Publisher Health

Pancreatic cancer is the third deadliest cancer in the United States, after lung and colorectal, though far less common. It is also among the hardest to effectively treat, with pancreatic cancer stem cells quickly developing resistance to conventional and targeted treatments, such as chemotherapy and emerging immunotherapies. As a result, the 5-year survival rate for people diagnosed with pancreatic cancer is just 10%.
In a new paper, published January 18, 2023 in Nature Communications, an international team of scientists, led by researchers at University of California San Diego School of Medicine and the Sanford Consortium for Regenerative Medicine, reveal another way in which the most-resistant pancreatic cancer cells defy treatment by leveraging a member of a group of proteins that ordinarily might suppress tumors to instead help cancer cells evade therapy and grow more quickly.
Previous research has shown that pancreatic cancer treatment resistance is caused by differing responses to conventional agents, fueled by the heterogeneity (diversity) of tumor cells — and in particular, stem cell characteristics that encourage therapy resistance.
In the new study, senior author Tannishtha Reya, PhD, formerly a professor of Pharmacology and Medicine and director of the Division of Cancer Biology at UC San Diego School of Medicine, and colleagues investigated how shifting epigenomics (the multitude of proteins that tell the genome what to do) rather than genomic changes (specific to the genes themselves) might be driving resistance.
“Pancreatic cancer stem cells, which are aggressive cancer cells that can resist conventional therapies and drive tumor relapse, rely upon epigenetic regulation to protect themselves and promote survival and growth,” said Reya, now a professor of Physiology and Cellular Biophysics at Columbia University and associate director of translational research at the Herbert Irving Comprehensive Cancer Center.
“We wanted to identify the underlying tools and mechanisms that cancer stem cells use to better understand treatment resistance — and perhaps how they might be circumvented.”
Reya and colleagues zeroed in on SMARCD3, a member of the SWI/SNF family of proteins that regulate chromatin, a mixture of DNA and proteins that form chromosomes and are required for stem cell function in development.
But while SWI-SNF subunits often act as tumor suppressors, the researchers found that SMARCD3 was amplified in cancer, notably abundant in pancreatic cancer stem cells and upregulated or increased in the human disease.
And when researchers deleted SMARCD3 in models of pancreatic cancer, the loss of the protein reduced the growth of tumors and improved survival, especially in the context of chemotherapy.
“Importantly, we found that SMARCD3 helps control lipid and fatty acid metabolism, which are associated with therapy resistance and poor prognosis in cancer,” said Reya.
“Our data suggest that therapy resistant pancreatic cancer cells depend upon SMARCD3 to help ensure a metabolic landscape in which they can avoid anti-cancer treatments and grow aggressively. That makes SMARCD3 an exciting new target for potential therapies.”
Co-authors include: L. Paige Ferguson, Matthew L. McDermott, Mari Nakamura, Kendall Chambers, Nirakar Rajbhandari and Michael Hamilton, all at UC San Diego and Sanford Consortium for Regenerative Medicine; Jovylyn Gatchalian, Nikki K. Lytle and Diana C. Hargreaves, Salk Institute for Biological Studies; Sara Brin Rosenthal and Vera Vavinskaya, UC San Diego; Sonia Albini, Université Paris-Saclay, Univ Evry, Inserm, Genethon, Integrare; Martin Wartenberg, Inti Zlobec and José A. Galván, Eva Karamitopoulou, all at University of Bern, Switzerland; Alexis Wascher and Andrew M. Lowy, UC San Diego and Moores Cancer Center; Christian M. Schürch, University Hospital and Comprehensive Cancer Center Tübingen, Germany; Pier Lorenzo Puri, Sanford Burnham Prebys Medical Discovery Institute; and Benoit G. Bruneau, UC San Francisco.

The evolutionary secrets that enable the medicinal herb known as barbed skullcap to produce cancer fighting compounds have been unlocked by a collaboration of UK and Chinese researchers.
The CEPAMS collaboration used DNA sequencing technology to assemble the genomic sequence of skullcap (Scutellaria barbata) known in China as banzhilian.
This gave researchers the genetic information — a microevolutionary history — required to identify how the plant produces the compound scutebarbatine A, which acts against a range of cancer cells.
Professor Cathie Martin, Group Leader at the John Innes Centre, and one of the authors of the study said, “We have found that the primary metabolite has activity against cancer cells but not non cancer cells which is especially important for an anti-cancer metabolite. Now we are looking to develop synthetic methods for producing more of the lead compound.”
In Traditional Chinese Medicine (TCM), to isolate medicinal chemistry from the plant, the herb is boiled in water for two hours and extract is dried to produce a powder and taken as a decoction (concentrated liquid).Now, with the knowledge of the genes that make up the biochemical pathway behind the anti-cancer activity of the herb, researchers are close to being able to synthesise larger quantities of compounds more rapidly and sustainably by using a host such as yeast.
The research which appears in the journal Molecular Plant is led by CEPAMS, a partnership between the John Innes Centre and the Chinese Academy of Science and supported by The Royal Society.
“This is a fantastic collaboration about developing interesting drug leads from natural resources and shows the practical value of focusing on the microevolution of a species” said Professor Martin.
The Skullcap genus has been used for centuries in TCM for treatment of different medical conditions. Clinical work has shown that preparations based on Scutellaria barbata during chemotherapy can reduce the risk of metastatic tumors.
CEPAMS Group Leader based at Shanghai Dr Evangelos Tatsis said, “Natural products have long been the lead compounds for the discovery of new drugs. By following the trail of the traditional Chinese plants, we can develop new anti-cancer medicines and this research marks a crucial step in that direction.”
Plant-based traditional medicines have long been used to provide leads for the new drug discovery, and plant natural products like vinblastine and taxol are used clinically as anticancer drugs.
TCM is one of the best catalogued systems with empirical information about the therapeutic properties of herbal remedies.
Anti-cancer drugs obtained from traditional Chinese medicine have higher efficacy than chemical synthetic drugs and with less toxic side effects. The genomes of medicinal skullcaps reveal the polyphyletic origins of clerodane diterpene biosynthesis in the family Laminiaceae, is published in Molecular Plant

Graphene-based olfactory sensors that can detect odor molecules based on the design of peptide sequences were recently demonstrated by researchers at Tokyo Tech. The findings indicated that graphene field-effect transistors (GFETs) functionalized with designable peptides can be used to develop electronic devices that mimic olfactory receptors and emulate the sense of smell by selectively detecting odor molecules.
Olfactory sensing or odor sensing is an integral part of many industries including healthcare, food, cosmetics, and environmental monitoring. At present, the most commonly used technique for detecting and estimating odor molecules is gas chromatography-mass spectrometry (GC-MS). Though very effective, GC-MS has some limitations, such as its bulky setup and limited sensitivity. As a consequence, scientists have been looking for more sensitive and easy-to-use alternatives.
In recent years, graphene field-effect transistors (GFETs) have begun being used to develop highly sensitive and selective odor sensors by integrating with olfactory receptors, also known as electronic noses. The atomically flat surfaces and high electron mobility of graphene surfaces make GFETs ideal for adsorbing odor molecules. However, the application of GFET as electrical biosensors with the receptors is severely limited by factors, such as the fragility of receptors and the lack of altanative synthetic molecules that can function as olfactory receptors.
A team of researchers from Tokyo Institute of Technology (Tokyo Tech) led by Prof. Yuhei Hayamizu set out to address these issues with GFET-based olfactory receptors. In their recent study published in Biosensors and Bioelectronics, the team designed and developed three new peptides for graphene biosensors that can detect odor molecules. Prof. Hayamizu explains “The sequence of peptides we designed needed to perform two main functions — acting as a biomolecular scaffold for self-assembly on a graphene surface and functioning as a bio-probe to bind the odor molecules. This would allow the peptides to cover the graphene surface in a self-assembling manner and functionalize the surface uniformly to capture odor molecules.”
The team carried out atomic force microscopy which showed that the peptides uniformly covered the graphene surface with the thickness of a single molecule. The functionalized graphene was then used to build a GFET setup for detecting odor molecules. After the assembly, the team injected limonene, menthol, and methyl salicylate as representative odor molecules into the GFET. The electrochemical measurements indicated that binding with the odor molecules reduced the conductivity of the graphene. The observations also revealed that the interaction between the three peptide sequences and the odor molecule gave rise to very distinct signatures. This confirmed that the GFET’s response to the odor molecules depended on the peptide design.
Furthermore, the team carried out real-time electrical measurements to monitor the kinetic response of the GFET. The observations indicated that the time constraint associated with the adsorption and desorption of odor molecules was unique for each of the peptide sequences. This behavior was further confirmed by principal component analysis. These observations confirmed that the new GFET setup was successful in electrically detecting the odor molecules with the help of the designed peptides.
“Our approach is simple and can be scaled up for mass production of peptide-based olfactory receptors that can mimic and miniaturize the natural protein receptors responsible for our sense of smell. We are a step closer to realizing the concept of electronic noses,” says Prof. Hayamizu.
The robust approach presented in this study opens new doors for the development of highly selective and sensitive GFET-based odor-sensing systems. These insights can also be put to use when designing advanced peptide sensors that can carry out multi-dimensional analysis of a range of odor molecules.

People with irritable bowel syndrome (IBS) have lower bacterial diversity in the intestine than do healthy people, according to a team of Korean investigators. The investigators believe that theirs is the first analysis to find a clear association between IBS and reduced diversity in the microbiota of the gut. The research appears in Microbiology Spectrum, an open-access journal of the American Society for Microbiology.
Normally, “More than 10,000 species of microorganism live in the human intestine,” said corresponding author Jung Ok Shim, M.D., Ph.D., professor of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Korea University College of Medicine, Seoul. Disruption of the microbiome of the human gastrointestinal tract can trigger IBS. Typically, IBS causes bloating, diarrhea, and stomach pain or cramps.
Previous studies of gut bacteria in patients with IBS have been controversial, with inconsistent results, due to small sample size and lack of consistent analytical methods used among these studies, said Shim. The investigators combined their own dataset with 9 published, shared datasets, encompassing 576 IBS patients and 487 healthy controls, analyzing them with a “unified data processing and analytical method.”
The researchers found that the gut bacterial community is less diverse in IBS patients than in healthy people, said Shim. Additionally, the abundance of 21 bacterial species differed between IBS patients and healthy controls. However, the findings were not statistically significant in the pediatric cohort due to small sample size.
The investigators proved that the disturbed gut bacterial community “is associated with IBS, though this does not mean that the relationship is causal,” said Shim. “Functional studies are needed to prove whether the change in gut micro-organisms contributes to development of IBS.”
Even though IBS is a common disorder, its pathogenesis remains unknown, and as yet there is no effective treatment strategy. “Based on the epidemiological studies of IBS patients, altered gut microbiota was proposed as one of the possible causes of IBS,” the researchers write. “Acute bacterial gastroenteritis can cause chronic, asymptomatic, low-grade intestinal wall inflammation sufficient to alter neuromuscular and epithelial cell function.”

Seeking to better understand more about the origins and movement of bubonic plague, in ancient and contemporary times, researchers at McMaster University, University of Sydney and the University of Melbourne, have completed a painstaking granular examination of hundreds of modern and ancient genome sequences, creating the largest analysis of its kind.
Despite massive advances in DNA technology and analysis, the origin, evolution and dissemination of the plague remain notoriously difficult to pinpoint.
The plague is responsible for the two largest and most deadly pandemics in human history. However, the ebb and flow of these, why some die out and others persist for years has confounded scientists.
In a paper published today in the journal Communications Biology, McMaster researchers use comprehensive data and analysis to chart what they can about the highly complex history of Y. pestis, the bacterium that causes plague.
The research features an analysis of more than 600 genome sequences from around the globe, spanning the plague’s first emergence in humans 5,000 years ago, the plague of Justinian, the medieval Black Death and the current (or third) Pandemic, which began in the early 20th century.
“The plague was the largest pandemic and biggest mortality event in human history. When it emerged and from what host may shed light on where it came from, why it continually erupted over hundreds of years and died out in some locales but persisted in others. And ultimately, why it killed so many people,” explains evolutionary geneticist Hendrik Poinar, director of McMaster’s Ancient DNA Centre.

Poinar is a principal investigator with the Michael G. DeGroote Institute for Infectious Disease Research and McMaster’s Global Nexus for Pandemics & Biological Threats.
The team studied genomes from strains with a worldwide distribution and of different ages and determined that Y. pestis has an unstable molecular clock. This makes it particularly difficult to measure the rate at which mutations accumulate in its genome over time, which are then used to calculate dates of emergence.
Because Y. pestis evolves at a very slow pace, it is almost impossible to determine exactly where it originated.
Humans and rodents have carried the pathogen around the globe through travel and trade, allowing it to spread faster than its genome evolved. Genomic sequences found in Russia, Spain, England, Italy and Turkey, despite being separated by years are all identical, for example, creating enormous challenges to determining the route of transmission.
To address the problem, researchers developed a new method for distinguishing specific populations of Y. pestis, enabling them to identify and date five populations throughout history, including the most famous ancient pandemic lineages which they now estimate had emerged decades or even centuries before the pandemic was historically documented in Europe.
“You can’t think of the plague as just a single bacterium,” explains Poinar. “Context is hugely important, which is shown by our data and analysis.”
To properly reconstruct pandemics of our past, present, and future, historical, ecological, environmental, social and cultural contexts are equally significant.
He explains that genetic evidence alone is not enough to reconstruct the timing and spread of short-term plague pandemics, which has implications for future research related to past pandemics and the progression of ongoing outbreaks such as COVID-19.

A University of Maryland-led team of scientists has deciphered the first comprehensive, continuous genome for a parasite responsible for transmitting Lyme disease and other serious infections to hundreds of thousands of Americans yearly. With their newly described genome for the black-legged tick, or deer tick, the researchers identified thousands of novel genes and new protein functions, including proteins associated with tick immunity, disease transmission and developmental stages.
This work provides valuable information for developing interventions for various tick-borne diseases, far surpassing previous efforts to sequence the tick’s genome, which resulted in partial genomes or fragments of genome with gaps and uncertainties.
The study was published January 19, 2023, in the journal Nature Genetics and was made possible by close collaborations between multiple academic institutions, industry and federal institutions.
“We are really excited to have this reference genome now, because there are so many unanswered questions about how these parasites evolved and transmit disease,” said Utpal Pal, senior author of the study and a professor in the Virginia-Maryland College of Veterinary Medicine at College Park. “We believe there are genetic factors that contribute to why these ticks are so good as disease vectors, but we can’t really understand it without a very good genome like this.”
Black-legged ticks (Ixodes scapularis) or closely-related species are widespread throughout North America, Europe, North Africa and Asia. They are the primary vectors of a number of diseases, including Lyme disease, which infects nearly half a million Americans annually. Yet many aspects of their biology remain unknown.
With a complete genome, scientists can begin to unravel the molecular mechanisms behind many aspects of the parasite’s biology and its interactions with both hosts and the diseases it transmits.

A black-legged tick’s genome is made up of more than 2 billion discrete pieces of DNA code (expressed as combinations of four nucleotides represented by the letters ATCG). Like letters that are bundled together to form words in a sentence, the DNA codes are bundled into genes that make up the genome.
Previous work to decipher the tick genome used many immature ticks or tick cells that had been grown in laboratories for multiple generations, which introduced errors, or combined samples from multiple individual ticks, resulting in fragmented bundles of code with many redundant snippets. Researchers had to reassemble the snippets, determining where each gene begins and ends and how they should be arranged.
To overcome these challenges, Pal and his colleagues combined two methods to sequence the genome of a single tick. One method deciphered the entire genome at once, creating a sequence that was complete, but a bit “fuzzy,” meaning the code wasn’t clear in many places. In the second method, the researchers used a common technique called Polymerase chain reaction or PCR to “amplify” small segments of the genome so it could be read more clearly. The team then combined the two results, which was a little like using a fuzzy, big picture image as a reference for assembling high-resolution puzzle pieces. Finally, the researchers used a technique called “Hi-C” to bridge small pieces of DNA into longer, contiguous threads.
The result is a high-quality, contiguous genome that is 98% complete. The new genome revealed that 40% of the annotations previously described for the black-legged tick relied on older technology and needed updating.
Next, the researchers compared their complete genome to snippets of genomes sequenced from 51 wild-caught ticks, showing that the new work could be used as a reference for identifying segments of genetic material from other individuals. This also identified unrecognized genetic diversity among groups of ticks from different regions in the U.S.
Finally, the team analyzed their tick genome to identify thousands of new genes and proteins and describe new critical functions of those genes. For example, in one experiment, they found some proteins were only present during certain phases of a tick’s life cycle or at specific stages during a tick’s blood meal and digestion. By knocking out a gene that tells tick cells to make one of those proteins, they were able to disrupt the tick’s feeding and digestion process.
Future work like this could help target gene-based therapies and vaccines that interrupt some part of the disease transmission cycle between ticks and humans.
An additional outcome of the study was that the researchers identified and described a more comprehensive genome for Rickettsia buchneri, the pathogenic bacteria that causes rickettsiosis.
The genomic resources described in the paper are publicly available through major databases and will be helpful in advancing tick research and preventive measures.

Medical science has not yet been able to explain why the Epstein-Barr virus triggers infectious mononucleosis (IM) in some people with initial infections and not in others. But now, a research team led by Elisabeth Puchhammer-Stöckl, head of the Center for Virology at MedUni Vienna, has identified a specific immune response to the virus as the cause, and as a potential target for the development of vaccines. The findings were recently published in the American Society of Hematology’s journal Blood.
Proliferation of the Epstein-Barr virus (EBV) in humans is normally combated by T cells as part of an antiviral immune response. By means of this important mechanism, certain EBV components (peptides) are presented to the T cells by a specific molecule (HLA-E), which is found on the surface of cells infected with EBV. This triggers a non-classical T-cell response that leads to the destruction of the infected cells. Due to a genetic variation (HLA-E*0103/0103), about one third of the population naturally has more HLA-E molecules on EBV-infected cells.
A recently published study has shown that the risk of developing IM following first-time infection with the Epstein-Barr virus depends strongly on this EBV-specific immune response. The investigation was conducted by a research team led by Elisabeth Puchhammer-Stöckl, head of the Center for Virology at MedUni Vienna, working in collaboration with colleagues from MedUni Vienna’s Department of Thoracic Surgery and Department of Medicine III, as well as researchers from the Erasmus University Medical Center in Rotterdam. “Our research revealed that people with the HLA-E*0103/0103 genetic variation have a lower risk of developing infectious mononucleosis than those who do not have the variation. Our experiments in the lab showed that this gene variation is associated with a highly pronounced EBV-specific -non-classical — immune response,” explained Hannes Vietzen from MedUni Vienna’s Center for Virology, the first author of the study.
Preventive and diagnostic possibilities
Of all the viral infections that affect humans, EBV is one of the most common. On initial infection, the virus causes IM in some children and young adults; this disease is characterised by non-specific symptoms, such as fever, as well as exhaustion that in some cases can last for several months. Until now, it was unclear why a first-time EBV infection only leads to IM in a minority of people, while most do not present any symptoms whatsoever. The researchers have not only identified the EBV-specific immune response as the cause of this phenomenon — the response could also be a prospective target for research into preventive measures: “This immune response was still measurable years after the initial EBV infection and generally provides long-lasting protection against reinfection with Epstein-Barr, so it might be worth focusing our attention on this mechanism with a view to developing new vaccines in future,” said Hannes Vietzen, looking ahead.
Another finding from the study could also open up new diagnostic options: “The combination of the unfavourable HLA-E genetic variation with certain EBV peptides also appears to play an important role in the development of EBV-associated lymphomas in transplant recipients,” Hannes Vietzen commented. “Analysis of the EBV strains found in these patients could be helpful in identifying high-risk patients at an early stage and treating them in good time.”

In the United States, turning 45 brings with it a rather unpleasant rite of passage: the beginning of regular colonoscopies, in which an endoscope equipped with a light and a camera is used to visually check the colon for signs of cancer. Relatively slow-growing, colorectal cancer can often be treated surgically if caught early. However, it becomes more difficult to treat the longer it lurks undetected, making it the fourth leading cause of cancer-related deaths in the country.
Despite the availability of this highly visual screening process, treatment decisions for individual patients are still largely guided by traditional histology — pathologists assess colorectal cancer by examining slides of tumor samples under a microscope.
Now, a team at Harvard Medical School has combined histology with cutting-edge single-cell imaging technologies to create large-scale 2D and 3D spatial maps of colorectal cancer. The maps, described in Cell, layer extensive molecular information on top of histological features to provide new information about the structure of the cancer, as well as how it forms, progresses, and interacts with the immune system.
“Our approach provides a molecular window into 150 years of diagnostic pathology — and reveals that many of the elements and structures traditionally thought to be isolated are actually interconnected in unexpected ways,” said co-senior author Peter Sorger, the Otto Krayer Professor of Systems Pharmacology in the Blavatnik Institute at HMS. “An analogy is that before we were just looking at the tail or the foot of the elephant, but now, for the first time, we can start to see the whole elephant at once.”
The maps are part of the team’s broader efforts to create atlases for different cancer types that will be freely available to the scientific community as part of the National Cancer Institute’s Human Tumor Atlas Network. Previously, the researchers used a similar approach to create in-depth maps of early-stage melanoma, and maps for other cancers are already in development. Ultimately, the team hopes that these cancer atlases will propel research and improve diagnosis and treatment.
Combining old and new
Histology has long been the cornerstone of cancer diagnosis and treatment: Pathologists examine a tumor sample stained with hematoxylin and eosin (H&E) under a microscope and pick out key features to determine the grade and stage of the cancer. This information is used by oncologists to develop a treatment plan, which usually involves some combination of surgery, drugs, and radiation. H&E-based histology is relatively simple, cheap, fast, and can reveal a lot about a tumor.

“Our existing maps of colorectal cancer originate in pathology — over the course of 150 years, we’ve figured out the most important H&E features for diagnosing a patient,” said co-senior author Sandro Santagata, HMS associate professor of systems biology and associate professor of pathology at Brigham and Women’s Hospital.
However, traditional histology has its limits — namely, it doesn’t capture a cancer’s molecular makeup or physical structure, which makes it difficult to fully take advantage of the information cancer researchers have gained over the past 50 years.
“Histology is extremely powerful, but we often don’t know what it means in modern molecular terms,” Sorger said.
In the new paper, the researchers combined histology with single-cell molecular imaging data acquired through a multiplexed imaging technique called cyclic immunofluorescence, or CyCIF. They used this information to create detailed 2D maps of large regions of colorectal cancer. First author Jia-Ren Lin, platform director in the Laboratory of Systems Pharmacology at HMS, led an effort to stitch these maps together to form a large-scale 3D reconstruction of a tumor.
“Our maps include information on almost 100 million cells from large pieces of tumors, and provide a rather unprecedented look at colorectal cancer,” Santagata said. They allow researchers to start asking key questions about differences between normal and tumor tissues and variation within a tumor, he added, and reveal “exciting architectural features that had never been observed before, as well as molecular changes associated with these features.”
The maps showed that a single tumor can have more and less invasive sections, and more or less malignant-looking regions — resulting in histological and molecular gradients where one part of a tumor transitions into the next.

“Within each tumor, there is a wide range of properties of colorectal cancer — we see many different regions and neighborhoods that have distinct characteristics, as well as the transitions between them,” Santagata said. From here, he added, scientists can now explore what drives these differences within individual tumors.
For example, the maps showed that immune environments varied dramatically within a single tumor.
“They were as different across a single tumor as among tumors — which is important because tumor-immune interactions are what you are trying to target with immunotherapy,” Sorger said. Similar to their finding in melanoma, the researchers observed that the T cells tasked with fighting off the cancer were not directly suppressed by tumor cells, but rather by other immune cells in the environment around the tumor.
“This gives us a whole new appreciation for how diverse and plastic the tumor environments are — they are rich communities, and we are now better equipped to figure out how they develop,” Santagata said.
The maps also provided new insights into the architecture of the tumors. For example, scientists had previously identified what they thought were 2D pools of a mucus-like substance called mucin with clusters of cancer cells floating inside. However, in the new study, the 3D reconstruction revealed that these mucin pools are, in fact, a series of caverns interconnected by channels, with finger-like projections of cancer cells.
“It’s a wild, new look at these tumor structures that we never really appreciated before,” Santagata said. “Because we can see them in 3D, we have a crisp, clean view of the structures, and we can now study why they are there, how they form, and how they shape tumor evolution.”
Translating results
Ultimately, the goal of these colorectal cancer maps is the same as it is for all of the cancer atlases the team is developing: to advance research and improve diagnosis and treatment. Precision medicine, which involves tailoring therapy to an individual patient’s cancer, is becoming an increasingly important part of treatment, Sorger noted, yet it can go only so far with pathology and genetics alone.
“The big translational story here is building the knowledge to make precision medicine practical for most patients,” he said. “We are currently working with Brigham and Women’s and the Dana-Farber Cancer Institute to determine how our methods can be used in a clinical setting.”
“This is allowing us to extract a whole additional layer of molecular and structural features that we think will provide diagnostic and prognostic information and improve our ability to target these cancers,” Santagata added.
Now, the researchers want to further refine their ability to create 3D reconstructions of tumors and continue integrating new imaging technologies into their maps. They also want to build a bigger cohort of colorectal cancer samples for mapping and explore the basic biology of the disease that their maps have highlighted.
For Sorger, the project represents an unusual collaboration between pathologists, engineers, and computational scientists: As the imaging data rolled in, the computational scientists used machine learning to identify interesting findings that they presented to the pathologists, and the pathologists flagged key features to be parsed with machine learning.
“This was an extraordinarily close conversation between the computational group and the pathology group, going back and forth between the rich history of medicine known to pathologists and modern machine learning methods.” Sorger said. “I think it’s an exciting glimpse of how these computation methods can be used in medicine in the future, wherein you tightly couple biologists and physicians with computation, rather than seeing them as replacements for each other.”
The team chose melanoma and colorectal cancer as a starting point because they are common cancers with unmet medical needs that consist of large, solid tumors and require important treatment decisions. Next, the researchers plan to tackle breast cancer and brain cancer. They also want to train other scientists to use the imaging technologies to build their own cancer maps, which would pave the way for the creation of even more atlases.
“A new era in molecular pathology is beginning, and this is a deep look at a tumor that is showing us how remarkable the findings can be,” Santagata said.
Authorship, funding, disclosures
Additional authors include Shu Wang, Yu-An Chen, Clarence Yapp, Madison Tyler, and Maulik Nariya of HMS; Shannon Coy of HMS and Brigham and Women’s; and Cody Heiser and Ken Lau of Vanderbilt University School of Medicine.
Support for the research was provided by the National Institutes of Health (U54-CA225088; U2C-CA233280; U2C-CA233262; U2C-CA233291; R01-DK103831; T32-GM007748, P30-CA06516), Ludwig Cancer Research, the Gray Foundation, and the David Liposarcoma Research Initiative.
Sorger is on the board of directors of Glencoe Software and Applied BioMath, the scientific advisory board for RareCyte, NanoString, and Montai Health and is a consultant for Merck. Chen is a consultant for RareCyte.

Researchers have designed the first ‘living medicine’ to treat lung infections. The treatment targets Pseudomonas aeruginosa, a type of bacteria which is naturally resistant to many types of antibiotics and is a common source of infections in hospitals.
The treatment involves using a modified version of the bacterium Mycoplasma pneumoniae, removing its ability to cause disease and repurposing it to attack P. aeruginosa instead. The modified bacterium is used in combination with low doses of antibiotics that would otherwise not work on their own.
Researchers tested the efficacy of the treatment in mice, finding that it significantly reduced lung infections. The ‘living medicine’ doubled mouse survival rate compared to not using any treatment. Administering a single, high dose of the treatment showed no signs of toxicity in the lungs. Once the treatment had finished its course, the innate immune system cleared the modified bacteria in a period of four days.
The findings are published in the journal Nature Biotechnology and are supported by the “la Caixa” Foundation through the CaixaResearch Health call. The study was led by researchers at the Centre for Genomic Regulation (CRG) and Pulmobiotics in collaboration with the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic de Barcelona and the Institute of Agrobiotechnology (IdAB), a joint research institute of Spain’s CSIC and the government of Navarre.
P. aeruginosa infections are difficult to treat because the bacteria lives in communities that form biofilms. Biofilms can attach themselves to various surfaces in the body, forming impenetrable structures that escape the reach of antibiotics.
P. aeruginosa biofilms can grow on the surface of endotracheal tubes used by critically-ill patients who require mechanical ventilators to breathe. This causes ventilator-associated pneumonia (VAP), a condition which affects one in four (9-27%) patients who require intubation. The incidence exceeds 50% for patients intubated because of severe Covid-19. VAP can extend the duration in intensive care unit for up to thirteen days and kills up to one in eight patients (9-13%).

The authors of the study engineered M. pneumoniae to dissolve biofilms by equipping it with the ability to produce various molecules including pyocins, toxins naturally produced by bacteria to kill or inhibit the growth Pseudomonas bacterial strains. To test its efficacy, they collected P. aeruginosa biofilms from the endotracheal tubes of patients in intensive care units. They found the treatment penetrated the barrier and successfully dissolved the biofilms.
“We have developed a battering ram that lays siege to antibiotic-resistant bacteria. The treatment punches holes in their cell walls, providing crucial entry points for antibiotics to invade and clear infections at their source. We believe this is a promising new strategy to address the leading cause of mortality in hospitals,” says Dr. María Lluch, Chief Scientific Officer at Pulmobiotics, co-corresponding author of the study and principal investigator at the International University of Catalonia.
With the aim of using the ‘living medicine’ to treat VAP, the researchers will carry out further tests before reaching the clinical trial phase. The treatment is expected to be administered using a nebulizer, a?device that?turns liquid medicine into a mist which is then inhaled through a mouthpiece or a mask.
M. pneumoniae is one of the smallest known species of bacteria. Dr. Luis Serrano, Director of the CRG, first had the idea to modify the bacteria and use it as a ‘living medicine’ two decades ago. Dr. Serrano is a specialist in synthetic biology, a field that involves repurposing organisms and engineering them to have new, useful abilities. With just 684 genes and no cell wall, the relative simplicity of M. pneumoniae makes it ideal for engineering biology for specific applications.
One of the advantages of using M. pneumoniae to treat respiratory diseases is that it is naturally adapted to lung tissue. After administering the modified bacterium, it travels straight to the source of a respiratory infection, where it sets up shop like a temporary factory and produces a variety of therapeutic molecules.

By showing that M. pneumoniae can tackle infections in the lung, the study opens the door for researchers creating new strains of the bacteria to tackle other types of respiratory diseases such as lung cancer or asthma. “The bacterium can be modified with a variety of different payloads — whether these are cytokines, nanobodies or defensins. The aim is to diversify the modified bacterium’s arsenal and unlock its full potential in treating a variety of complex diseases,” says ICREA Research Professor Dr. Luis Serrano.
In addition to designing the ‘living medicine’, Dr. Serrano’s research team are also using their expertise in synthetic biology to design new proteins that can be delivered by M. pneumoniae. The team are using these proteins to target inflammation caused by P. aeruginosa infections.
Though inflammation is the body’s natural response to an infection, excessive or prolonged inflammation can damage lung tissue. The inflammatory response is orchestrated by the immune system, which release mediator proteins such as cytokines. One type of cytokine — IL-10 — has well-known anti-inflammatory properties and is of growing therapeutic interest.
Research published in the journal Molecular Systems Biology by Dr. Serrano’s research group used protein-design softwares ModelX and FoldX to engineer new versions of IL-10 purposefully optimised to treat inflammation. The cytokines were designed to be created more efficiently and to have higher affinity, meaning less cytokines are needed to have the same effect.
The researchers engineered strains of M. pneumoniae that expressed the new cytokines and tested its efficacy in the lungs of mice with acute P. aeruginosa infections. They found that engineered versions of IL-10 were significantly more effective at reducing inflammation compared to the wild type IL-10 cytokine.
According to Dr. Ariadna Montero Blay, co-corresponding author of the study in Molecular Systems Biology, “live biotherapeutics such as M. pneumoniae provide ideal vehicles to help overcome the traditional limitations of cytokines and unlock their huge potential in treating a variety of human diseases. Engineering cytokines as therapeutic molecules was critical to tackle inflammation. Other lung diseases such as asthma or pulmonary fibrosis could also stand to benefit from this approach.”

Asian diets feature rice as a staple grain, contributing towards nearly 90% of the world’s rice consumption. Brown rice, in particular, is known to have several health benefits. As a regular addition to the diet, it can help reduce body weight, lower cholesterol, and suppress inflammation. The ability of brown rice to neutralize reactive oxygen species and prevent cellular damage is vital to many of its health-promoting effects. Although previous studies have shown that the antioxidant compounds in brown rice can protect cells against oxidative stress, knowledge regarding which major compound contributes towards these beneficial properties has long remained a mystery.
In a recent study led by Professor Yoshimasa Nakamura from the Graduate School of Environmental and Life Science, Okayama University, researchers from Japan have identified cycloartenyl ferulate (CAF) as the main “cytoprotective” or cell-protecting compound in brown rice. CAF is a unique compound owing to its hybrid structure. As Professor Nakamura explains, “CAF is a hybrid compound of polyphenol and phytosterol and is expected to be a potent bioactive substance with various pharmacological properties, such as antioxidant effect and blood fat-lowering effect.”
The study published on January 3, 2023 in volume 24 issue 1 of International Journal of Molecular Sciences, was co-authored by Hongyan Wu, from Dalian Polytechnic University, and Toshiyuki Nakamura, from the Graduate School of Environmental and Life Science at Okayama University. In it, the researchers provide evidence of CAF’s antioxidant properties by demonstrating that it can protect cells from stress caused by hydrogen peroxide. Although hydrogen peroxide is a by-product of a cell’s metabolic processes, abnormal amounts of the compound can be toxic to cells and cause irreversible damage. Treatment of cells with CAF increased their resistance to toxic stress induced by hydrogen peroxide. Moreover, CAF provided greater protection from hydrogen peroxide-induced stress compared to alpha-tocopherol and gamma-tocopherol, two other prominent antioxidant compounds that were earlier speculated to be major contributors to the antioxidant capacity of brown rice.
According to the study’s estimates, the amount of CAF in the whole grain of brown rice is five-fold higher than that of other antioxidant compounds found in brown rice. Further, CAF increases the concentration of heme oxygenase-1 or HO-1, an enzyme that facilitates the production of antioxidants. “We demonstrated here that CAF significantly increased the mRNA level of HO-1, the small molecular weight antioxidant-producing enzyme, at concentrations similar to that required for cytoprotective effects in resistance to oxidative damage,” Professor Nakamura explains.
The researchers further explored this mechanism of action through experiments where blocking HO-1 activity using inhibitors reduced the antioxidant effect of CAF considerably. The high abundance and unique mechanism of action are evidence that CAF is the major contributing antioxidant in brown rice.
Through this study, the researchers have not only uncovered the secret to the health benefits of brown rice, but also locked down on the component that is majorly responsible for these benefits. This will allow the use of CAF in the development of better novel supplements and food products focused on consumer health. As an optimistic Professor Nakamura observes, “Our study can help in the development of new functional foods and supplements based on the functionality of CAFs, like CAF-based nutraceuticals.”