St. Jude tool gets more out of multi-omics data

An upgraded computational tool from St. Jude Children’s Research Hospital, Memphis, TN, can find potentially druggable hidden drivers of cancer and other biological processes using multi-omics data. 

Despite the astounding advances made in understanding the biological underpinnings of cancer, many cancers are missing obvious genetic drivers. When scientists can’t pinpoint the factors that drive cancer, treating it can be much more difficult. Scientists at St. Jude Children’s Research Hospital hope to solve that problem with an updated way to analyze multi-omic (primarily transcriptomics and proteomics) data. The researchers created a next-generation computational tool to gain new insights from biological data and find hidden druggable targets.

The updated application, NetBID2, successfully uncovers difficult-to-identify proteins that drive biological processes (such as rapid cell growth) contributing to cancer. These hidden drivers present new therapeutic opportunities, either because existing drugs can already target them or because they might inspire drug developers to make new therapeutics.

“We made it easier to find hidden drivers,” said Jiyang Yu, Ph.D., St. Jude Department of Computational Biology. “Finding hidden drivers is important because many of these are potentially druggable targets. NetBID2 can find these drivers and potentially move them quickly into clinical trials. We may be able to re-purpose an already FDA-approved drug that targets an identified hidden driver to a completely different patient population that may benefit.”

A network approach to finding hidden drivers

Large sets of RNA sequencing data from specific cells or cancer types can contain valuable information necessary to find hidden drivers of disease; however, standard analysis tools struggle to find them. NetBID2 is a sequel to the original tool developed by Yu in 2018. He specifically designed these tools to find hidden drivers by squeezing out more from “big data.”

“NetBID2 enables us to maximize the data we have,” said Yu, “particularly RNA sequencing data. It goes beyond the traditional mutation or differential gene expression data to expose hidden events and information that may be functionally important.”

Hidden drivers cannot be discovered by conventional genomics or sequencing approaches because their activity depends on post-translational modifications and other mechanisms that are invisible to traditional sequencing but affect the expression of other genes.

Therefore, NetBID2 takes RNA sequencing data, then generates a gene-gene interactome. This interactome tracks the relationships between driver candidates and their downstream effector genes to determine which signaling proteins are most central to the key relationships that fuel disease. These “central hubs” directing the network are the hidden drivers.

“NetBID2 looks for a hidden driver like the FBI would look for a crime boss,” Yu said. “If you look at the suspect, there’s no direct evidence to connect them with any crime. The way to capture them is first to build a network of associates. We do the same when we build the biological network by collecting a lot of data on its members and their relationships. Then we look for the boss’s first neighbors in the network when we look at a hidden driver’s activity. That’s the only way to capture the boss — by inference from their activities — otherwise, there is no way to identify them. We find these hidden drivers’ guilt by association.”

As proof of the tool’s capabilities, the St. Jude group showed it could find biologically meaningful hidden drivers in three unrelated samples. Using NetBID2, the team found unappreciated roles for MYC in adult lung cancer and for NOTCH1 in difficult-to-treat pediatric leukemia that standard differential expression analysis at the mRNA or protein levels hadn’t uncovered, despite the genes’ having been previously linked to cancer. They also found an unappreciated role for Gabpa in normal immune cell function. The gene’s importance was context-specific in each case, highlighting the need for targeted analyses.

The software’s other capabilities, such as new visualization tools, are meant to facilitate further analysis and discovery of hidden drivers from complex networks of RNA-seq and, in some cases, proteomics data.

NetBID2 is freely available on a GitHub repository. The St. Jude Cloud, which includes a NetBID2 app and data from many multi-omics projects, is also freely available for other scientists to use for further discovery of hidden drivers of basic biology and disease.

The study’s first writer is Xinran Dong, formerly of St. Jude. The other writers are Liang Ding, Andrew Thrasher, Xinge Wang (formerly), Jingjing Liu, Qingfei Pan, Jordan Rash, Yogesh Dhungana, Xu Yang, Isabel Risch (formerly), Yuxin Li (formerly), Lei Yan, Michael Rusch, Clay McLeod, Koon-Kiu Yan, Junmin Peng, Hongbo Chi, and Jinghui Zhang, all of St. Jude.

The study was supported by grants from the National Institutes of Health (R01GM134382, U01CA264610, and P30CA021765-403 41S3) and ALSAC, the fundraising and awareness organization of St. Jude.

Why do Champagne bubbles rise the way they do?

The chain of bubbles from Champagne and sparkling wine rise in a straight line. The bubble chain in many beers veers off to the side when they rise, making it look like multiple bubbles rise at once. Videos: Madeline Federle and Colin Sullivan

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Brown, University of Toulouse scientists’ Champagne bubbles discovery is worthy of a toast

Fluid mechanics researchers from Brown University and the University of Toulouse found that surfactants give the celebratory drink its stable and signature straight rise of bubbles. 

Here are some scientific findings worthy of a toast: Researchers from Brown University and the University of Toulouse in France have explained why bubbles in Champagne fizz up in a straight line while bubbles in other carbonated drinks, like beer or soda, don’t.

The findings are based on a series of numerical and physical experiments, including, of course, pouring out glasses of Champagne, beer, sparkling water, and sparkling wine. The results not only explain what gives Champagne its line of bubbles but may hold important implications for understanding bubbly flows in the field of fluid mechanics. 

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“This is the type of research that I've been working out for years,” said Brown Engineering professor Roberto Zenit, who was one of the paper’s authors. “Most people have never seen an ocean seep or an aeration tank but most of them have had a soda, a beer, or a glass of Champagne. By talking about Champagne and beer, our master plan is to make people understand that fluid mechanics is important in their daily lives.”

The team’s goal was to investigate the stability of bubble chains in carbonated drinks. Part of the signature experience of enjoying these beverages is the tiny or large bubbles that form when the drink is poured, creating a visible chain of bubbles and fizz. Depending on the drink and its ingredients, the fluid mechanics involved are all different.

When it comes to Champagne and sparkling wine, for instance, the gas bubbles that continuously appear rise rapidly to the top in a single-file line and keep doing so for some time. This is known as a stable bubble chain. With other carbonated drinks, like beer, many bubbles veer off to the side, making it look like multiple bubbles are coming up at once. This means the bubble chain isn’t stable.

The chain of bubbles from Champagne and sparkling wine rise in a straight line. The bubble chain in many beers veers off to the side when they rise, making it look like multiple bubbles rise at once. 

The researchers set out to explore the mechanics of what makes bubble chains stable and if they could recreate them, making unstable chains as stable as they are in Champagne or prosecco.

The results of their experiments indicate that the stable bubble chains in Champagne and other sparkling wines occur due to ingredients that act as soap-like compounds called surfactants. These surfactant-like molecules help reduce the tensions between the liquid and the gas bubbles, making for a smooth rise to the top.

“The theory is that in Champagne these contaminants that act as surfactants are the good stuff,” said Zenit, senior author of the paper. “These protein molecules that give flavor and uniqueness to the liquid are what makes the bubbles chains they produce stable.”

The experiments also showed the stability of bubbles is impacted by the size of the bubbles themselves. They found that the chains with large bubbles have a wake similar to that of bubbles with contaminants, leading to a smooth rise and stable chains.

In beverages, however, bubbles are always small. It makes surfactants the key ingredient to producing straight and stable chains. Beer, for example, also contains surfactant-like molecules but, depending on the type of beer, the bubbles can rise in straight chains or not. In contrast, bubbles in carbonated water are always unstable since no contaminants are helping the bubbles move smoothly through the wake flows left behind by the other bubbles in the chain.

“This wake, this velocity disturbance, causes the bubbles to be knocked out,” Zenit said. “Instead of having one line, the bubbles end up going up in more of a cone.”

The results of the new study go well beyond understanding the science that goes into celebratory toasts, the researchers said. The findings provide a general framework in fluid mechanics for understanding the formation of clusters in bubbly flows, which have economic and societal value.

Technologies that use bubble-induced mixing, like aeration tanks at water treatment facilities, for instance, would benefit greatly from researchers having a clearer understanding of how bubbles cluster, their origins, and how to predict their appearance. In nature, understanding these flows may help better explain ocean seeps in which methane and carbon dioxide emerge from the bottom of the ocean.

The experiments the research team ran were relatively straightforward — and some could even be run in any local pub. To observe the bubble chains, the researchers poured glasses of carbonated beverages including Pellegrino sparkling water, Tecate beer, Charles de Cazanove Champagne, and a Spanish-style brut.

To study the bubble chains and what goes into making them stable, they filled a small rectangular plexiglass container with liquid and inserted a needle at the bottom so they could pump in gas to create different kinds of bubble chains.

In this figure from the paper, the researchers show that when the frequency of gas bubbles is increased in a clean liquid to the rate of bubble chains in Champagne, the chain quickly loses stabilization. Courtesy of Roberto Zenit.

The researchers then gradually added surfactants or increased bubble size. They found that when they made the bubbles larger, they could make unstable bubble chains become stable, even without surfactants. When they kept a fixed bubble size and only added surfactants, they found they could also go from unstable chains to stable ones.

The two experiments indicate that there are two distinct possibilities to stabilize a bubble chain: adding surfactants and making bubbles bigger, the researchers explain in the paper.

The researchers performed numerical simulations on a computer to explain some of the questions they couldn’t explain through the physical experiments, such as calculating how much of the surfactants go into the gas bubbles, the weight of the bubbles, and their precise velocity.

They plan to keep looking into the mechanics of stable bubble chains to apply them to different aspects of fluid mechanics, especially in bubbly flows.

“We’re interested in how these bubbles move and their relationship to industrial applications and in nature,” Zenit said.

Holger Schmidt's lab develops unique, highly sensitive devices to detect pathogen biomarkers. (photo by Nick Gonzales)
Holger Schmidt's lab develops unique, highly sensitive devices to detect pathogen biomarkers. (photo by Nick Gonzales)

UCSC prof Schmidt creates a deep neural network that provides robust detection of disease biomarkers in real time

Sophisticated systems for the detection of biomarkers — molecules such as DNA or proteins that indicate the presence of a disease — are crucial for real-time diagnostic and disease-monitoring devices.

The lab's work includes the development of both hardware and software for high-accuracy biomarker detection. Holger Schmidt, a distinguished professor of electrical and computer engineering at UC Santa Cruz, and his group have long been focused on developing unique, highly sensitive devices called optofluidic chips to detect biomarkers.  

Schmidt’s graduate student Vahid Ganjalizadeh led an effort to use machine learning to enhance their systems by improving its ability to classify biomarkers accurately. The deep neural network he developed classifies particle signals with 99.8 percent accuracy in real-time, on a system that is relatively cheap and portable for point-of-care applications.

When taking biomarker detectors into the field or a point-of-care setting such as a health clinic, the signals received by the sensors may not be as high quality as those in a lab or a controlled environment. This may be due to various factors, such as the need to use cheaper chips to bring down costs, or environmental characteristics such as temperature and humidity. 

To address the challenges of a weak signal, Schmidt and his team developed a deep neural network that can identify the source of that weak signal with high confidence. The researchers trained the neural network with known training signals, teaching it to recognize potential variations it could see so that it can recognize patterns and identify new signals with very high accuracy. 

First, a parallel cluster wavelet analysis (PCWA) approach designed in Schmidt’s lab detects that a signal is present. Then, the neural network processes the potentially weak or noisy signal, identifying its source. This system works in real-time, so users are able to receive results in a fraction of a second. 

“It’s all about making the most of possibly low-quality signals, and doing that really fast and efficiently,” Schmidt said. 

A smaller version of the neural network model can run on portable devices. In the paper, the researchers run the system over a Google Coral Dev board, a relatively cheap edge device for the accelerated execution of artificial intelligence algorithms. This means the system also requires less power to execute the processing compared to other techniques. 

“Unlike some research that requires running on supercomputers to do high-accuracy detection, we proved that even a compact, portable, relatively cheap device can do the job for us,” Ganjalizadeh said. “It makes it available, feasible, and portable for point-of-care applications.”

The entire system is designed to be used completely locally, meaning the data processing can happen without internet access, unlike other systems that rely on cloud supercomputing. This also provides a data security advantage, because results can be produced without the need to share data with a cloud server provider. 

It is also designed to be able to give results on a mobile device, eliminating the need to bring a laptop into the field. 

“You can build a more robust system that you could take out to under-resourced or less-developed regions, and it still works,” Schmidt said.  

This improved system will work for any other biomarkers Schmidt’s lab’s systems have been used to detect in the past, such as COVID-19, Ebola, flu, and cancer biomarkers. Although they are currently focused on medical applications, the system could potentially be adapted for the detection of any type of signal. 

To push the technology further, Schmidt and his lab members plan to add dynamic signal processing capabilities to their devices. This will simplify the system and combine the processing techniques needed to detect signals at both low and high concentrations of molecules. The team is also working to bring discrete parts of the setup into the integrated design of the optofluidic chip.

Webb finds water vapor, but from a rocky planet or its star?

The most common stars in the universe are red dwarf stars, which means that rocky exoplanets are most likely to be found orbiting such a star. Red dwarf stars are cool, so a planet has to hug it in a tight orbit to stay warm enough to potentially host liquid water (meaning it lies in the habitable zone). Such stars are also active, particularly when they are young, releasing ultraviolet and X-ray radiation that could destroy planetary atmospheres. As a result, one important open question in astronomy is whether a rocky planet could maintain, or re-establish, an atmosphere in such a harsh environment. 

To help answer that question, astronomers used NASA’s James Webb Space Telescope to study a rocky exoplanet known as GJ 486 b. It is too close to its star to be within the habitable zone, with a surface temperature of about 800 degrees Fahrenheit (430 degrees Celsius). And yet, their observations using Webb’s Near-Infrared Spectrograph (NIRSpec) show hints of water vapor. If the water vapor is associated with the planet, that would indicate that it has an atmosphere despite its scorching temperature and proximity to its star. Water vapor has been seen on gaseous exoplanets before, but to date, no atmosphere has been definitely detected around a rocky exoplanet. However, the team cautions that the water vapor could be on the star itself – specifically, in cool starspots – and not from the planet at all.

“We see a signal, and it’s almost certainly due to water. But we can't tell yet if that water is part of the planet's atmosphere, meaning the planet has an atmosphere, or if we’re just seeing a water signature coming from the star,” said Sarah Moran of the University of Arizona in Tucson, lead author of the study.

“Water vapor in an atmosphere on a hot rocky planet would represent a breakthrough for exoplanet science. But we must be careful and make sure that the star is not the culprit,” added Kevin Stevenson of the Johns Hopkins University Applied Physics Laboratory in Laurel, Maryland, principal investigator on the program.

GJ 486 b is about 30% larger than Earth and three times as massive, which means it is a rocky world with stronger gravity than Earth. It orbits a red dwarf star in just under 1.5 Earth days. It is expected to be tidally locked, with a permanent day side and a permanent night side.

GJ 486 b transits its star, crossing in front of the star from our point of view. If it has an atmosphere, then when it transits starlight would filter through those gasses, imprinting fingerprints in the light that allow astronomers to decode its composition through a technique called transmission spectroscopy.

The team observed two transits, each lasting about an hour. They then used three different methods to analyze the resulting data. The results from all three are consistent in that they show a mostly flat spectrum with an intriguing rise at the shortest infrared wavelengths. The team ran supercomputer models considering several different molecules and concluded that the most likely source of the signal was water vapor.

While the water vapor could potentially indicate the presence of an atmosphere on GJ 486 b, an equally plausible explanation is water vapor from the star. Surprisingly, even in our own Sun, water vapor can sometimes exist in sunspots because these spots are very cool compared to the surrounding surface of the star. GJ 486 b’s host star is much cooler than the Sun, so even more water vapor would concentrate within its starspots. As a result, it could create a signal that mimics a planetary atmosphere.

“We didn't observe evidence of the planet crossing any starspots during the transits. But that doesn't mean that there aren't spots elsewhere on the star. And that's exactly the physical scenario that would imprint this water signal into the data and could wind up looking like a planetary atmosphere,” explained Ryan MacDonald of the University of Michigan in Ann Arbor, one of the study’s co-authors.

A water vapor atmosphere would be expected to gradually erode due to stellar heating and irradiation. As a result, if an atmosphere is present, it would likely have to be constantly replenished by volcanoes ejecting steam from the planet’s interior. If the water is indeed in the planet’s atmosphere, additional observations are needed to narrow down how much water is present.

Future Webb observations may shed more light on this system. An upcoming Webb program will use the Mid-Infrared Instrument (MIRI) to observe the planet’s day side. If the planet has no atmosphere or only a thin atmosphere, then the hottest part of the day side is expected to be directly under the star. However, if the hottest point is shifted, that would indicate an atmosphere that can circulate heat.

Ultimately, observations at shorter infrared wavelengths by another Webb instrument, the Near-Infrared Imager and Slitless Spectrograph (NIRISS), will be needed to differentiate between the planetary atmosphere and starspot scenarios.

“It’s joining multiple instruments together that will pin down whether or not this planet has an atmosphere,” said Stevenson.