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Researchers in Germany Sequence Genome of Bubonic Plague Bacteria Taken from Remains of Man who Lived More than 5,000 Years Ago

Advancements in genetic sequencing continue to enable microbiologists and genetic scientists to explore the origins and mutations of deadly diseases

Microbiologists and researchers can now study the gene sequence of 5,000-year-old bubonic plague bacteria. The scientific team that achieved this feat of gene sequencing believes this is the oldest case of the ancient strain of the plague found to date.

Scientists working at the Institute of Clinical Molecular Biology (IKMB) at the Kiel University and the Centre for Baltic and Scandinavian Archaeology (ZBSA) in Germany, and at the Institute of Latvian History (LVI) at the University of Latvia, recently found remnants of Yersinia Pestis, the infectious bacterium that causes the bubonic plague, in the jawbone of a man who lived more than 5,000 years ago.

For microbiologists, this demonstrates how advances in gene sequencing technologies are allowing scientists to go further back in time to look at how the genomes of bacteria and viruses have evolved and mutated. This helps science understand the process of genetic mutation, as well as learning which mutations survived because they could more easily infect humans.

The scientists published their findings in the peer-reviewed journal Cell Reports, titled, “A 5,000-Year-Old Hunter-Gatherer Already Plagued by Yersinia Pestis

Missing Gene has ‘Dramatic Influence on Virulence’ of Plague

To conduct their study, the researchers sequenced the genomes of samples from the teeth and bones of four hunter-gatherers and tested the remains for bacterial and viral pathogens. They found evidence of Yersinia pestis (Y. pestis) in the dental remains of a 20- to 30-year-old male dubbed RV 2039.

The jaw bones used for the research were discovered in the late 1800s in the Rinnukalns, a stone age settlement unearthed in present-day Republic of Latvia in the late 19th century.

Missing Genetic Element in Ancient Bacterium

The scientists were surprised to find evidence of Y. pestis in the remains and noted that the analysis of the microbe lacked a crucial genetic element observed in later strains of the bacteria. Missing was the gene that allows biting fleas to act as vectors to spread the plague to humans.

“What’s so surprising is that we see already in this early strain more or less the complete genetic set of Y. pestis, and only a few genes are lacking,” said biochemist and archeologist Ben Krause-Kyora, Professor and head of the Ancient DNA (aDNA) Laboratory at the University of Kiel in Germany, and one of the authors of the study, in a press release.

“But even a small shift in genetic settings can have a dramatic influence on virulence,” he added.

This absent gene also is responsible for creating the pus-filled buboes associated with the Black Death (bubonic plague) that occurred in the 1300s. The Black Death killed 75 million to 200 million people worldwide, mostly in Eurasia and North Africa. It is to date the most fatal pandemic recorded in human history.

Professor Ben Krause-Kyora and colleagues

“Different pathogens and the human genome have always evolved together,” said Professor Ben Krause-Kyora (above left with and Steve Zäuner at center and Dr. Silvia Codreanu-Windauer at right), in the press release. “We know Y. pestis most likely killed half of the European population in a short time frame, so it should have a big impact on the human genome. But even before that, we see major turnover in our immune genes at the end of the Neolithic Age, and it could be that we were seeing a significant change in the pathogen landscape at that time as well,” he added. (Photo copyright: Mittelbayerische.)

A Less Lethal Bubonic Plague?

Although RV 2039 most likely perished from the bubonic plague, the researchers believe his strain of the infection was more mild, less contagious, and not as lethal as the later genetic mutations of the bacteria that caused the Black Death pandemic. The researchers concluded that the man most likely contracted the disease through a bite from an infected rodent or other animal, the press release notes.

“Isolated cases of transmission from animals to people could explain the different social environments where these ancient diseased humans are discovered,” Krause-Kyora said in the press release. “We see it in societies that are herders in the steppe, hunter-gatherers who are fishing, and in farmer communities—totally different social settings but always spontaneous occurrence of Y. pestis cases.”

From Animal Bite to Flea Infection in 7,000 Years’ Worth of Mutations

The Y. pestis bacteria that infected RV 2039, the researchers surmised, most likely split from its predecessor, Yersinia pseudotuberculosis, which first appeared on Earth about 7,000 years ago. It most likely took Y. pestis over a thousand years to acquire all the mutations necessary for flea-based transmission of the bacteria to humans, the researchers noted.

“What’s most astonishing is that we can push back the appearance of Y. pestis 2,000 years farther than previously published studies suggested,” Krause-Kyora said. “It seems that we are really close to the origin of the bacteria.”

It is unknown how many cases still occur worldwide due to unreliable diagnoses and poor reporting in developing countries. However, data from the World Health Organization (WHO) states that there were 3,248 cases of plague reported worldwide between 2010 and 2015, including 584 deaths. Currently, the three most endemic countries for plague are the Democratic Republic of the Congo, Madagascar, and Peru.

The researchers’ findings illustrate how advances in gene sequencing technologies are helping microbiologists, virologists, and genetic scientists understand the affect mutations have on diseases that have plagued humans since the beginning of humanity itself.

Will this lead to new genomic diagnostics? Perhaps. The research is worth watching.

—JP Schlingman

Related Information

What a 5,000-year-old Plague Victim Reveals about the Black Death’s Origins

A 5,000-year-old Hunter-gatherer Already Plagued by Yersinia Pestis

This 5,000-year-old Man had the Earliest Known Strain of Plague

Five Things You Might Not Know about the Plague (Not Including the Fact That it Still Exists)

Plague: Frequently Asked Questions

Plague: Key Facts

CDC Announces Presence of Rare, Tropical Illness in Three Non-adjacent States and Genetic Testing Indicates There May Be a Common Source of Exposure

Microbiologists will want to take note of the CDC’s statement that the illness can masquerade as other diseases

It is the latest example of a bacterium uncommon in the United States that has infected patients in this country—one of whom has died. The three infected patients live in separate states, but genetic analysis indicates their cases may be related.

Microbiologists and clinical laboratory managers may want to read the recent official health advisory from the Centers for Disease Control and Prevention (CDC).  It announced that the Kansas Department of Health and Environment, the Texas Department of State Health Services, and the Minnesota Department of Health, were working with the CDC to investigate “three cases of Burkholderia pseudomallei (melioidosis) infections.”

According to the health alert, “Based on genomic analysis, these three cases (one male, two females; two adults and one child) may share a potential common source of exposure. The first case, identified in March 2021, was fatal. Two other patients were identified in May 2021, one of whom is still hospitalized. One has been discharged to a transitional care unit. None of the patients’ families reported a history of traveling outside of the continental United States.”

The CDC warned, “Symptoms of melioidosis are varied and nonspecific and may include pneumonia, abscess formation, and/or blood infections. Due to its nonspecific symptoms, melioidosis can initially be mistaken for other diseases such as tuberculosis, and proper treatment may be delayed.”

Microbiology Laboratories Should Be on Alert

Melioidosis is typically only seen in subtropical and tropical regions and can be highly fatal. It is unknown how the trio of patients who contracted the illness became infected, but according to the CDC the cases do appear to be connected.

“Testing suggests a common source of infection, but that source has not yet been identified,” a CDC representative told Gizmodo. “CDC is working with states to assess exposures or products these individuals have in common, as well as environmental samples from the states where cases have been identified. Additionally, CDC experts are providing epidemiologic assistance to help investigate the cause of infection,” the CDC added.

Peter Hotez, MD, PhD

“Melioidosis is a serious neglected tropical disease of Southeast Asia, India, and Australia where it is a major cause of pneumonia, abscesses, and sepsis. The fact that it may be gaining a foothold in the US is concerning,” pediatrician Peter Hotez, MD, PhD (above), Dean of the National School of Tropical Medicine, Professor of Pediatrics and Molecular Virology and Microbiology at Baylor College of Medicine, and Director of the Center for Vaccine Development at Texas Children’s Hospital, told Gizmodo. Clinical laboratories and microbiologists will want to monitor these cases for future developments. (Photo copyright: Baylor College of Medicine.)  

Melioidosis, also called Whitmore’s disease, was first described by Alfred Whitmore, an English pathologist, in 1912 in what is now present-day Myanmar. The bacterium (Burkholderia pseudomallei) can be found in contaminated soil and water. It is predominately found in tropical climates in Southeast Asia and northern Australia and can affect humans and many species of animals.

Researchers believe the disease may be acquired through the inhalation of contaminated dust particles or water droplets, the ingestion of contaminated water or soil-contaminated food, or other contact with tainted soil, especially through skin abrasions. It is very rare to contract melioidosis from infected individuals.

Melioidosis Masquerades as Other Illnesses

The symptoms of melioidosis are wide-ranging and non-specific and can resemble those of other illnesses. In addition, there are several types of the illness, and they can each act differently depending on where the infection is in the body. The most common symptoms of melioidosis include:

Localized Infection:

  • Localized pain or swelling
  • Fever
  • Ulceration
  • Abscess

Pulmonary Infection:

  • Cough
  • Chest pain
  • High fever
  • Headache
  • Anorexia

Bloodstream Infection:

  • Fever
  • Headache
  • Respiratory distress
  • Abdominal discomfort
  • Joint pain
  • Disorientation

Disseminated Infection:

  • Fever
  • Weight loss
  • Stomach or chest pain
  • Muscle or joint pain
  • Headache
  • Central nervous system/brain infection
  • Seizures

According to the CDC, the time between an exposure to Burkholderia pseudomallei and the first emergence of Melioidosis symptoms is not clearly defined but could range from one day to many years. However, most infected individuals begin experiencing symptoms of melioidosis within two to four weeks after exposure.

Melioidosis is difficult to diagnose, and some automated bacterial reading instruments can mistake Burkholderia pseudomallei for other bacteria. It is estimated that the disease accounts for 89,000 deaths per year worldwide. Delays in diagnosis and treatment often lead to poor patient outcomes and the mortality rate can exceed 40% in some regions, Nature reported. 

The illness is typically treated with appropriate drug therapies including intravenous antimicrobial medications, such as Ceftazidime or Meropenem, followed by an oral antimicrobial therapy such as Trimethoprim-sulfamethoxazole or Amoxicillin/Clavulanic Acid. It may take several months for a patient to be cured of melioidosis, depending on the extent of the infection.

Deadly Bacterium’s Countries of Origin and Spread to the US

According to CDC data, the greatest number of melioidosis cases are reported in Thailand, Malaysia, Singapore, and northern Australia. Cases also have been reported in other Asian countries as well as Mexico and Central America.

Burkholderia pseudomallei does not occur naturally in the US, and cases of melioidosis identified in the US are usually only seen in world travelers and immigrants who come from countries where the disease is widespread. The bacterium has been found in soil in Mexico, so it is possible that it could spread to parts of the US, which has led to concern among microbiologists.

“Due to changes in weather patterns, some pathogens that normally were not present in a particular area might start causing disease,” Alfredo Torres, PhD, Associate Provost, Department of Microbiology and Immunology, University of Texas Medical Branch, told Gizmodo. “Therefore, it is important to make the health professionals aware of this pathogen and the disease that it causes, so quick identification can be done, and treatment is properly used to save lives. Without that, it might be too late for the next melioidosis patient when the proper diagnosis is done.”

The CDC has suggested that healthcare workers consider melioidosis as a possible diagnosis for patients who have compatible symptoms, even if they have not recently traveled outside of the US.

CDC Suggests Rerunning Certain Clinical Laboratory Tests

Because Burkholderia pseudomallei can be mistaken for other bacteria, the CDC also urges the rerunning of clinical laboratory tests using automated identification, especially if another bacterium that is often mistaken for Burkholderia pseudomallei is present, Gizmodo noted.

“CDC encourages healthcare workers to be aware of the potential for more cases and to report cases to their state health departments,” the CDC stated.

The CDC considers the risk of melioidosis to the public in the US to be low, and that the chances of a potential outbreak are unlikely. However, the origins of these three cases remain a mystery and warrant further investigation.

Microbiologists and clinical laboratories should be aware of and remain alert about this potentially fatal illness. It is possible that more cases will arise in the future, especially in the three states where it has already been found.

—JP Schlingman

Related Information

CDC Warns Doctors about a Mystery Bacterial Outbreak with No Clear Origin

CDC: Melioidosis

What is Melioidosis? CDC Investigates Three Cases of Rare Bacterial Infection in the US

CDC Probes How People Contracted a Dangerous Infection Found in the Tropics—without Leaving the US

Nature Reviews Disease Primers: Melioidosis

Potentially Fatal Fungus Invades Hospitals and Public Is Not Informed

Cancer Researchers Use Astronomy Analysis Algorithms to Develop Platform for Locating and Examining Predictive Biomarkers in Tumors

Yet another example that technologies from non-medical fields continue to find their way into anatomic pathology and clinical laboratory medicine

Anatomic pathologists and medical laboratory scientists may soon have new tools in the fight against cancer, thanks to researchers at the Mark Foundation Center for Advanced Genomics and Imaging at Johns Hopkins University and Bloomberg-Kimmel Institute for Cancer Immunotherapy.

Using algorithmic technology designed for mapping the stars, the scientists have created an imaging/spatial location platform called AstroPath which may help oncologists develop immunotherapies that work best on specific cancers. Such a capability is key to effective precision medicine techniques.

Dark Daily has regularly pointed out that technologies developed in other fields of science will eventually be brought into anatomic pathology and clinical laboratory medicine. Use of the star-mapping technology in oncology and the diagnosis of cancer is one such example.

In “Analysis of Multispectral Imaging with the AstroPath Platform Informs Efficacy of PD-1 Blockade,” published in the journal Science, the multi-institution research team wrote, “Here, we present the AstroPath platform, an end-to-end pathology workflow with rigorous quality control for creating quantitative, spatially resolved mIF [multiplex immunofluorescence] datasets. Although the current effort focused on a six-plex mIF assay, the principles described here provide a general framework for the development of any multiplex assay with single-cell image resolution. Such approaches will vastly improve the standardization and scalability of these technologies, enabling cross-site and cross-study comparisons. This will be essential for multiplex imaging technologies to realize their potential as biomarker discovery platforms and ultimately as standard diagnostic tests for clinical therapeutic decision-making.

“Drawing from the field of astronomy, in which petabytes of imaging data are routinely analyzed across a wide spectral range, [the researchers] developed a platform for multispectral imaging of whole-tumor sections with high-fidelity single-cell resolution. The resultant AstroPath platform was used to develop a multiplex immunofluorescent assay highly predictive of responses and outcomes for melanoma patients receiving immunotherapy,” the researchers added.

Using Star Mapping Software to Fight Cancer

“The application of advanced mapping techniques from astronomy has the potential to identify predictive biomarkers that will help physicians design precise immunotherapy treatments for individual cancer patients,” said Michele Cleary, PhD, CEO of the Mark Foundation for Cancer Research, in a Johns Hopkins news release.

Although the universe we live in and the universe of a cancerous tumor may not seem related, the fact is the same visualization technology can be used to map them both.

“What should be pointed out is that astronomy is mapping the sky in three dimensions, so keeping the spatial relationships while also identify each heavenly body is the goal of these algorithms,” said Robert Michel, Publisher and Editor-in-Chief of Dark Daily and its sister publication The Dark Report.

“Both aspects of that information technology have value in surgical pathology, where the spatial relationship of different cells and cell structures is relevant and important while also having the ability to identify and characterize different types of cells and cell structures. This technology appears to also be capable of identifying multiple biomarkers,” he added.

AstroPath graphic

The image above, taken from the researchers’ Science paper, illustrates the “strong parallels between multispectral analyses in astronomy and emerging multiplexing platforms for pathology.” The researchers wrote, “the next generation of tissue-based biomarkers are likely to be identified by use of large, well-curated datasets. To that end, image analysis approaches originally developed for astronomy were applied to pathology specimens to produce trillions of pixels of robust tissue imaging data and facilitate assay and atlas development.” Anatomic pathologists may be direct recipients of new cancer diagnostic tools based on the AstroPath platform. (Photo copyrights: Johns Hopkins University/Mark Foundation Center for Advanced Genomics/Bloomberg-Kimmel Institute.)

AstroPath Provides 1,000 Times the Information Content from A Single Biopsy

According to the news release, “[The researchers] characterized the immune microenvironment in melanoma biopsies by examining the immune cells in and around the cancer cells within the tumor mass and then identified a composite biomarker that includes six markers and is highly predictive of response to a specific type of an immunotherapy called Anti-PD-1 therapy.”

This is where the use of AstroPath is truly innovative. Previously, researchers could only identify those biomarkers one at a time, through a painstaking process.

“For the last 40 years, pathology analysis of cancer has examined one marker at a time, which provides limited information,” said Drew Pardoll, MD, PhD, Director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy and a Johns Hopkins professor of oncology, in the news release. “Leveraging new technology, including instrumentation to image up to 12 markers simultaneously, the AstroPath imaging algorithms provide 1,000 times the information content from a single biopsy than is currently available through routine pathology,” he added.

More information about a cancerous tumor means clinicians have more tools to combat it. Treatment becomes less about finding the right immunotherapy and more about treating it immediately.

“This facilitates precision cancer immunotherapy—identifying the unique features of each patient’s cancer to predict who will respond to a given immunotherapy, such as anti-PD-1, and who will not. In doing so, it also advances diagnostic pathology from uniparameter to multiparameter assays,” Pardoll said.

Big Data and Data Analysis Is the Future of Precision Medicine

The use of data in science is changing how researchers, clinicians, pathologists, and others provide healthcare in the modern world. When it is properly collected and analyzed, data holds the key to precision medicine’s personalized and targeted patient care.

“Big data is changing science. There are applications everywhere, from astronomy to genomics to oceanography,” said Alexander S. Szalay, PhD, Bloomberg Distinguished Professor and Professor in the Department of Computer Science at Johns Hopkins University, and Director of the Institute for Data Intensive Engineering and Science (IDIES), in the news release.

“Data-intensive scientific discovery is a new paradigm. The technical challenge we face is how to get consistent, reproducible results when you collect data at scale. AstroPath is a step towards establishing a universal standard,” he added.

Should AstroPath prove to be a clinically safe and accurate method for developing precision medicine cancer therapies, anatomic pathologists can look forward to exciting new ways to diagnose cancer and determine the best courses of treatment based on each patient’s unique medical needs.

—Dava Stewart

Related Information

Astronomy Meets Pathology to Identify Predictive Biomarkers for Cancer Immunotherapy

Analysis of Multispectral Imaging with the AstroPath Platform Informs Efficacy of PD-1 Blockade

Astronomy Meets Pathology: An Interdisciplinary Effort to Discover Predictive Biomarker Signatures for Immuno-Oncology

From Stars to Cells: Johns Hopkins Researchers Discover Predictive Spatial Phenotypic Signatures with AstroPath

Astronomy and Pathology Join Forces to Predict Immunotherapy Response: Q/A with Spatial Biology Experts

Swiss Researchers Develop a Multi-omic Tumor Profiler to Inform Clinical Decision Support and Guide Precision Medicine Therapy for Cancer Patients

New biomarkers for cancer therapies derived from the research could usher in superior clinical laboratory diagnostics that identify a patient’s suitability for personalized drug therapies and treatments

In another advancement toward accurate precision medicine, Swiss researchers from the University Hospitals of Zurich and Basel, ETH Zurich, the University of Zurich, and pharmaceutical company Roche have developed a multi-omic tumor profiling technology for cancer patients they hope will isolate biomarkers that allow doctors to tailor drug therapies to individual patients’ medical needs.

Once approved for clinical use, not only would these biomarkers become targets for specific cancer therapies, they also would require development of new diagnostic tests that anatomic pathologists could use to determine whether a biomarker was present in a patient.

If yes, the drug can be administered. If no, the patient is not a candidate for that drug. Thus, this research may produce both diagnostic biomarkers and therapeutic targets.

The researchers published their study in the journal Cancer Cell, titled, “The Tumor Profiler Study: Integrated, Multi-omic, Functional Tumor Profiling for Clinical Decision Support.”

Relevance of In-Depth Tumor Profiling to Support Clinical Decision-Making

In the Swiss “Tumor Profiler” (TuPro) project, the research team is examining the cellular composition and biology of tumors of 240 patients with melanoma, ovarian cancer, and acute myeloid leukemia. Recruitment for the study began in 2018. Today, the melanoma cohort is fully enrolled, and the ovarian cancer and acute myeloid leukemia cohorts are nearing complete enrollment.

“The Tumor Profiler Study is an observational clinical study combining a prospective diagnostic approach to assess the relevance of in-depth tumor profiling to support clinical decision-making (“fast diagnostic loop”) with an exploratory approach to improve the biological understanding of disease (“exploratory science loop”),” the TuPro website states.

Tumor Profiler graphic

The graphic above taken from the Tumor Profiler project paper illustrates how the TuPro study’s workflow entails patient enrollment, sample collection, analysis by different technology platforms, and data integration, creation and discussion of molecular research and summary reports, discussion of treatment options in pre-tumor boards and the final treatment decision in tumor boards. (Photo copyright: Cancer Cell.)

“For this study of melanoma, ovarian carcinoma, and acute myeloid leukemia tumors, in addition to the emerging standard diagnostic approaches of targeted NGS panel sequencing and digital pathology, extensive characterization is performed using the following exploratory technologies: single-cell genomics and transcriptomics, proteotyping, CyTOF, imaging CyTOF, pharmacoscopy, and 4i drug response profiling (4i DRP),” the TuPro website explains.

In their published paper, the Swiss researchers say these three cancers were selected for the study “based on the potential clinical benefit and availability of sufficient tumor material for simultaneous analysis across all technologies.”

Gunnar Rätsch PhD

According to a University Hospital Basel blog post, the TuPro project examination of each cancer tumor goes “much further than the limited use of molecular biological methods” used by leading hospitals. “This results in huge amounts of data per patient, which we process and analyze using data science methods,” stated data scientist Gunnar Rätsch, PhD (above), Professor for Biomedical Informatics at ETH Zurich and one of the study’s corresponding authors, in the blog post. This research could lead to new precision medicine biomarkers for clinical laboratory cancer diagnostics and therapies. (Photo copyright: ETH Zurich.)

The TuPro Project’s findings are available to doctors who analyze them at interdisciplinary tumor board meetings and generate treatment options, creating a “fast diagnostic loop” with an estimated four-week turnaround time from surgery to tumor board. “This approach has the potential to alter current diagnostics and paves the way for the translation of comprehensive molecular profiling into clinical decision-making,” the study’s authors wrote in Cancer Cell.

Could Oncologists Be Making Better Precision Medicine Decisions?

In its writeup on the TuPro Project’s research, Precision Oncology News concluded that the Swiss study “is rooted in the researchers’ notion that oncologists are not making the best personalized treatment decisions for patients by relying just on targeted DNA profiling using next-generation sequencing and digital pathology-based tests.

“The researchers within the TuPro consortium hypothesized that integrating a more comprehensive suite of omics tests could lead to a more complete understanding of patients’ tumors, including providing insights into the tumor microenvironment, heterogeneity, and ex vivo responses to certain drugs. This, in turn, could help inform the best course of treatment,” Precision Oncology News added.

“With the Tumor Profiler study, we want to show that the widespread use of molecular biological methods in cancer medicine is not only feasible, but also has specific clinical benefits,” said TuPro consortium member Viola Heinzelmann-Schwarz, MD, Head of Gynecological Oncology at University Hospital Basel, in an ET Zurich news release.

New Precision Medicine Biomarkers from TuPro’s Molecular Analysis

Researchers in the study also are investigating whether and what influence the molecular analysis had on doctors’ therapy decisions.

The University Hospital Basal blog notes the long-term benefits of the Tumor Profiler approach is to expand the personalized-medicine therapy options for patients, including determining whether patients would benefit in certain cases “if they were not treated with drugs from standard therapy, but with drugs that have been approved for other types of cancer.”

Anatomic pathologists and clinical laboratory scientists will want to take note of the TuPro project’s ultimate success or failure, since it could usher in changes in cancer treatments and bring about the need for new diagnostic tests for cancer biomarkers.

—Andrea Downing Peck

Related Information

The Tumor Profiler Study: Integrated, Multi-omic, Functional Tumor Profiling for Clinical Decision Support

The Tumor Profiler Study: Integrated, Multi-omic, Functional Tumor Profiling for Clinical Decision Support

Detailed Profile of Tumors

Swiss Study to Prospectively Assess Value of Multi-Omic, Functional Tumor Profiling

Attention All Surgical Pathologists: Algorithms for Automated Primary Diagnosis of Digital Pathology Images Likely to Gain Regulatory Clearance in Near Future

Hello primary diagnosis of digital pathology images via artificial intelligence! Goodbye light microscopes!

Digital pathology is poised to take a great leap forward. Within as few as 12 months, image analysis algorithms may gain regulatory clearance in the United States for use in primary diagnosis of whole-slide images (WSIs) for certain types of cancer. Such a development will be a true revolution in surgical pathology and would signal the beginning of the end of the light microscope era.

A harbinger of this new age of digital pathology and automated image analysis is a press release issued last week by Ibex Medical Analytics of Tel Aviv, Israel. The company announced that its Galen artificial intelligence (AI)-powered platform for use in the primary diagnosis of specific cancers will undergo an accelerated review by the Food and Drug Administration (FDA).

FDA’s ‘Breakthrough Device Designation’ for Pathology AI Platform

Ibex stated that “The FDA’s Breakthrough Device Designation is granted to technologies that have the potential to provide more effective treatment or diagnosis of life-threatening diseases, such as cancer. The designation enables close collaboration with, and expedited review by, the FDA, and provides formal acknowledgement of the Galen platform’s utility and potential benefit as well as the robustness of Ibex’s clinical program.”

“All surgical pathologists should recognize that, once the FDA begins to review and clear algorithms capable of using digital pathology images to make an accurate primary diagnosis of cancer, their daily work routines will be forever changed,” stated Robert L. Michel, Editor-in-Chief of Dark Daily and its sister publication The Dark Report. “Essentially, as FDA clearance is for use in clinical care, pathology image analysis algorithms powered by AI will put anatomic pathology on the road to total automation.

“Clinical laboratories have seen the same dynamic, with CBCs (complete blood counts) being a prime example. Through the 1970s, clinical laboratories employed substantial numbers of hematechnologists [hematechs],” he continued. “Hematechs used a light microscope to look at a smear of whole blood that was on a glass slide with a grid. The hematechs would manually count and record the number of red and white blood cells.

“That changed when in vitro diagnostics (IVD) manufacturers used the Coulter Principle and the Coulter Counter to automate counting the red and white blood cells in a sample, along with automatically calculating the differentials,” Michel explained. “Today, only clinical lab old-timers remember hematechs. Yet, the automation of CBCs eventually created more employment for medical technologists (MTs). That’s because the automated instruments needed to be operated by someone trained to understand the science and medicine involved in performing the assay.”

Primary Diagnosis of Cancer with an AI-Powered Algorithm

Surgical pathology is poised to go down a similar path. Use of a light microscope to conduct a manual review of glass slides will be supplanted by use of digital pathology images and the coming next generation of image analysis algorithms. Whether these algorithms are called machine learning, computational pathology, or artificial intelligence, the outcome is the same—eventually these algorithms will make an accurate primary diagnosis from a digital image, with comparable quality to a trained anatomic pathologist.

How much of a threat is automated analysis of digital pathology images? Computer scientist/engineer Ajit Singh, PhD, a partner at Artiman Ventures and an authority on digital pathology, believes that artificial intelligence is at the stage where it can be used for primary diagnosis for two types of common cancer: One is prostate cancer, and the other is dermatology.

Ajit Singh, PhD speaking at the Executive War College

On June 17, Ajit Singh, PhD (above), Partner at Artiman Ventures, will lead a special webinar and roundtable discussion for all surgical pathologists and their practice administrators on the coming arrival of artificial intelligence-powered algorithms to aid in the primary diagnosis of certain cancers. Regulatory approval for such solutions may happen by the end of this year. Such a development would accelerate the transition from light microscopes to a fully digital pathology workflow. Singh is shown above addressing the 2018 Executive War College. (Photo copyright: The Dark Report.)

“This is particularly true of prostate cancer, which has far fewer variables compared to breast cancer,” stated Singh in an interview published by The Dark Report in April. (See TDR, “Is Artificial Intelligence Ready for First Use in Anatomic Pathology?” April 12, 2021.)

“It is now possible to do a secondary read, and even a first read, in prostate cancer with an AI system alone. In cases where there may be uncertainty, a pathologist can review the images. Now, this is specifically for prostate cancer, and I think this is a tremendous positive development for diagnostic pathways,” he added.

Use of Digital Pathology with AI-Algorithms Changes Diagnostics

Pathologists who are wedded to their light microscopes will want to pay attention to the impending arrival of a fully digital pathology system, where glass slides are converted to whole-slide images and then digitized. From that point, the surgical pathologist becomes the coach and quarterback of an individual patient’s case. The pathologist guides the AI-powered image analysis algorithms. Based on the results, the pathologist then orders supplementary tests appropriate to developing a robust diagnosis and guiding therapeutic decisions for that patient’s cancer.

In his interview with The Dark Report, Singh explained that the first effective AI-powered algorithms in digital pathology will be developed for prostate cancer and skin cancer. Both types of cancer are much less complex than, say, breast cancer. Moreover, the AI developers have decades of prostate cancer and melanoma cases where the biopsies, diagnoses, and downstream patient outcomes create a rich data base from which the algorithms can be trained and tuned.

To help surgical pathologists, pathologist-business leaders, and pathology group practice administrators understand the rapid developments in AI-powered digital pathology analysis, Dark Daily is conducting “Clinical-Grade Artificial Intelligence (AI) for Your Pathology Lab: What’s Ready Now, What’s Coming Soon, and How Pathologists Can Profit from Its Use,” on Thursday, June 17, 2021, from 1:00 PM to 2:30 PM EDT.

This webinar is organized as a roundtable discussion so participants can interact with the expert panelists. The Chair and Moderator is Ajit Singh, PhD, Adjunct Professor at the Stanford School of Medicine and Partner at Artiman Ventures.

Panelists for June 17 webinar, Clinical-Grade Artificial Intelligence (AI) for Your Pathology Lab: What’s Ready Now, What’s Coming Soon, and How Pathologists Can Profit from Its Use

The panelists (above) represent academic pathology, community hospital pathology, and the commercial sector. They are:

Because the arrival of automated analysis of digital pathology images will transform the daily routine of every surgical pathologist, it would be beneficial for all pathology groups to have one or more of their pathologists register and participate in this critical webinar.

The roundtable discussion will help them understand how quickly AI-powered image analysis is expected be cleared for use by the FDA in such diseases as prostate cancer and melanomas. Both types of cancers generate high volumes of case referrals to the nation’s pathologists, so potential for disruption to long-standing client relationships, and the possible loss of revenue for pathology groups that delay their adoption of digital pathology, can be significant.

On the flip side, community pathology groups that jump on the digital pathology bandwagon early and with the right preparation will be positioned to build stronger client relationships, increase subspecialty case referrals, and generate additional streams of revenue that boost partner compensation within their group.

Act now to guarantee your place at this important webinar. Click HERE to register, or copy and paste the URL https://www.darkdaily.com/webinar/clinical-grade-artificial-intelligence-for-your-pathology-lab/ into your browser.

Also, because so many pathologists are working remotely, Dark Daily has arranged special group rates for pathology practices that would like their surgical pathologists to participate in this important webinar and roundtable discussion on AI-powered primary diagnosis of pathology images. Inquire at info@darkreport.com or call 512-264-7103.

—Michael McBride

Related Information:

Ibex Granted FDA Breakthrough Device Designation: Ibex’s Galen AI-powered platform is recognized by the FDA as breakthrough technology with the potential to more effectively diagnose cancer

Is Artificial Intelligence Ready for First Use in Anatomic Pathology?

Medscape Report on Physician Salaries in 2020 Shows Pathologists at Middle in Pay, but Near Top in Job Satisfaction

Though pathology salaries rank 16th among 29 medical specialties, it is in the top 10 among specialties that attract women and respondents say that comes with a lot of paperwork

Despite “hardships” brought on by the COVID-19 pandemic, 18,000 physicians in more than 29 medical specialties who participated in Medscape’s 2021 Physician Compensation Report said that, overall, their 2020 income was similar to prior years. Pathologists reported earnings in 2020 of $316,000, $28,000 below the average specialist’s salary of $344,000.

The average pathologist’s salary ranked 16th among medical specialty salaries.

Compared to 2019, medical specialists on average made $2,000 less in 2020. The average salary for primary care doctors was $242,000 in 2020, down $1,000 from 2019, according to a Medscape news release.

“Physicians experienced a challenging year on numerous fronts, including weathering the volatile financial impact of lockdowns,” said Leslie Kane, Senior Director, Medscape Business of Medicine, in the news release. “Our report shows that many were able to pivot to use telemedicine and focus on tactics that would protect their practices.”

Medscape, a health information provider that is part of the WebMD network, said that in addition to telehealth, doctors turned to MACRA (Medicare Access and CHIP Reauthorization Act of 2015) value-based payment reward programs and other strategies to minimize the effects of office closures last year.

“COVID took a terrible emotional toll on physicians and healthcare workers, and many are still struggling financially, but our findings showed that physicians will innovate and change quickly to meet the needs of patients through extremely difficult times,” said Leslie Kane (above), Senior Director, Medscape’s Business of Medicine, in the news release. Pathologists who were at the center of the nation’s COVID-19 pandemic response would likely echo her sentiments. (Photo copyright: Medscape.)

Pathology Salary Unchanged

To complete its study, Medscape asked physicians to take a 10-minute online survey. The reported findings included responses from 17,903 physicians (61% male, 36% female) practicing in more than 29 specialties between October 2020 and February 2021.

Pathologists who participated in the survey reported no change in their annual salary since 2019. Other specialties that reported no salary change include:

  • Family medicine,
  • Infectious diseases,
  • Ophthalmology, and
  • Orthopedics/orthopedic surgery.

Top 10 Medical Specialty Salaries

Medscape’s report listed these top-10 medical specialties as earning the highest salaries (see the graphic below for the full list of medical specialties surveyed):

Specialist Salary Increases and Decreases

Contrary to what many specialists reported, plastic surgeons did not experience slowdowns in appointments during the COVID-19 pandemic. In fact, not only did plastic surgeons earn the most, at 10% they are the medical specialists who got the biggest increase in pay of previous years as well.

According to the American Academy of Facial Plastic and Reconstructive Surgery (AAFPRS), which conducted its own salary survey of its member surgeons, “70% of AAFPRS surgeons report an increase in bookings and treatments over the course of the COVID-19 pandemic, with nine in 10 facial plastic surgeons indicating an increase of more than 10%. Surgical procedures are the most common procedures as part of this upsurge, perhaps cancelling out any decreases that might have resulted from the economic crisis and lockdowns.”

Other specialist salaries which Medscape found increased in 2020 include:

  • Oncology: up 7%
  • Rheumatology and cardiology: up 5%
  • Diabetes/endocrinology: up 4%
  • Neurology, critical care, psychiatry: up 3%
  • General surgery, urology, public health/preventive medicine: up 2%

Medical specialties that reported reductions in salary included:

  • Otolaryngology and allergy/immunology: down 9%
  • Pediatrics and anesthesiology: down 5%
  • Dermatology: down 4%
  • Pulmonary medicine, physical medicine, gastroenterology, and radiology: down 3%
  • Emergency medicine and internal medicine: down 1%

About 92% of physicians surveyed indicated that the COVID-19 pandemic caused their income to decline. Also, 22% of doctors noted they experienced loss of work hours.

Pathologists Received Low Average Bonuses

Reporting on receipt of incentive bonuses, Medscape ranked pathology in the bottom half of its list with $42,000 as an average bonus. The top incentive bonuses went to those practicing:

  • Orthopedics/orthopedics surgery: $116,000
  • Ophthalmology: $87,000
  • Otolaryngology: $72,000

About 59% of primary care physicians and 55% of specialists surveyed reported receiving an incentive bonus.

Pathologists Rank High in Job Satisfaction

In responding to a question about compensation, pathologists ranked near the top (seventh position) with 64% saying they are content with their pay. Others expressing salary satisfaction included:

  • Oncology: 79%
  • Psychiatry: 69%
  • Plastic surgery: 68%
  • Dermatology: 67%
  • Public health/preventive medicine: 66%
  • Radiology: 65%
  • Pathology: 64%

Pathology Popular Among Women MDs

Medscape found that women MDs chose certain medical specialties more often than others, including pathology, which ranked eighth. The top eight specialties employing female physicians are:

  • Pediatrics: 61%
  • Obstetrics/gynecology: 59%
  • Diabetes/endocrinology: 50%
  • Family medicine: 47%
  • Dermatology: 46%
  • Infectious diseases: 46%
  • Internal medicine: 44%
  • Pathology: 43%

Specialties with the fewest female physicians are:

  • Plastic and general surgery: 20%
  • Cardiology: 14%
  • Urology: 11%
  • Orthopedics/orthopedics surgery: 9%

Pathology a Leader in Paperwork

Medscape also surveyed physicians as to the estimated hours they spend per week on paperwork and administration. Here, pathology ranked the fifth highest with 19%, while radiologists and hospital-based physicians were third from the bottom with 11.6%.

Specialists that reported the highest hours spent on paperwork include:

  • Infectious diseases: 24%
  • Public health/preventive medicine: 20.7%
  • Nephrology: 19.8%
  • Internal medicine: 19.7%
  • Pathology: 19%

If They Could Do It Again, Most Would

Amid a trying year, the Medscape survey respondents made an encouraging point: 78% of them said they would choose medicine as a career again. And 85% of pathologists said they would choose the same specialty.

Medscape’s report may be helpful to hospital-based clinical laboratory leaders preparing salary budgets and to pathologists in salary negotiations and determining professional responsibilities.

—Donna Marie Pocius

Related Information:

Medscape Physician Compensation Report: The Recovery Begins 2021

Medscape Physician Compensation Report Shows Salaries Held Steady Despite Pandemic

A Pandemic of Dysmorphia: “Zooming” into the Perception of Our Appearance

AAFPRS Announces annual Survey Results, A Look at How COVID-19 Disrupted Facial Plastic Surgery

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