Cellular healthcare is an approach that goes beyond clinical laboratory testing to identify the location of specific cancer cells and aid in treatment decisions
Advances in synthetic biology and genetic engineering are leading to development of bacterial biosensors that could eventually aid pathologists and clinical laboratories in diagnosis of many types of cancers.
One recent example comes from researchers at the University of California San Diego (UCSD) who worked with colleagues in Australia to engineer bacteria that work as “capture agents” and bind to tumorous material.
The KRAS gene is associated with colorectal cancer. The researchers named their development the Cellular Assay for Targeted CRISPR-discriminated Horizontal gene transfer (CATCH).
CATCH successfully detected cancer in the colons of mice. The researchers believe it could be used to diagnose cancers, as well as infections and other diseases, in humans as well, according to a UCSD news release.
“If bacteria can take up DNA, and cancer is defined genetically by a change in its DNA, then, theoretically, bacteria could be engineered to detect cancer,” gastroenterologist Daniel Worthley, PhD, a cancer researcher at Colonoscopy Clinic in Brisbane, Australia, told MedicalResearch.com. This research could eventually provide clinical laboratories and anatomic pathologists with new tools to use in diagnosing certain types of cancer. (Photo copyright: Colonoscopy Clinic.)
Tapping Bacteria’s Natural Competence
In their Science paper, the researchers acknowledged other synthetic biology achievements in cellular biosensors aimed at human disease. But they noted that more can be done by leveraging the “natural competence” skill of bacteria.
“Biosensors have not yet been engineered to detect specific extracellular DNA sequences and mutations. Here, we engineered naturally competent Acinetobacter baylyi (A. baylyi) to detect donor DNA from the genomes of colorectal cancer cells, organoids, and tumors,” they wrote.
“Many bacteria can take up DNA from their environment, a skill known as natural competence,” said Rob Cooper, PhD, co-first author of the study and a scientist at US San Diego’s Synthetic Biology Institute, in the news release. A. baylyi is a type of bacteria renowned for success in doing just that, the NCI article pointed out.
This enabled them to explore “free-floating DNA sequences on a genomic level.”
Those sequences were compared to “known cancer DNA sequences.”
A. baylyi (genetically modified) was tested on its ability to detect “mutated and healthy KRAS DNA.”
Only bacteria that had “taken up mutated copies of KRAS … would survive treatment with a specific drug.”
“It was incredible when I saw the bacteria that had taken up the tumor DNA under the microscope. The mice with tumors grew green bacterial colonies that had acquired the ability to be grown on antibiotic plates,” said Josephine Wright, PhD, Senior Research Fellow, Gut Cancer Group, South Australian Health and Medical Research Institute (SAHMRI), in the news release.
Detecting DNA from Cancer Cells In Vitro and in Mice
Findings in vitro and in mice include the following:
The engineered bacteria enabled detection of DNA with KRAS G12D from colorectal cancer cells made in the lab, NCI reported.
When mice were injected with colorectal cancer cells, the researchers’ technology found tumor DNA, Engadget reported.
The study adds to existing knowledge of horizontal gene transfer from bacteria to bacteria, according to UCSD.
“We observed horizontal gene transfer from the tumor to the sensor bacteria in our mouse model of colorectal cancer. This cellular assay for targeted, CRISPR-discriminated horizontal gene transfer (CATCH) enables the biodetection of specific cell-free DNA,” the authors wrote in Science.
“Colorectal cancer seemed a logical proof of concept as the colorectal lumen is full of microbes and, in the setting of cancer, full of tumor DNA,” gastroenterologist Daniel Worthley, PhD, a cancer researcher at Colonoscopy Clinic in Brisbane, Australia, told MedicalResearch.com.
Finding More Cancers and Treatment
More research is needed before CATCH is used in clinical settings. The scientists are reportedly planning on adapting CATCH to multiple bacteria that can locate other cancers and infections.
“The most exciting aspect of cellular healthcare … is not in the mere detection of disease. A laboratory can do that,” wrote Worthley in The Conversation. “But what a laboratory cannot do is pair the detection of disease (a diagnosis) with the cells actually responding to the disease [and] with appropriate treatment.
“This means biosensors can be programmed so that a disease signal—in this case, a specific sequence of cell-free DNA—could trigger a specific biological therapy, directly at the spot where the disease is detected in real time,” he added.
Clinical laboratory scientists, pathologists, and microbiologists may want to stay abreast of how the team adapts CATCH, and how bacterial biosensors in general continue to develop to aid diagnosis of diseases and improve ways to target treatment.
The focus of the ongoing GenoVA study is to “determine the clinical effectiveness of polygenic risk score testing among patients at high genetic risk for at least one of six diseases measured by time-to-diagnosis of prevalent or incident disease over 24 months,” according to the National Institutes of Health.
The scientists used data obtained from 36,423 patients enrolled in the Mass General Brigham Biobank. The six diseases they researched were:
The polygenic scores were then tested among 227 healthy adult patients to determine their risk for the six diseases. The researchers found that:
11% of the patients had a high-risk score for atrial fibrillation,
7% for coronary artery disease,
8% for diabetes, and
6% for colorectal cancer.
Among the subjects used for the study:
15% of the men in the study had a high-risk score for prostate cancer, and
13% of the women in the study had a high score for breast cancer.
The researchers concluded that the implementation of PRS may help improve disease prevention and management and give doctor’s a way to assess a patient’s risk for these conditions. They published their findings in the journal Nature Medicine, titled, “Development of a Clinical Polygenic Risk Score Assay and Reporting Workflow.”
“We have shown that [medical] laboratory assay development and PRS reporting to patients and physicians are feasible … As the performance of PRS continues to improve—particularly for individuals of underrepresented ancestry groups—the implementation processes we describe can serve as generalizable models for laboratories and health systems looking to realize the potential of PRS for improved patient health,” the researchers wrote.
Using PRS in Clinical Decision Support
Polygenetic risk scores examine multiple genetic markers for risk of certain diseases. A calculation based on hundreds or thousands of these genetic markers could help doctors and patients make personalized treatment decisions, a core tenet of precision medicine.
“As a primary care physician myself, I knew that busy physicians were not going to have time to take an entire course on polygenic risk scores. Instead, we wanted to design a lab report and informational resources that succinctly told the doctor and patient what they need to know to make a decision about using a polygenic risk score result in their healthcare,” epidemiologist Jason Vassy, MD, told The Harvard Gazette. Vassy is Associate Professor, Harvard Medical School at VA Boston Healthcare System and one of the authors of the research.
“This is another great example of precision medicine,” Jason Vassy, MD (above), Adjunct Assistant Professor, General Internal Medicine at Boston University School of Medicine, told WebMD. “There’s always been a tantalizing idea that someone’s genetic makeup might help tailor preventative medicine and treatment.” Personalized clinical laboratory testing is increasingly becoming based on an individual’s genetics. (Photo copyright: Harvard Medical School.)
Increasing Diversity of Patients in Genomic Research
The team did encounter some challenges during their analysis. Because most existing genomic research was performed on persons of European descent, the risk scores are less accurate among non-European populations. The researchers for this study addressed this limitation by applying additional statistical methods to qualify accurate PRS calculations across multiple racial groups.
“Researchers must continue working to increase the diversity of patients participating in genomics research,” said Matthew Lebo, PhD, Chief Laboratory Director, Laboratory Molecular Medicine, at Mass General Brigham and one of the authors of the study. “In the meantime, we were heartened to see that we could generate and implement valid genetic scores for patients of diverse backgrounds,” he told The Harvard Gazette.
The team hopes the scores may be utilized in the future to help doctors and patients make better decisions regarding preventative care and screenings.
“It’s easy to say that everyone needs a colonoscopy at age 45,” Vassy told WebMD. “But what if you’re such a low risk that you could put it off for longer? We may get to the point where we understand risk so much that someone may not need one at all.”
Future of PRS in Clinical Decision Making
The scientists plan to enroll more than 1,000 patients in a new program and track them for two years to assess how medical professionals use PRS in clinical care. It is feasible that patients who are at high risk for certain diseases may opt for more frequent screenings or take preventative medicines to mitigate their risk.
“Getting to that point will take time,” Vassy added. “But I can see this type of information playing a role in shared decision making between doctor and patient in the near future.”
The team also established resources and educational materials to assist both doctors and patients in using the scores.
“It’s still very early days for precision prevention,” Vassy noted, “but we have shown it is feasible to overcome some of the first barriers to bringing polygenic risk scores into the clinic.”
More research and studies are needed to prove the effectiveness of using PRS tests in clinical care and determine its role in customized treatment plans based on personal genetics. Nevertheless, pathologists and medical scientists will want to follow the GenoVA study.
“It is probably most helpful to think of polygenic risk scores as a risk factor for disease, not a diagnostic test or an indication that an individual will certainly develop the disease,” Vassy said. “Most diseases have complex, multifactorial etiologies, and a high polygenic risk score is just one piece of the puzzle.”
Pathologists and clinical laboratory managers may want to stay informed as researchers in the GenoVA study tease new useful diagnostic insights from their ongoing study of the whole human genome. Meanwhile, the GenoVA team is moving forward with the 1,000-patient study with the expectation that this new knowledge may enable earlier and more accurate diagnoses of the health conditions that were the focus of the GenoVA study.
GI pathologists will be interested in how the Endoculus device uses tank-like treads to traverse the gastrointestinal tract, where it can capture images and perform biopsies
Gastroenterologists (GI) may soon gain a useful new tool for use in gathering both biopsies and diagnostic information when examining the gastrointestinal tract. Ongoing development of a new robotic device promises both capabilities using technology that will be of interest to GI pathologists and clinical laboratory scientists.
The minute robotic device uses tank-like treads to traverse the colon. While there, it can capture live images and perform biopsies under the control of a gastroenterologist. The researchers believe the robotic technology will benefit GIs performing the colonoscopies as well as the pathologists called upon to analyze biopsies.
“Currently, endoscopy consists of a gastroenterologist using a semi-rigid, long rope-like device and endoscope to propel through your colon manually,” Gregory Formosa, PhD (above) a member of the AMTL team that developed Endoculus, said in a YouTube video describing the device. “We think that a robotic capsule endoscope can replace conventional endoscopes by making them faster, safer, and more robust than a human operator can do currently with traditional techniques,” he added. (Photo copyright: University of Colorado.)
AMTL researcher Gregory Formosa, PhD, said the team’s goal is to “have a capsule-sized robot that can actively traverse [a patient’s] entire gastrointestinal tract and send out diagnostics in real time, as well as autonomously navigate itself to localize problematic areas within [the] intestinal tract.”
Formosa noted that colorectal cancer is “the third-most fatal and diagnosed cancer in the United States.” But if caught at an early stage, these cancers are “95% treatable,” he added. “So, if we can get people screened early, we definitely can reduce the fatality rate of colorectal cancers significantly.”
Currently about the size of a C battery, Endoculus (above) is a “fully packed medical device, complete with a camera, an air pump for inflating the colon, a water pump for cleaning, and a tool port for holding biopsy snares,” states a University of Colorado news story, titled, “A Robot May One Day Perform Your Colonoscopy.” (Photo copyright: University of Colorado.)
How Endoculus Works
One key to the device are the four treads, which are designed for traction on digestive tissue.
“You have to forget about everything you know from a locomotion standpoint because driving around inside the body is very different than driving around in a car,” said Rentschler in the University of Colorado news story. “The environment is highly deformable. It’s very slick. There are sharp peaks that you have to go over.”
The university news story noted the current availability of ingestible “pill cams” that can take photos as they travel through the digestive system. But once swallowed, their movements cannot be controlled.
“For our robots to be able to reach those regions that [can be] reached with a pill-cam—but also be able to stop and look around—that could be a big paradigm shift in the way we view these procedures,” said Micah Prendergast, PhD, an AMTL research team member.
Could Biopsies Be Diagnosed In Situ with Endoculus?
The researchers currently view Endoculus as a potentially better way to perform conventional biopsies. But could it lead to bigger advancements?
“Researchers continue to develop devices to help various specialist physicians—in this case GIs—do more when treating patients,” said Dark Daily Publisher and Editor-in-Chief Robert Michel. “This device fits that description. It is designed to improve the ability of GIs to evaluate the colon. Not only does this device do that, but it can also collect a biopsy at sites of interest. In this way, it is a device that can be a benefit to pathologists who will analyze the biopsy.
“With improvements in digital cameras and associated AI-powered analytical tools, the day might not be far off when a device like this can use the camera and artificial intelligence to diagnose the tissue of interest in situ,” he added. “This might create the opportunity for pathologists to be present in the exam room during the procedure, or even viewing the images remotely.
“Not only would that eliminate the need to collect a tissue specimen that must then be sent to a pathology lab, but it would create a new opportunity for pathologists to add value to patient care while shortening the time to diagnosis for the tissue of interest during these procedures,” Michel noted.
Many other healthcare systems also are partnering with private genetic testing companies to pursue research that drive precision medicine goals
It is certainly unusual when a major health network announces that it will give away free genetic tests to 10,000 of its patients as a way to lay the foundation to expand clinical services involving precision medicine. However, pathologists and clinical laboratory managers should consider this free genetic testing program to be the latest marketplace sign that acceptance of genetic medicine continues to move ahead.
Notably, it is community hospitals that are launching this
new program linked to clinical laboratory research that uses genetic tests for
specific, treatable conditions. The purpose of such genetic research is to
identify patients who would benefit from test results that identify the best
therapies for their specific conditions, a core goal of precision medicine.
Clinical laboratory leaders will be interested in this
initiative, as well other partnerships between healthcare systems and private
genetic testing companies aimed at identifying and enrolling patients in
research studies for disease treatment protocols and therapies.
The Future of Precision Medicine
Modern Healthcare reported that data from the WholeMe DNA study, which was funded through donations to the AdventHealth Foundation, also will be used by the healthcare network for research beyond FH, as AdventHealth develops its genomics services. The project’s cost is estimated to reach $2 million.
“Genomics is the future of medicine, and the field is rapidly evolving. As we began our internal discussions about genomics and how to best incorporate it at AdventHealth, we knew research would play a strong role,” Wes Walker MD, Director, Genomics and Personalized Health, and Associate CMIO at AdventHealth, told Becker’s Hospital Review.
“We decided to focus on familial hypercholesterolemia
screening initially because it’s a condition that is associated with
life-threatening cardiovascular events,” he continued. “FH is treatable once
identified and finding those who have the condition can lead to identifying
other family members who are subsequently identified who never knew they had
the disease.”
The AdventHealth Orlando website states that participants in the WholeMe study receive information stored in a confidential data repository that meets HIPAA security standards. The data covers ancestry and 22 other genetic traits, such as:
Asparagus Odor Detection
Bitter Taste
Caffeine Metabolism
Cilantro Taste Aversion
Circadian Rhythm
Coffee Consumption
Delayed Sleep
Earwax Type
Endurance vs Power
Exercise Impact on Weight
Eye Color
Freckling
Hair Curl and Texture
Hand Grip Strength
Height
Lactose Tolerance
Sleep Duration
Sleep Movement
Sleeplessness
Sweet Tooth
Tan vs. Sunburn
Waist Size
Those who test positive for a disease-causing FH variant will be referred by AdventHealth for medical laboratory blood testing, genetic counseling, and a cardiologist visit, reported the Ormond Beach Observer.
One in 250 people have FH, and 90% of them are undiagnosed,
according to the FH Foundation,
which also noted that children have a 50% chance of inheriting FH from parents
with the condition.
AdventHealth plans to expand the free testing beyond central
Florida to its 46 other hospitals located in nine states, Modern Healthcare
noted.
Other Genetics Data Company/Healthcare Provider Partnerships
Helix (above) is one of the world’s largest CLIA-certified, CAP-accredited next-generation sequencing labs. The partnership with AdventHealth offered study participants Exome+: a panel-grade medical exome enhanced by more than 300,000 informative non-coding regions; a co-branded ancestry + traits DNA product for all participants; secure storage of genomic data for the lifetime of the participant; infrastructure and data to facilitate research; and in-house clinical and scientific expertise, according to Helix’s website. (Photo copyright: Orlando Sentinel.)
Business Insider noted that Helix has focused on clinical partnerships for about a year and seems to be filling a niche in the genetic testing market.
“Helix is able to sidestep the costs of direct-to-consumer
marketing and clinical test development, while still expanding its customer
base through predefined hospital networks. And the company is in a prime
position to capitalize on providers’ interest in population health management,”
Business Insider reported.
Ochsner’s program is the first “fully digital population
health program” aimed at including clinical genomics data in primary care in an
effort to affect patients’ health, FierceHealthcare
reported.
Hereditary breast and ovarian cancer due to
mutations in BRCA1 and BRCA2 genes;
Lynch
syndrome, associated with colorectal and other cancers; and
FH.
Color also offers genetic testing and whole genome sequencing services to NorthShore’s DNA10K program, which plans to test 10,000 patients for risk for hereditary cancers and heart diseases, according to news release.
And, Jefferson Health offered Color’s genetic testing to the healthcare system’s 33,000 employees, 10,000 of which signed up to learn their health risks as well as ancestry, a Color blog post states.
“Understanding the genome warning signals of every patient will be an essential part of wellness planning and health management,” said Geisinger Chief Executive Officer David Feinberg, MD, when he announced the new initiative at the HLTH (Health) Conference in Las Vegas. “Geisinger patients will be able to work with their family physician to modify their lifestyle and minimize risks that may be revealed,” he explained. “This forecasting will allow us to provide truly anticipatory healthcare instead of the responsive sick care that has long been the industry default across the nation.”
It will be interesting to see how and if genetic tests—free
or otherwise—will advance precision medicine goals and population health
treatments. It’s important for medical laboratory leaders to be involved in health
network agreements with genetic testing companies. And clinical laboratories should
be informed whenever private companies share their test results data with
patients and primary care providers.
Doctors may begin ordering FITs in greater numbers, increasing the demand on clinical laboratories to process these home tests
All clinical laboratory managers and pathologists know that timely screening for colon cancer is an effective way to detect cancer early, when it is easiest to treat. But, invasive diagnostic approaches such as colonoscopies are not popular with consumers. Now comes news of a large-scale study that indicates the non-invasive fecal immunochemical test (FIT) can be as effective as a colonoscopy when screening for colon cancer.
FITs performed annually may be as effective as colonoscopies at detecting colorectal cancer (CRC) for those at average risk of developing the disease. That’s the conclusion of a study conducted at the Regenstrief Institute, a private, non-profit research organization affiliated with the Indiana University School of Medicine in Indianapolis, Ind.
The researchers published their findings in the Annals of Internal Medicine (AIM), a journal published by the American College of Physicians (ACP). The team reviewed data from 31 previous studies. They then analyzed the test results from more than 120,000 average-risk patients who took a FIT and then had a colonoscopy. After comparing the results between the two tests, the researchers concluded that the FIT is a sufficient screening tool for colon cancer.
FIT is Easy, Safe, and Inexpensive
As a medical laboratory test, the FIT is low risk, non-invasive,
and inexpensive. In addition, the FIT can detect most cancers in the first
application, according to the Regenstrief Institute researchers. They recommend
that the FIT be performed on an annual basis for people at average risk for
getting colorectal cancers.
“This non-invasive test for colon cancer screening is available for average risk people,” Imperiale told NBC News. “They should discuss with their providers whether it is appropriate for them.”
FIT is performed in the privacy of the patient’s home. To
use the test, an individual collects a bowel specimen in a receptacle provided
in a FIT kit. They then send the specimen to a clinical laboratory for
evaluation. The FIT requires no special preparations and medicines and food do
not interfere with the test results.
Thomas Imperiale, MD (above), is a Lawrence Lumeng Professor of Gastroenterology and Hepatology at Indiana University School of Medicine, and a research scientist at the Regenstrief Institute. He led a study which concluded that FITs are as effective as colonoscopies at detecting cancer in average risk patient populations. Should these conclusions become widely accepted, doctors may begin ordering FITs in greater numbers, increasing the demand on clinical laboratories that process the tests. (Photo copyright: Indiana University School of Medicine.)
‘A Preventative Health Success Story’
The FIT can be calibrated to different sensitivities at the
lab when determining results. Imperiale and his team found that 95% of cancers
were detected when the FIT was set to a higher sensitivity, however, that
setting resulted in 10% false positives. At lower sensitivity the FIT produced
fewer false positives (5%), but also caught fewer cancers (75%). However, when
the FIT was performed every year, the cancer detection rate was similar at both
sensitivities over a two-year period.
“FIT is an excellent option for colon cancer screening only if it is performed consistently on a yearly basis,” Felice Schnoll-Sussman, MD, told NBC News. Sussman is a gastroenterologist and Professor of Clinical Medicine at Weill Cornell Medicine. “Colon cancer screening and its impact on decreasing rates of colon cancer is a preventative health success story, although we have a way to go to increase rates to our previous desired goal of 80% screened in the US by 2018.”
The FIT looks for hidden blood in the stool by detecting protein hemoglobin found in red blood cells. A normal result indicates that FIT did not detect any blood in the stool and the test should be repeated annually. If the FIT comes back positive for blood in the stool, other tests, such as a sigmoidoscopy or colonoscopy should be performed. Cancers in the colon may not always bleed and the FIT only detects blood from the lower intestines.
Patients are Skipping the Colonoscopy
Approximately 35% of individuals who should be receiving colonoscopies do not undergo the test, NBC News noted. The American Cancer Society (ACS) lists the top five reasons people don’t get screened for colorectal cancer are that they:
fear the test will be difficult or painful;
have no family history of the disease and feel
testing is unnecessary;
have no symptoms and think screening is only for
those with symptoms;
are concerned about the costs associated with
screening; and
they are concerned about the complexities of
taking the tests, including taking time off from work, transportation after the
procedure, and high out-of-pocket expenses.
“Colorectal cancer screening is one of the best opportunities to prevent cancer or diagnose it early, when it’s most treatable,” Richard Wender, MD, Chief Cancer Control Officer for the ACS stated in a press release. “Despite this compelling reason to be screened, many people either have never had a colorectal cancer screening test or are not up to date with screening.”
Colorectal cancer is the third most common cancer diagnosed in both men and women in the United States. The ACS estimates there will be 101,420 new cases of colon cancer and 44,180 new cases of rectal cancer diagnosed this year. The disease is expected to be responsible for approximately 51,020 deaths in 2019.
New cases of the disease have been steadily decreasing over
the past few decades in most age populations, primarily due to early screening.
However, the overall death rate among people younger than age 55 has increased
1% per year between 2007 and 2016. The ACS estimates there are now more than
one million colorectal cancer survivors living in the US.
The ACS recommends that average-risk individuals start
regular colorectal cancer screenings at age 45. The five-year survival rate for
colon cancer patients is 90% when there is no sign that the cancer has spread
outside the colon.
Clinical laboratory professionals may find it unpleasant to
test FIT specimens. Opening the specimen containers and extracting the samples
can be messy and malodorous. However, FITs are essential, critical tests that
can save many lives.
