UNC’s novel way to visualize the human proteome could lead to improved clinical laboratory tests along with the development of new therapies
Diagnostic testing based on proteomics is considered to be a field with immense potential in diagnostics and therapeutics. News of a research breakthrough into how scientists can visualize protein activity within cells will be of major interest to the pathologists, PhDs, and medical laboratory scientists who specialize in clinical laboratory testing involving proteins.
Proteins are essential to all life and to the growth, maintenance, and repair of the human body. So, a thorough understanding of how they function within living cells would be essential to informed medical decision-making as well. And yet, how proteins go about doing their work is not well understood.
That may soon change. Scientists at the University of North Carolina (UNC) School of Medicine have developed an imaging method that could provide new insights into how proteins alter their shapes within living cells. And those insights may lead to the development of new therapies and medical treatments.
Dubbed “binder-tag” by the UNC scientists, their new technique “allows researchers to pinpoint and track proteins that are in a desired shape or ‘conformation,’ and to do so in real time inside living cells,” according to a UNC Health news release.
Two labs in the UNC School of Medicine’s Department of Pharmacology collaborated to develop the binder-tag technique:
“No one has been able to develop a method that can do, in such a generalizable way, what this method does. So, I think it could have a very big impact,” said lead author of the UNC study Klaus Hahn PhD (above), in the news release. “With this method we can see, for example, how microenvironmental differences across a cell affect, often profoundly, what a protein is doing,” he added. This research may enlarge scientists’ understanding of how the human proteome works and could lead to new medical laboratory tests and therapeutic drugs. (Photo copyright: UNC School of Medicine.)
How Binder-Tag Works
During their study, the UNC scientists developed binder-tag “movies” that allow viewers to see how the binder-tag technique enables the tracking of active molecules in living cells.
The technique involves two parts: a fluorescent binder and a molecular tag that is attached to the proteins of interest.
When inactive, the tag is hidden inside the protein, but when the protein is ready for action it changes shape and exposes the tag.
The binder then joins with the exposed tag and fluoresces. This new fluorescence can easily be tracked within the cell.
Nothing else in the cell can bind to the binder or tag, so they only light up when in contact on the active protein.
This type of visualization will help researchers understand the dynamics of a protein in a cell.
“The method is compatible with a wide range of beacons, including much more efficient ones than the interacting beacon pairs required for ordinary FRET [fluorescence resonance energy transfer]. Binder-tag can even be used to build FRET sensors more easily. Moreover, the binder-tag molecules were chosen so that nothing in cells can react with them and interfere with their imaging role,” Hahn said in the news release.
“Only upon exposure can the peptide specifically interact with a reporter protein (the binder). Thus, simple fluorescence localization reflects protein conformation. Through direct excitation of bright dyes, the trajectory and conformation of individual proteins can be followed,” the UNC researchers wrote in Cell. “The simplicity of binder-tag can provide access to diverse proteins.”
The UNC researchers’ binder-tag technique is a way to overcome the dire challenge of seeing tiny and hard-working proteins, Cosmos noted. Typical light microscopy does not enable a view of molecules at work. This paves the way for the new binder-tag technique, UNC pointed out.
“With this method, we can see, for example, how microenvironmental differences across a cell affect—and often profoundly—what a protein is doing,” Hahn said. “For a lot of protein-related diseases, scientists haven’t been able to understand why proteins start to do the wrong thing. The tools for obtaining that understanding just haven’t been available.”
More Proteins to Study
More research is needed before the binder-tag method can be used in diagnostics. Meanwhile, the UNC scientists intend to show how binder-tag can be applied to other protein structures and functions.
“The human proteome has between 80,000 and 400,000 proteins, but not all at one time. They are expressed by 20,000 to 25,000 human genes. So, the human proteome has great promise for use in diagnostics, understanding disease, and developing therapies,” said Robert Michel, Editor-in-Chief of Dark Daily and its sister publication The Dark Report.
Medical scientists and diagnostics professionals will want to stay tuned to discover more about the tiny—though mighty—protein’s contributions to understanding diseases and patient treatment.
AUSTIN, Texas (March 30, 2021) — SARS-CoV-2 has been mutating at a rate of about one to two mutations per month. The emergence of multiple SARS-CoV-2 variants brings fast-moving questions for clinical laboratory administrators about the ability to identify new potential coronavirus SARS-CoV-2 variants. One of the most notable is how standard COVID-19 testing can be positioned to detect these new variants, particularly now that the S-gene dropout issue has been discovered.
Listen to this free webinar on demand, sponsored by Thermo Fisher Scientific, and learn the importance of early detection of these emerging SARS-CoV-2 variants and the steps your lab can take to confidently detect the COVID-19 virus with a very high degree of specificity and sensitivity, and identify the S-gene dropout.
This informative recorded webinar features the following panel of experts: Peter De Hoff, PhD, Project Scientist, Department of Reproductive Medicine, Sanford Consortium for Regenerative Medicine, UC San Diego; Manoj Gandhi, MD, PhD, Senior Medical Director, Thermo Fisher Scientific, San Francisco, CA; Karthik Gangavarapu, PhD Student, Andersen and Su Labs, Scripps Research Institute, La Jolla, CA; and Shashank Sathe, Bioinformatics Programmer, Yeo Lab, UC San Diego, San Diego, CA.
Tune into this 60-minute program and you will:
Get key insights into the novel SARS-CoV-2 strains including the UK variant (B.1.1.7) and the South African variant (B.1.351/501Y.V2) and the significant mutations associated with these variants
Understand automation and miniaturization of clinical SARS-CoV-2 RT-qPCR testing for population genomic surveillance
Learn how the TaqPath workflow addresses the S-gene dropout issue by detecting this unique variant
Discover how the mutations in these “variants of concern” are relevant to the different TaqPath COVID-19 assays
Hear how UCSD and Scripps are collaborating to deliver rapid and cost-effective genomic epidemiology to public health officials, and much more
Established in 1995, The Dark Report is the leading source of exclusive business intelligence for laboratory CEOs, COOs, CFOs, Pathologists, and Senior industry executives. It is widely read by leaders in laboratory medicine and diagnostics. The Dark Report produces Dark Daily, as well as the renowned Executive War College on Laboratory and Pathology Managementevery spring.
With $191 million in startup capital, the genomics startup will draw on existing genetic databases to create personalized medicine therapies for chronic diseases
Why do some people get sick while others do not? That’s what genetic researchers at Maze Therapeutics want to find out. They have developed a new approach to using tools such as CRISPR gene editing to identify and manipulate proteins in genetic code that may be the key to providing personalized protection against specific diseases.
If viable, the results of Maze’s research could mean the development of specific drugs designed to mimic genetic code in a way that is uniquely therapeutic to specific patients. This also would create the need for clinical laboratories to sequence and analyze patients’ DNA to determine whether a patient would be a candidate for any new therapies that come from this line of research.
Based in San Francisco, Maze Therapeutics (Maze) is studying modifier genes—genes that affect the phenotype or physical properties of other genes—and attempting to create drugs that replicate them, reported MIT Technology Review. Maze believes that genetic modifiers could afford a “natural form of protection” against disease.
“If you have a disease-causing gene, and I have the disease-causing gene, why is it that you may be healthy and I may be sick? Are there other genes that come into play that provide a protective effect? Is there a drugging strategy to recover normal phenotype and recover from the illness?” Maze Chief Executive Officer Jason Coloma, PhD, asked in an interview with FierceBiotech.
In 2019, Maze received $191 million in financing from Third Rock Ventures, ARCH Venture Partners, and others, to find ways to translate their findings into personalized medicines, according to a news release. And with the availability of international public genetic databases and CRISPR gene editing, now may be good timing.
“This was the perfect time to get into this space with the tools that were being developed and the amount of data that has been accumulated on the human genetic side,” Charles Homcy, MD, Third Rock Ventures Partner and Maze Scientific Founder, told Forbes, which noted that Maze is tapping existing population-wide genetic databases and large-scale studies, including the United Kingdom’s Biobank and Finland’s Finngen.
To help find genetic modifier drug targets, Maze is accessing CRISPR gene editing capabilities. Jonathan Weissman, PhD, Maze Scientific Founder and Professor of Cellular Molecular Pharmacology at University of California, San Francisco (UCSF), told MIT Technology Review: “You take a cell with a disease-causing gene and then see if you can turn it back to normal. We can do 100,000 experiments at once because each cell is its own experiment.”
“At Maze, we are focused on expanding our understanding of the natural disease protection provided by genetic modifiers through an integrated approach that combines studying natural human genetic variation across the globe and conducting large-scale experiments of gene perturbations,” Charles Homcy, MD (above), Founder and interim CEO of Maze and a partner at Third Rock Ventures, said in a news release. “Through our integrated approach, we believe we will create novel medicines based around those modifiers to treat a number of diseases.” (Photo copyright: Forbes.)
Using CRISPR to Identify the Cause of Disease
One drug research program reportedly progressing at Maze involves developing gene therapy for the neurogenerative disease amyotrophic lateral sclerosis (ALS). The program borrows from previous research conducted by Aaron Gitler, PhD, Professor of Genetics at Stanford University and Maze co-founder, which used CRISPR to find genetic modifiers of ALS. The scientists found that when they removed the protein coding gene TMX2 (Thioredoxin Related Transmembrane Protein 2), the toxicity of proteins building the disease was reduced, reported Chemical and Engineering News.
“We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells,” Gitler and colleagues wrote in Nature Genetics. “Together, our results demonstrate the promise of using CRISPR-Cas9 screens in defining the mechanisms of neurodegenerative diseases.”
“We have the flexibility to think differently. We like to
think of ourselves as part of this new breed of biotech companies,” Coloma told
FierceBiotech.
It’s an exciting time. Clinical laboratories can look
forward to new precision medicine diagnostic tests to detect disease and
monitor the effects of patient therapies. And the research initiatives by Maze
and other genetic companies represent a new approach in the use of genetic code
to create specific drug therapies targeted at specific diseases that work best
for specific patients.
The companion diagnostics that may come from this research would
be a boon to anatomic pathology.
Some companies save so much in healthcare cost they pay their employees to participate in medical tourism programs
Medical tourism is not new, but it’s changing, and clinical laboratories have a role to play in the models employers use to save money on their employees’ health coverage costs.
Employers that manage the entire process—from securing
passports for their employees, to ensuring they have access to high-quality care
outside the country’s borders—report saving money as well as simplifying the
process for their employees. An apparent win-win.
However, questions linger about:
Availability of diagnostic testing and clinical
laboratories;
If patients treated outside the US receive
adequate protections; and
Whether the quality of care is equal to that in
the US.
One recent example of a company helping employers and employees receive high quality care outside of the US is NASH—the North American Specialty Hospital. NASH was featured in a Kaiser Health News (KHN) article that described one patient’s experience traveling to Cancún for a surgical procedure.
Location, Pre-Existing Conditions, Length of Stay, Etc.,
Affect Final Bill in US
One of NASH’s corporate clients is Ashley Furniture Industries. Headquartered
in Arcadia, Wis., the American home furnishings manufacturer and retailer employs
approximately 17,000 people, including Terry Ferguson. Terry’s wife, Donna, is
the patient highlighted in the KHN story.
One of the healthcare providers NASH partners with is Galenia Hospital, a 55-bed general services hospital in Cancún, Mexico. NASH leases the entire third floor of the hospital. Galenia is next door to a Four Points Sheraton Hotel, making lodging a simple matter for medical tourists.
Currently, NASH focuses on orthopedic surgeries such as total
knee replacements, the medical procedure Donna Ferguson underwent.
A 2015 BlueCross
BlueShield study showed that costs for total-knee-replacement surgery in
the US averaged about $31,000. However, depending on where the surgery takes
place, it can cost as low as $11,317 (Alabama) and as high as $69,654 (New York
City). Pre-existing conditions, length of time in the operating room, number of
days in the hospital, and numerous other factors contribute to the final bill.
NASH, however, sets the final price is up front.
Some Companies Pay Their Employees to Use Medical Tourism
With the average cost for the surgery coming in at around
$12,000, the cost savings to employers is so great some companies actually pay employees
who are willing to travel for procedures, KHN reported. Donna Ferguson paid
no co-pays for her surgery, paid nothing out of pocket for travel or lodging
while in Cancún, and the Ferguson’s received a $5,000 check from Ashley
Furniture.
Ferguson told KHN, “It’s been a great experience.
Even if I had to pay, I would come back here because it’s just a different
level of care—they treat you like family.”
That’s important for hospitals, clinical laboratories, and
all healthcare providers in America to consider. In the minds of patients,
quality of care starts with their experience at the hands of the provider.
Donna Ferguson (center) is shown above meeting Thomas Parisi, MD, JD (left), a surgeon with the Orthopedic Institute of Wisconsin, for the first time in Cancún the day before he performed her knee replacement surgery. Clinical laboratory tests, X-rays, and other diagnostics took place in the US prior to Ferguson’s authorization to undergo surgery in Mexico. (Photo copyright: Rocco Saint-Mleux/KHN.)
Clinical Laboratory Tests in US, Surgery in Mexico
Prior to traveling outside the US for surgery, Ferguson
underwent a physical exam, X-rays, and other diagnostic testing to ensure the
treatment approach was the best for her. Once that was confirmed, IndusHealth, Ashely’s medical travel
plan administrator, “coordinated [Donna’s] medical care and made travel
arrangements, including obtaining passports, airline tickets, hotel and meals,”
for both Donna and Terry Ferguson, KHN reported.
It seems reasonable to assume that NASH has agreements with
multiple clinical pathology laboratories and healthcare facilities throughout
the US for patients to get the tests they need prior to surgery. Partnerships
with medical tourism companies may well represent an avenue for pathology
laboratories to pursue.
Protections for Patients
So, why hasn’t medical tourism become the healthcare juggernaut some experts predicted? Managed Care suggests one reason is that Americans tend to be skeptical of the quality of care they will receive in a foreign facility.
“Building a familiar culture in a foreign destination may be appealing to some American consumers, but I do not see it as a sustainable business,” Health consultant Irving Stackpole, PhD, MEd, Psychology, told KHN. “It’s not unusual for people thinking about this to have doctors, family, and friends who will see this as a high-risk undertaking.”
Several factors helped Ferguson feel better about her
decision to travel to Mexico for surgery. One is that Galenia is credentialed.
Managed Care notes, “A number of organizations credential international facilities. The American Medical Association guidelines for medical tourism recommend that foreign medical providers have accreditation from the Joint Commission International or a similar organization.”
In addition to a credentialed facility and a highly trained
surgeon, NASH also provides US malpractice insurance coverage, giving patients
recourse in the event something goes wrong. Ferguson and American patients like
her would be able to sue in the US if care under this arrangement was not
successful.
Medical Tourism Pays Surgeon’s Full Fee
One fascinating twist in this story is that an American physician was flown to Cancun to perform this operation and was paid his full fee. The surgeon scheduled to perform Ferguson’s operation, Thomas Parisi, MD, JD, trained at the Mayo Clinic. He traveled from Wisconsin to Cancún to perform the procedure. “Dr. Parisi trained at Mayo, and you can’t do any better than that,” Ferguson told KHN.
KHN reported that Parisi spent less than 24 hours in
Cancun and was paid $2,700 for this surgery. That fee is three times of the
amount Medicare pays for this procedure. Further, Parisi’s fee was
significantly above what many managed care plans would negotiate for this type
of surgery.
American-trained physicians are common at many of the
facilities credentialed by the Joint Commission International. “Many overseas
hospitals are staffed in part by physicians and other health professionals who
were trained in US hospitals. One hospital in India has 200 US-trained
board-certified surgeons,” wrote James E. Dalen, MD,
MPH, ScD, and Joseph S. Alpert,
MD, in “Medical Tourists: Incoming and Outgoing,” published in The American
Journal of Medicine (AMJMED).
“In the past, medical tourism has been mostly a blind leap to a country far away, to unknown hospitals and unknown doctors with unknown supplies, to a place without US medical malpractice insurance. We are making the experience completely different and removing as much uncertainty as we can,” James Polsfut, CEO and Chairman, North American Specialty Hospital (NASH), told KHN.
Clinical laboratories in America may find opportunities
providing testing services to medical tourism organizations like NASH. It’s
worth investigating.
SIDM estimates approximately one in 10 patients with serious medical conditions are initially misdiagnosed, a problem that can be addressed if the right medical laboratory test is ordered at the right time for individual patients
Clinical
laboratory leaders know that lab tests are essential to a large proportion
of medical diagnoses. Therefore, any formal effort to reduce diagnostic errors that
affects how doctors order and use lab tests also will impact medical
laboratories that perform those tests.
“Diagnostic error is one of the most important safety
problems in healthcare today and causes the most patient harm,” said Paul L. Epner, CEO and
co-founder of the SIDM, in a news
release. “While many organizations have diagnostic quality on their radar,
it generally is not seen as a top priority. Those who’ve joined the coalition
acknowledge that diagnostic quality and safety are vital to improving
healthcare.”
To participate in the coalition, organizations must promise
to pursue ways to circumvent troublesome diagnostic errors and submit action
plans to the SIDM outlining proposals to diminish such errors. There are no
fees associated with being part of the coalition.
12-Million Patients Each Year Affected by Diagnostic
Errors
Epner told Modern
Healthcare that this coalition is the only one that exists that focuses
solely on diagnostic errors and ways to eradicate them. “There are a lot of
systematic things that we understand are problems, but we aren’t very good at
implementing solutions,” he said. “In terms of having standard solutions, we
are early.”
The National
Academy of Medicine (NAM) defines diagnostic error as “the failure to
establish an accurate and timely explanation of the patient’s health problem(s)
or to communicate that explanation to the patient. Simply put, these are
diagnoses that are missed altogether, wrong, or should have been made much
earlier.”
The SIDM website lists the following key sources for
acquiring data on diagnostic errors:
Autopsy data;
Physician self-reports of experiencing
diagnostic error;
Patient self-reports of experiencing diagnostic
error;
Hospital incident reporting systems;
Statistical analysis of unexpected
hospitalizations;
Research studies designed to measure diagnostic
error; and
Medical malpractice claims data.
“Providing an accurate medical diagnosis is complex and involves uncertainty, but it’s obviously essential to effective and timely treatment,” Paul L. Epner, CEO and co-founder of the SIDM, said in a news release announcing the formation of the coalition. “Nearly everyone will receive an inaccurate diagnosis at some point in their life and for some, the consequences will be grave. Major improvement is needed to systematically identify how to improve diagnostic quality and reduce harm to patients.” (Photo copyright: Society to Improve Diagnosis in Medicine.)
The SIDM
states that diagnostic errors affect an estimated 12-million patients in
the US each year, and that approximately one in 10 patients with a serious
medical condition are initially misdiagnosed. In addition, an estimated 40,000
to 80,000 people die each year from diagnostic errors in US hospitals, and it
is probable that at least that many patients suffer from permanent disability
annually due to improper diagnosis. It is also likely that diagnostic errors
cause more harm to patients than all other medical errors combined and are
responsible for an increasing number of malpractice cases, the SIDM notes.
John’s Hopkins Finds Most Misdiagnoses in Three
Categories of Medicine
A study published in the peer-reviewed journal Diagnosis,
reported that one in three malpractice cases that resulted in death or serious
harm to patients are due to misdiagnosis. The research for this study was
carried out by a team from the Johns Hopkins University
School of Medicine and was funded by the SIDM.
After analyzing more than 55,000 malpractice claims, the
researchers found that 34% of those cases which resulted in death or permanent
disability could be attributed to inaccurate or delayed diagnosis, an SIDM
analysis of the John’s Hopkins study noted.
The research team also examined underlying disease states to
search for misdiagnosis patterns and discovered that three quarters or 74.1% of
the misdiagnosed cases occurred in just three categories of medical conditions:
Cancer (37.8%);
Vascular events (22.8%); and
Infection (13.5%).
These serious cases resulted in $1.8 billion in malpractice
payouts over the course of 10 years, according to the SIDM.
“It is not just inconvenient to have a wrong or delayed
diagnosis. For many patients, misdiagnosis causes severe harm and expense, and
in the worst cases, death,” said David
Newman-Toker, MD, PhD, Director, Armstrong
Institute Center for Diagnostic Excellence at Johns Hopkins University
School of Medicine, in an SIDM
news post. “If we’re going to reduce serious harms from medical errors,
major strides must be made to improve diagnostic accuracy and timeliness. This
study shows us where to focus to start making a difference for patients. It
tells us that tackling diagnosis in these three specific disease areas could
have a major impact on reducing misdiagnosis-related harms.”
The John’s Hopkins research confirms that misdiagnosis is a
common and costly form of medical errors that can have catastrophic results.
The team concluded that it will take a system-wide effort involving physicians,
patients, and their families to improve the accuracy of diagnosis.
The SIDM’s Coalition to Improve Diagnostics is one such
effort and is primarily supported by a $2.45 million grant awarded by the Gordon and Betty Moore Foundation. The main
purpose for this grant was to help increase awareness about diagnostic errors
and develop ways to prevent such errors in the future.
“We think this is a new frontier of safety and quality we
want to be part of,” Daniel
Yang, MD, Program Officer for Diagnostic Excellence Initiative at the Moore
Foundation, told Modern Healthcare.
Clinical laboratory tests are essential to the diagnostic
process. Therefore, lab managers and staff should constantly review their procedures
to ensure accuracy in testing and reporting of results to ordering physicians.
If preventable medical errors are to be significantly reduced, labs will be a
big part of the team effort that will make it happen.
