasticity means that the brain actually is able to create new connections, to change its wiring,” Repple said. If depression occurs when a brain has too few interconnections or loses some, then harnessing neuroplastic effects to increase interconnectedness might help lift a person’s mood.

Chronic Inflammation

Repple warns, however, that another explanation for the effects his team observed is also possible: Perhaps the depressed patients’ brain connections were impaired by inflammation. Chronic inflammation impedes the body’s ability to heal, and in neural tissue it can gradually degrade synaptic connections. The loss of such connections is thought to contribute to mood disorders.

Charles Nemeroff in a white lab coat.
Charles Nemeroff, a neuropsychiatrist at the University of Texas, Austin, thinks that in the future, treatments for depression will be tailored to individual patients by a more nuanced understanding of their risk factors.UT Austin Health

Good evidence supports this theory. When psychiatrists have evaluated populations of patients who have chronic inflammatory diseases like lupus and rheumatoid arthritis, they’ve found that “all of them have higher-than-average rates of depression,” said Charles Nemeroff, a neuropsychiatrist at the University of Texas, Austin. Of course, knowing that they have an incurable, degenerative condition may contribute to a patient’s depressed feelings, but the researchers suspect that the inflammation itself is also a factor.

Medical researchers have found that inducing inflammation in certain patients can trigger depression. Interferon alpha, which is sometimes used to treat chronic hepatitis C and other conditions, causes a major inflammatory response throughout the body by flooding the immune system with proteins known as cytokines — molecules that facilitate reactions ranging from mild swelling to septic shock. The sudden influx of inflammatory cytokines leads to appetite loss, fatigue and a slowdown in mental and physical activity — all symptoms of major depression. Patients taking interferon often report feeling suddenly, sometimes severely, depressed.

If overlooked chronic inflammation is causing many people’s depression, researchers still need to determine the source of that inflammation. Autoimmune disorders, bacterial infections, high stress and certain viruses, including the virus that causes Covid-19, can all induce persistent inflammatory responses. Viral inflammation can extend directly to tissues in the brain. Devising an effective anti-inflammatory treatment for depression may depend on knowing which of these causes is at work.

It’s also unclear whether simply treating inflammation could be enough to alleviate depression. Clinicians are still trying to parse whether depression causes inflammation or inflammation leads to depression. “It’s a sort of chicken-and-egg phenomenon,” Nemeroff said.

The Umbrella Theory

Increasingly, some scientists are pushing to reframe “depression” as an umbrella term for a suite of related conditions, much as oncologists now think of “cancer” as referring to a legion of distinct but similar malignancies. And just as each cancer needs to be prevented or treated in ways relevant to its origin, treatments for depression may need to be tailored to the individual.

If there are different types of depression, they may present similar symptoms — such as fatigue, apathy, appetite changes, suicidal thoughts, and insomnia or oversleeping — but they might emerge from completely different mixes of environmental and biological factors. Chemical imbalances, genes, brain structure and inflammation could all play a role to varying degrees. “In five or 10 years, we won’t be talking about depression as a unitary thing,” Sen said.

To treat depression effectively, medical researchers may therefore need to develop a nuanced understanding of the ways it can arise. Nemeroff expects that someday the gold standard for care won’t be just one treatment — it will be a set of diagnostic tools that can determine the best therapeutic approach to an individual patient’s depression, be it cognitive behavioral therapy, lifestyle changes, neuromodulation, avoiding genetic triggers, talk therapy, medication or some combination thereof.

That prediction may frustrate some physicians and drug developers, since it’s much easier to prescribe a one-size-fits-all solution. But “appreciating the true, real complexity of depression takes us down a path that is ultimately going to be most impactful,” Krystal said. In the past, he said, clinical psychiatrists were like explorers who landed on a tiny unknown island, set up camp, and got comfortable. “And then we discovered that there’s this whole, enormous continent.”

Why Earth’s Inner Core May Be Slowing Down

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The planet’s solid inner core might rotate at a different rate than the rest of the planet, and that rate might be changing

Why Earth's Inner Core May Be Slowing Down

Earth’s core structure. Elements of this image were furnished by NASA.

The spin of Earth’s inner core may have slowed, with the heart of the planet now rotating at a slightly more sluggish clip than the layers above, new research finds. The slowdown could change how rapidly the entire planet spins, as well as influence how the core evolves with time.

For the new study, published in the journal Nature Geoscience, scientists used a database of earthquakes to probe the behavior of Earth’s solid inner core over time. The inner core sits suspended like a ball bearing in the molten-metal ocean of the outer core. Because of this liquid cocoon, the “ball bearing” may not spin at the same rate as the rest of the planet. Over the years, some researchers have found that the core rotates slightly faster than the mantle and crust, a condition called “super rotation.” But studies have not returned consistent numbers, with the first study to observe differential core rotation estimating that the inner core rotates up to one degree faster per year than the rest of the planet; others found an annual speedup of just tiny fractions of a degree.

These differences aren’t dramatic. The variation in rotation time between the inner core and the rest of Earth is very minor. Nor are the differences a threat to life on the surface: In contrast to the 2003 science-fiction movie The Core, there’s no need to call in a crack team of geophysicists and astronauts to drill to the center of our planet and start blowing things up. At most, the inner core rotation might influence Earth’s overall spin and contribute to fluctuations in the planet’s magnetic field. Each year the core expands by about a millimeter, as some of the molten iron in the outer core solidifies, seismic studies have shown. The solidification also drives the circulation of the outer core, which, in turn, creates the planet’s magnetic field. The rotation of the inner core could influence this solidification process in ways that are not yet fully understood, thus impacting the magnetic field, says study author Xiaodong Song, a geophysicist at Peking University in China.

The rotation might also matter for how the inner core grows over billions of years, says John Vidale, a geophysicist at the University of Southern California who was not involved in the study, but who has researched core rotation.

The catch, however, is that no one really knows how fast the inner core spins. In the new study, Song and geophysicist Yi Yang, also at Peking University, found that the core appeared to hold a steady spin, faster than the overall spin of Earth, between the 1970s and the early 2000s. Around 2009, though, that spin rather abruptly slowed to match Earth’s speed and then perhaps slowed so much that the rest of the planet now spins faster, Song says.

Song and Yang measured this spin by using pairs of almost-identical earthquakes that originated at the same spots, separated only by time. Because the quakes are nearly identical, their shock waves should also look identical when they travel through the core and back out, where they are detected by seismometers around the planet—that is, unless the core itself changes and alters the path of one earthquake’s waves relative to the other. If the core is spinning differently than the rest of the planet, identical earthquake waves that happen months or years apart will hit the core at slightly different spots and therefore bounce back with some subtle differences. The researchers compared quake waves going back to 1964 to track the changes in how the core might be moving over time. If they’re right, the spin of the core now lags that of the overall planet by a tiny amount.

“We are hypothesizing that this [slowed rotation] will continue in the coming years and decades, and we should be able to see that in [our] relatively short human time frame,” Song says.

The new findings likely won’t end the debate over the inner core. The work is well done and does an admirable job of combining different data, Vidale says. But there are several competing explanations for what’s going on. For example, Vidale’s research hints that the core may alter its rotation every six years or so, while researchers Guanning Pang and Keith Koper reported a single “lurch” in the early 2000s and little change since in a 2022 study. “I don’t view [the new work] as entirely conclusive,” Vidale says.

Lianxing Wen, a geodynamicist at Stony Brook University, who was not involved in the new study, also researches the core’s spin. He doesn’t believe the inner core spins any differently than the rest of the planet. A better explanation for the changes in seismic waves that travel through the core, Wen says, is that the surface of the inner core isn’t smooth like a ball bearing but rather uneven and constantly changing. “We believe the inner core has a shifting topography that best explains observed temporal changes of seismic waves that reflect off the inner core,” he says. The new research, Wen says, misinterprets these changes as caused by the core’s spin rather than to its fluctuating surface.

Fortunately, Song says, the seismic monitoring of Earth is better than ever, yielding far richer data about the planet’s interior than in earlier decades. By continuing to watch earthquake waves, the researchers should be able to show whether they’re right about the inner core’s spin.

“The exciting news,” Song says, “is that we don’t have to wait too long.”

Multidrug Nanoparticle Platform Improves Drug Delivery against Cancer

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In a study of mice, MIT chemists demonstrated that their multidrug nanoparticle shrank tumors much more than when drugs were given at the same ratio but untethered to a particle. Their nanoparticle platform could potentially be deployed to deliver drug combinations against a variety of cancers.

Their findings are published in Nature Nanotechnology in an article titled, “Molecular bottlebrush prodrugs as mono- and triplex combination therapies for multiple myeloma.”

“Cancer therapies often have narrow therapeutic indexes and involve potentially suboptimal combinations due to the dissimilar physical properties of drug molecules,” wrote the researchers. “Nanomedicine platforms could address these challenges, but it remains unclear whether synergistic free-drug ratios translate to nanocarriers and whether nanocarriers with multiple drugs outperform mixtures of single-drug nanocarriers at the same dose. Here we report a bottlebrush prodrug (BPD) platform designed to answer these questions in the context of multiple myeloma therapy.”

“There’s a lot of interest in finding synergistic combination therapies for cancer, meaning that they leverage some underlying mechanism of the cancer cell that allows them to kill more effectively, but oftentimes we don’t know what that right ratio will be,” explained Jeremiah Johnson, PhD, an MIT professor of chemistry and one of the senior authors of the study.

For several years, Johnson’s lab has been working on polymer nanoparticles designed to carry multiple drugs. In the new study, he and his team focused on a bottlebrush-shaped particle.

“If we want to make a bottlebrush that has two drugs or three drugs or any number of drugs in it, we simply need to synthesize those different drug-conjugated monomers, mix them together, and polymerize them. The resulting bottlebrushes have exactly the same size and shape as the bottlebrush that only has one drug, but now they have a distribution of two, three, or however many drugs you want within them,” Johnson said.

The researchers first tested particles carrying just one drug: bortezomib, which is used to treat multiple myeloma, a cancer that affects a type of B cells known as plasma cells. Bortezomib is a proteasome inhibitor, a type of drug that prevents cancer cells from breaking down the excess proteins they produce.

On its own, bortezomib tends to accumulate in red blood cells, which have high proteasome concentrations. However, when the researchers gave their bottlebrush prodrug version of the drug to mice, they found that the particles accumulated primarily in plasma cells because the bottlebrush structure protects the drug from being released right away, allowing it to circulate long enough to reach its target.

“If you inject three drugs into the body, the likelihood that the correct ratio of those drugs will arrive at the cancer cell at the same time can be very low. The drugs have different properties that cause them to go to different places, and that hinders the translation of these identified synergistic drug ratios quite immensely,” Johnson said.

In tests in two mouse models of multiple myeloma, the researchers observed that three-drug bottlebrushes with a synergistic ratio significantly inhibited tumor growth compared to the free drugs given at the same ratio and to mixtures of three different single-drug bottlebrushes.

“We were happy to see that the bortezomib bottlebrush prodrug on its own was an excellent drug, displaying improved efficacy and safety compared to bortezomib, and that has led us to pursue trying to bring this molecule to the clinic as a next-generation proteasome inhibitor,” Johnson said. “It has completely different properties than bortezomib and gives you the ability to have a wider therapeutic index to treat cancers that bortezomib has not been used in before.”

Johnson’s lab is also working on using these particles to deliver therapeutic antibodies along with drugs, as well as combining them with larger particles that could deliver messenger RNA along with drug molecules. “The versatility of this platform gives us endless opportunities to create new combinations,” he added.

Zinc Finger Design AI Tool Opens Door to Large-Scale Gene Therapies

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Researchers at the University of Toronto (U of T) and NYU Grossman School of Medicine have developed a novel artificial intelligence technology, called ZFDesign, that can design zinc finger (ZF) proteins to target any stretch of DNA in the human genome, opening a door toward gene therapies for a broader range of health conditions. The researchers fed data from billions of interactions between ZF proteins and DNA into a machine-learning model, which can then generate engineered zinc fingers that bind to the given DNA sequence.

“Designing zinc fingers to bind specific DNA targets has been an unsolved problem for decades,” said Philip M. Kim, PhD, a professor in the Donnelly Centre for Cellular and Biomolecular Research at U of T’s Temerty Faculty of Medicine. “Our work should enable a new generation of in vivo therapeutics, which have proven difficult to develop with CRISPR and other DNA targeting technologies.”

David Ichikawa, PhD, a former graduate student at NYU Langone Health, added: “Our program can identify the right grouping of zinc fingers for any modification, making this type of gene editing faster than ever before.”

Ichikawa is lead author of the team’s published paper in Nature Biotechnology, which is titled “A universal deep-learning model for zinc finger design enables transcription factor reprogramming.” The investigators stated, “In this study, we present ZFDesign, a hierarchical attention-based artificial intelligence model trained on comprehensive screens of ZF–DNA interactions that consider the influence of multiple adjacent finger environments … ZFDesign captures these influences to provide a general design model for ZF arrays.”

Disorders including cystic fibrosis, Tay-Sachs disease, and sickle cell anemia are caused by errors in the order of DNA bases that encode the operating instructions for every human cell. Scientists can in some cases correct these mistakes with gene editing methods. Other conditions are caused not by a mistake in the DNA code itself, but by problems in how the cellular machinery reads DNA—epigenetics.

A gene often partners with transcription factors that tell the cell how much of that protein to make. When this process goes awry, over- or underactive genes can contribute to diseases including diabetes, cancer, and neurological disorders. As a result, researchers have been exploring ways to restore normal epigenetic activity. “Programmable regulation of gene expression would offer both powerful research tools as well as enormous therapeutic potential,” the authors stated. “Diseases caused by haploinsufficiency, gain-of-function mutations, or misexpression of a gene can be directly treated by modification of gene expression.”

ZFs are a common class of human proteins that regulate such gene expression, a process that transcribes genetic information into RNA molecules and proteins. Scientists have long seen their potential because they naturally bind with DNA, are less likely than CRISPR and related technologies to trigger an immune reaction, and are small enough to work with clinical delivery methods. ZF editing can both change and control genes. Among the most abundant protein structures in the human body, ZFs can guide DNA repair by grabbing onto scissor-like enzymes and directing them to cut faulty segments out of the code.

Similarly, ZFs can also hook onto transcription factors and pull them toward a gene segment in need of regulation. By customizing these instructions, genetic engineers can tailor any gene’s activity.

A drawback, however, is that artificial ZFs are challenging to design for a specific task. “… the structurally intricate engagement of ZF domains with DNA has made their design challenging,” the authors pointed out. Since these proteins attach to DNA in complex groups, researchers would need to be able to tell—out of countless possible combinations—how every ZF interacts with its neighbor for each desired genetic change. So, for every new DNA target, scientists would have to engineer a new protein through a laborious and often unsuccessful workflow. The investigators noted, “While the potential utility of designer ZF arrays has long been recognized, their engineering has remained challenging with no proper design code having emerged thus far.”

This is not for lack of effort, they continued, because multiple approaches have been used to generate ZF libraries and ZF modules to provide designer ZF arrays. Even so, the team stated, “These approaches either require multiple rounds of laborious selection that produce ZFs with inconsistent activity or the application of preselected modules that often fail when expressed out of their selected context.”

The newly reported ZFDesign approach solves this problem with a universal model that offers ease of use comparable to CRISPR, and potentially higher DNA specificity. The technology uses artificial intelligence to model and design the interactions. “Because half of human TFs use ZFs to engage DNA, we reasoned that these endogenous ZF domains could be seamlessly replaced by designed ZFs without impacting the protein’s regulatory function,” the team commented. “This approach presents the designed ZFs in the exact context in which ZFs would occur naturally in the parent protein.”

“I think this system levels the playing field for zinc fingers and CRISPR,” said Kim, who is also a professor of molecular genetics and computer science at U of T. “CRISPR is very established for fundamental science, but our system has many advantages for applications in living systems, in particular, that zinc fingers are human proteins and would be safer as injected drugs.”

The ZFDesign technology can also generate many different proteins that do the same thing, offering more options for moving treatments toward the clinic. “Our program can identify the right grouping of zinc fingers for any modification, making this type of gene editing faster than ever before,” commented Ichikawa.

The ZF model has been developed with a research group at NYU Langone Health, led by Marcus Noyes, PhD, an assistant professor of biochemistry and molecular pharmacology in the Institute for Systems Genetics at the Grossman School of Medicine.

The model is based on data generated by the screen of billions of possible ZF-DNA interactions in the researchers’ labs. The Noyes lab has studied zinc fingers for years, and compiled data on 49 billion interactions among zinc finger proteins and DNA by creating high-throughput screens of several zinc finger libraries. Their approach combined two levels of data: interactions between single zinc fingers and DNA, and between each zinc finger and its neighboring finger. These zinc finger pair interactions influence DNA binding and hence gene expression.

The machine learning model developed by Kim and his group mirrors the data synthesis approach in the Noyes lab. “Our model is hierarchical, so it takes advantage of existing data from their first stage of screening—and a subset of their stage-two data—to develop predictions about which zinc fingers will be compatible with others in certain contexts,” said co-first author Osama Abdin, a doctoral student in Kim’s lab.

The model is based in part on technology that also forms the basis of ChatGPT, a software application developed by OpenAI that simulates human conversation. The model generates amino acid sequences for ZF proteins using large, highly detailed data sets and techniques similar to natural language processing.

The researchers showed the utility of the ZF system by reprogramming human transcription factors—ZF proteins that regulate the transcription of DNA to RNA. Working with professors Tim Hughes, PhD, and Mikko Taipale, PhD, in the Donnelly Centre, they tweaked the DNA binding targets of several transcription factors and programmed them to either activate or repress multiple genes. “We present a generalizable design method that allows for the seamless replacement of a TF natural DNA-binding domain to direct the TF to any target of interest,” the authors stated. “These RTFs [reprogrammed transcription factors] can produce activation and repression activities similar to CRISPR-based tools, establishing these proteins as attractive therapeutics comprising solely human components.”

Clinical application of reprogrammed transcription factors could target diseases caused by haploinsufficiency—deletion or inactivation of a copied gene, as in some cancers and the connective tissue disorders known as Ehlers-Danlos syndrome—or those linked to toxic genetic repeats, as in neurodegenerative conditions such as ALS, Parkinson’s, and Huntington’s disease.

Kim said the system already generates designs for ZF proteins with clinical potential, and that both his team in Toronto and the group in New York were surprised by how well it worked. The new system also holds promise for gene editing and other applications where CRISPR is useful, although its impact will likely be strongest in the area of reprogramming transcription factors, Kim said. The study authors add that besides posing a lower immune risk, the small size of zinc-finger tools may also provide more flexible gene therapy techniques compared with CRISPR by enabling more ways to deliver the tools to the right cells in patients.

“By speeding up zinc-finger design coupled with their smaller size, our system paves the way for using these proteins to control multiple genes at the same time,” said Noyes. “In the future, this approach may help correct diseases that have multiple genetic causes, such as heart disease, obesity, and many cases of autism.”

The developers further commented, “ZFDesign represents an important advance because the design of ZFs for any given target is now available at the push of a button and is open to the academic community for the study of a myriad of academic and therapeutic applications, with the advantages of small size and low immunogenicity.”

Noyes, an assistant professor in the department of biochemistry and molecular pharmacology at NYU Langone, cautioned that, while promising, ZFs can be difficult to control. Since they are not always specific to a single gene, some combinations can affect DNA sequences beyond a particular target, leading to unintended changes in genetic code. As a result, Noyes said the team next plans to refine its AI program so it can build more precise ZF groupings that only prompt the desired edit. Noyes is also a member of NYU Langone’s Institute for System Genetics.

The next step is to improve specificity in the system. “The current model is designed to optimize the engagement of a given zinc finger protein with its target, but has no built-in awareness of interactions to other targets,” said Kim. “Optimizing for specificity will entail modeling these other interactions.”

The researchers are well on their way to building a model that offers more specificity, Kim said. “There is a lot of excitement around this work in the fields of epigenetics and gene therapy, and I look forward to seeing what we can achieve with this technology.”

Noyes is a co-founder of TBG Therapeutics, which is developing methods to design ZFs and apply them to treatments for diseases with genetic components.

Scientists Create Shape-Shifting Robot That Can Melt Through Prison Bars

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If you thought “Terminator 2” was too far-fetched, think again.

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Judgment Day

Your eyes don’t deceive you: researchers have created an actual humanoid shape-shifting robot — or in their parlance, “shape-morphing” — capable of liquefying and then reforming itself again. In other words, the lilliputian bot looks a lot like a prototype of the T-1000 in 1991’s “Terminator 2,” once again proving that you should never doubt the visions of James Cameron.

In a new study published in the journal Cells, the researchers wanted to bridge the gap between traditional, hard-bodied robots and “soft” robots typically made of more malleable but consequently weaker materials. Inspired by squishy sea cucumbers, they saw the shifting between states as the best path forward.

And clearly, that worked out for them. Have a look at this demonstration in which a robot shaped like a LEGO minifigure melts through tiny prison bars, in a clear homage to one of Robert Patrick’s most iconic scenes in Cameron’s action epic.

It’s not exactly the T-1000—yet. But researchers have created a liquid metal robot that can mimic the shape-shifting abilities of the silvery, morphing killer robot in Terminator 2: Judgement Day. https://t.co/tyNW1CPLCy pic.twitter.com/WV5NIsQQHn

— News from Science (@NewsfromScience) January 25, 2023

Material Response

To accomplish this, the team created a novel form of gallium based, phase-shifting material called “magnetoactive solid-liquid phase transitional matter” (MPTM).

Whereas other phase-shifting materials require an external heat source like heat guns and electrical currents, MPTM needs only be induced by a magnetic field before heating up, thanks to magnetic particles embedded in the gallium.

These, combined with the metal’s low melting point of just under 86 degrees Fahrenheit, make it easy for a robot made of the stuff to liquefy relatively quickly.

“The magnetic particles here have two roles,” explained senior author Carmel Majidi, an engineer from Carnegie Mellon University, in a press release.  “One is that they make the material responsive to an alternating magnetic field, so you can, through induction, heat up the material and cause the phase change. But the magnetic particles also give the robots mobility and the ability to move in response to the magnetic field.”

Medical Extractor

The researchers believe MPTM could have useful — albeit highly specific — applications in engineering and medical challenges.

In addition to the “T2” demonstration, the team also used their bot, this time taking the more practical shape of a thin block, to extract a foreign object from a model human stomach by melting over it and then wriggling out of the organ.

“Future work should further explore how these robots could be used within a biomedical context,” Majidi said. “What we’re showing are just one-off demonstrations, proofs of concept, but much more study will be required to delve into how this could actually be used for drug delivery or for removing foreign objects.”

We can hope that’s how the remarkable technology will pan out — as opposed to it being used to hunt down humanity’s John Connors.