The resulting genomic dataset may provide useful diagnostic insights that can be used by clinical laboratory and pathology professionals to learn how and why some people age with good health
Why do some seniors age in good health and other seniors
suffer with multiple chronic conditions? A new genetic database is using whole-genomic
sequencing (WGS) to answer that question in ways that may benefit medical
laboratories.
Because of the rapid aging of populations in the United
States and other developed nations throughout the world, there is keen interest
in how to keep seniors healthy. In fact, developing effective lab testing
services in support of improved senior health is one of the big opportunities
for both clinical laboratories and anatomic
pathology groups.
Until recent years, most clinical
pathologists dealt primarily with lab tests that used specimens such as blood
and urine. However, genetics researchers are using WGS to discover new causes
for many chronic illnesses. And the tools these researchers are developing offer
pathologists and clinical
laboratories powerful new ways to help doctors diagnose disease.
Through the use of WGS, the MGRB now features a huge
database of thousands of healthy elderly people. The data it contains may enable
pathology scientists to learn, from a genetic standpoint, why some people age
healthfully while others do not.
The researchers published their work titled, “The Medical
Genome Reference Bank: A Whole-Genome Data Resource of 4,000 Healthy Elderly
Individuals. Rationale and Cohort Design,” in the European Journal of
Human Genetics.
Finding New Applications for Genetic Data
According to the UNSW published study, “The MGRB is comprised
of individuals consented through the biobank programs of two contributing
studies … Each sample is from an individual who has lived to [greater than or
equal to] 70 years with no reported history or current diagnosis of
cardiovascular disease, dementia, or cancer, as confirmed by the participating
studies at recent follow-up study visits.”
The researchers noted in their paper, “Aged and healthy
populations are more likely to be selectively depleted of pathogenic alleles, and therefore
particularly suitable as a reference population for the major diseases of
clinical and public health importance.”
The MGRB plans to make its database openly accessible to the
international research community through its website once all 4,000 samples
have been sequenced. Currently, about 3,000 of the samples have been analyzed,
as noted on the Garvan website,
which is tracking the MGRB’s progress.
“The Medical Genome Reference Bank can tell us much about what it means to grow old but remain well, and is a powerful tool to help us deconstruct the genetics of common diseases,” said David Thomas, PhD (above), an NHMRC Principal Research Fellow, Director of The Kinghorn Cancer Center, and Head of the Cancer Division of the Garvan Institute in New South Wales, AU, in a statement reported by GenomeWeb. (Photo copyright: South West Sydney Research.)
Personal Genetic Data in Precision Medicine
“The integration of genomic knowledge and technologies into
healthcare is revolutionizing the way we approach clinical and public health
practice,” Caron
M. Molster, et al, noted in, “The Evolution of Public Health
Genomics: Exploring Its Past, Present, and Future,” published in Frontiers
in Public Health. Molster is Manager at the Health Department Western
Australia in Perth, and lead author of the paper.
“Public health genomics has evolved to responsibly integrate
advancements in genomics into the fields of personalized
medicine and public health,” the researchers wrote.
The 100,000
Genomes Project in the United Kingdom is sequencing the genomes of people
who have rare diseases and their families. Researchers all over the world are collecting
genomic data with plans to use it in different ways, and on various chronic
disease populations, in pursuit of precision medicine
goals.
Molster and her co-authors noted the comparable development
of genetic sequencing and precision medicine in their paper.
“Parallel to the developments in precision medicine has been
the advancement of technologies that enable the production, aggregation,
analysis, and dissemination of extremely large volumes of individual- and
population-level data on genes, environment, behavior, and other social and
economic determinants of health. These data have proven useful in finding new
correlations, patterns and trends, particularly those involving complex
interactions, in relation to diseases, pathogens, exposures, behaviors,
susceptibility (risk), and health outcomes in populations,” they wrote.
According to Paul Lacaze, PhD,
Head of the Public Health Genomics Program at Monash University, one of the
challenges in interpreting whole-genome data in order to diagnose disease is
“discriminating rare candidate disease-causing variants from the large numbers
of benign variants unique to each individual. Reference populations are
powerful filters,” he noted in the MGRB paper.
The MGRB database provides just such a powerful reference
population, giving researchers who are studying specific diseases a tool for
comparison.
Other Studies into Heathy Aging
Other initiatives to create datasets of genome information
for specific populations also are underway. The Scripps
Translational Science Institute (STSI) in La Jolla, Calif., has been
studying healthy aging since 2007. That’s when STSI launched the Wellderly Study,
according to a news
release. As of 2016, they had sequenced the genomes of 600 study
participants, as well as 511 samples for comparison from a study being conducted
separately by the Inova Translational Medicine Institute, a paper in Nature noted.
Another effort being conducted in China involves a database
called PGG.Population.
These researchers seek to “create a comprehensive depository of geographic and
ethnic variation of human genome, as well as a platform bringing influence on
future practitioners of medicine and clinical investigators,” according to
their 2018 paper published in Nucleic Acids
Research.
In this case, rather than identifying common genomic
variants among a specific population, such as the healthy elderly, the
researchers are working to understand how genetic variations are distributed
among specific populations. “The PGG.Population database documents 7,122
genomes representing 356 global populations from 107 countries and provides
essential information for researchers to understand human genomic diversity and
genetic ancestry,” wrote the researchers.
Each of these disparate datasets represents paths of
investigation that could lead to a better understanding of personal and public health.
As technologies continue to develop that enable scientists to sift through the
massive amount of WGS data being generated, a clearer picture of what healthy
aging at the genetic level looks like will likely emerge.
Precision medicine is leading to precision public health,
and clinical pathology laboratories are important parts of the public health
puzzle.
Patient privacy, ethics of monetizing not-for-profit data, and questions surrounding industry conflicts appear after the public announcement of an arrangement to grant exclusive access to academic pathology slides and samples
Clinical laboratories and anatomic pathology groups already serve as gatekeepers for a range of medical data used in patient treatments. Glass slides, paraffin-embedded tissue specimens, pathology reports, and autopsy records hold immense value to researchers. The challenge has been how pathologists (and others) in a not-for-profit academic center could set themselves up to potentially profit from their exclusive access to this archived pathology material.
Now, a recent partnership between Memorial Sloan Kettering Cancer Center (MSK) and Paige.AI (a developer of artificial intelligence for pathology) shows how academic pathology laboratories might accomplish this goal and serve a similar gatekeeper role in research and development using the decades of cases in their archives.
The arrangement, however, is not without controversy.
New York Times, ProPublica Report
Following an investigative report from the New York Times (NYT) and ProPublica, pathologists and board members at MSK are under fire from doctors and scientists there who have concerns surrounding ethics, exclusivity, and profiting from data generated by physicians and but owned by MSK.
“Hospital pathologists have strongly objected to the Paige.AI deal, saying it is unfair that the founders received equity stakes in a company that relies on the pathologists’ expertise and work amassed over 60 years. They also questioned the use of patients’ data—even if it is anonymous—without their knowledge in a profit-driven venture,” the NYT article states.
Prominent members of MSK are facing scrutiny from the media and peers—with some relinquishing stakes in Paige.AI—as part of the backlash of the report. This is an example of the perils and PR concerns lab stakeholders might face concerning the safety of data sharing and profits made by medical laboratories and other diagnostics providers using patient data.
Controversy Surrounds Formation of Paige.AI/MSK Partnership
In February 2018, Paige.AI announced closing the deal on a $25-million round of Series A funding, and in gaining exclusive access to 25-million pathology slides and computational pathology intellectual property held by the Department of Pathology at Memorial Sloan Kettering. Coverage by TechCrunch noted that while MSK received an equity stake as part of the licensing agreement, they were not a cash investor.
Creation of the company involved three hospital insiders and three additional board members with the hospital itself established as part owner, according to STAT.
Unnamed officials told the NYT that board members at MSK only invested in Paige.AI after earlier efforts to generate outside interest and investors were unsuccessful. NYT’s coverage also notes experts in non-profit law and corporate governance have raised questions as to compliance with federal and state laws that govern nonprofits in light of the Paige.AI deal.
Growing Privacy Fallout and Potential Pitfalls for Medical Labs
The original September 2018 NYT coverage noted that Klimstra intends to divest his ownership stake in Paige.AI. Later coverage by NYT in October, notes that Democrat Representative Debbie Dingell of Michigan submitted a letter questioning details about patient privacy related to Paige.AI’s access to MSK’s academic pathology resources.
According to the NYT, MSK also issued a memo to employees announcing new restrictions on interactions with for-profit companies with a moratorium on board members investing in or holding board positions in startups created within MSK. The nonprofit further noted it is considering barring hospital executives from receiving compensation for their work on outside boards.
However, MSK told the NYT this only applies to new deals and will not affect the exclusive deal between Paige.AI and MSK.
“We have determined,” MSK wrote, “that when profits emerge through the monetization of our research, financial payments to MSK-designated board members should be used for the benefit of the institution.”
There are no current official legal filings regarding actions against the partnership. Despite this, the arrangement—and the subsequent fallout after the public announcement of the arrangement—serve as an example of pitfalls medical laboratories and other medical service centers considering similar arrangements might face in terms of public relations and employee scrutiny.
Risk versus Reward of Monetizing Pathology Data
While the Paige.AI situation is only one of multiple concerns now facing healthcare teams and board members at MSK, the events are an example of risks pathologists take when playing a role in a commercial enterprise outside their own operations or departments.
In doing so, the pathologists investing in and shaping the deal with Paige.AI brought criticism from reputable sources and negative exposure in major media outlets for their enterprise, themselves, and MSK as a whole. The lesson from this episode is that pathologists should tread carefully when entertaining offers to access the patient materials and data archived by their respective anatomic pathology and clinical laboratory organizations.
SHERLOCK makes accurate, fast diagnoses for about 61-cents per test with no refrigeration needed; could give medical laboratories a new diagnostic tool
The tool is called SHERLOCK, which stands for (Specific High-sensitivity Enzymatic Reporter unLOCKing). And it is causing excitement in the scientific community for several reasons:
It can detect pathogens in extremely small amounts of genetic matter;
Tests can be performed using urine and/or saliva rather than blood;
The tests are extremely sensitive; and they
Cost far less than the diagnostic tests currently in use.
How SHERLOCK and CRISPR Differ and Why That’s Important
Scientists have long suspected that CRISPR could be used to detect viruses. However, far more attention has been given to the its genome editing capabilities. And, there are significant differences between how CRISPR and SHERLOCK work. According to the Science article, when CRISPR is used to edit genes, a small strip of RNA directs an enzyme capable of cutting DNA to a precise location within a genome. The enzyme that CRISPR uses is called Cas9 (CRISPR associated protein 9). It works like scissors, snipping the strand of DNA, so that it is either damaged or replaced by a healthy, new sequence.
SHERLOCK, however, uses a different enzyme—Cas13a (originally dubbed C2c2 by the researchers who discovered it). Cas13a goes to RNA, rather than DNA, and once it starts cutting, it doesn’t stop. It chops through any RNA it encounters. The researchers who developed SHERLOCK describe these cuts as “collateral cleavage.” According to an article published by STAT, “All that chopping generates a fluorescent signal that can be detected with a $200 device or, sometimes, with the naked eye.”
The screenshot above is from a video in which Feng Zhang, PhD (center), a Core Member of the Broad Institute at MIT and one of the lead researchers working on SHERLOCK, and his research team, explain the difference and value SHERLOCK will make in the detection of diseases like Zika. Click on the image above to watch the video. (Video copyright: Broad Institute/MIT.)
Early Stage Detection in Clinical Laboratories
A research paper published in Science states that SHERLOCK can provide “rapid DNA or RNA detection with attomolar sensitivity and single-base mismatch specificity.” Attomolar equates to about one part per quintillion—a billion-billion. According to the article on the topic also published in Science, “The detection sensitivity of the new CRISPR-Cas13a system for specific genetic material is one million times better than the most commonly used diagnostic technique.” Such sensitivity suggests that clinical laboratories could detect pathogens at earlier stages using SHERLOCK.
The Stat article notes that, along with sensitivity, SHERLOCK has specificity. It can detect a difference of a single nucleotide, such as the difference between the African and Asian strains of Zika (for example, the African strain has been shown to cause microcephaly, whereas the Asian strain does not). Thus, the combination of sensitivity and specificity could mean that SHERLOCK would be more accurate and faster than other diagnostic tests.
Clinicians in Remote Locations Could Diagnose and Treat Illness More Quickly
Perhaps one of the most important aspects of SHERLOCK is the portability and durability of the test. It can be performed on glass fiber paper and works even after the components have been freeze dried. “We showed that this system is very stable, so you can really put it on a piece of paper and it will survive. You don’t have to refrigerate it all the times,” stated Feng Zhang, PhD, in an interview with the Washington Post. Zhang is a Core Member of the Broad Institute at MIT and was one of the scientists who developed CRISPR.
The researchers note that SHERLOCK could cost as little as 61-cents per test to perform. For clinicians working in remote locations with little or no power, such a test could improve their ability to diagnose and treatment illness in the field and possibly save lives.
“If you had something that could be used as a screening test, very inexpensively and rapidly, that would be a huge advance, particularly if it could detect an array of agents,” stated William Schaffner, MD, Professor and Chair of the Department of Preventive Medicine at Vanderbilt University Medical Center, in the Post article. Schaffner describes the Broad Institute’s research as being “very, very provocative.”
The test could radically change the delivery of care in more modern settings, as well. “It looks like one significant step on the pathway [that] is the Holy Grail, which is developing point-of-care, or bedside detection, [that] doesn’t require expensive equipment or even reliable power,” noted Scott Weaver, PhD, in an article on Big Think. Weaver is a Professor and Director at the Institute for Human Infections and Immunity University of Texas Medical Branch in Galveston, Texas.
Just the Beginning
Anatomic pathologists and clinical laboratories will want to follow SHERLOCK’s development. It could be on the path to fundamentally transforming the way disease gets diagnosed in their laboratories and in the field.
According to the Post article, “The scientists have filed several US patent applications on SHERLOCK, including for uses in detecting viruses, bacteria, and cancer-causing mutations.” In addition to taking steps to secure patents on the technology, the researchers are exploring ways to commercialize their work, as well as discussing the possibility of launching a startup. However, before this technology can be used in medical laboratory testing, SHERLOCK will have to undergo the regulatory processes with various agencies, including applying for FDA approval.
New discoveries about the genetics of prostate cancer could lead to better tools for diagnosing the disease and selecting effective therapies based on each patient’s specific physiology
In recent decades, the biggest challenge for urologists, and for the pathologists who diagnosed the prostate tissue specimens they referred, has been how to accurately differentiate between non-aggressive prostate cancer, which can exist for decades with no apparent symptoms, and aggressive prostate cancer that kills quickly.
Thus, a research study that has identified unique genetic features within prostate cancer that can help determine if the cancer is aggressive or not, and whether certain drugs may be effective, is good news for men, for urologists, and for the clinical laboratories that will be called upon to perform testing.
These types of breakthroughs bring precision medicine ever closer to having viable tools for effective diagnosis of different types of cancer.
Genetic Fingerprints of Cancer Tumor Types
One such study into the genetic pathways of prostate cancer is bringing precision medicine ever-closer to the anatomic pathology laboratory. Researchers from the Princess Margaret Cancer Centre, which is associated with the University of Toronto Faculty of Medicine, have discovered that some tumors in prostate cancer have a genetic fingerprint that may indicate whether or not the disease will become more aggressive and less responsive to treatment.
Robert Bristow, MD, PhD, and Paul Boutros, PhD, conducted a study of nearly 500 Canadian men who had prostate cancer. Published in the journal Nature, the researchers examined the genetic sequences of those tumors, looking for differences between those that responded to surgery or radiation and those that did not.
In the video above, Dr. Robert Bristow, clinician-scientist at Princess Margaret Cancer Centre, discusses the findings of a key piece in the genetic puzzle that explains why men born with a BRCA2 mutation develop aggressive prostate cancer. (Caption and photo copyright: University Health Network/Princess Margaret Cancer Centre.)
According to a FierceBiotech article, approximately 30% of men who have a type of prostate cancer thought to be curable eventually develop an aggressive metastatic type of the disease. About half of the men who developed a metastatic form of cancer had mutations to three specific genes:
“This information gives us new precision about the treatment response of men with prostate cancer and important clues about how to better treat one set of men versus the other to improve cure rates overall,” stated Bristow in a University Health Network (UHN) press release.
In another study, researchers looked at 15 patients with BRCA2-inheritied prostate cancer and compared the genomic sequences of those tumors to a large group of sequences from tumors in less-aggressive cancer cases. According to a ScienceDaily news release, they found that only 2% of men with prostate cancer have the BRCA2-inherited type.
Knowing what type of cancer a man has could be critically important for clinicians tasked with prescribing the most efficient therapies.
“The pathways that we discovered to be abnormal in the localized BRCA2-associated cancers are usually only found in general population cancers when they become resistant to hormone therapy and spread through the body,” noted Bristow in the ScienceDaily release. If clinicians knew from diagnosis that the cancer is likely to become aggressive, they could choose a more appropriate therapy from the beginning of treatment.
Genetic Mutations Also Could Lead to Breast and Brain Cancer Treatments
BRCA mutations have also been implicated in breast, ovarian, and pancreatic cancers, among some other types. The knowledge that BRCA1 and BRACA2 mutations could indicate a more aggressive cancer is likely to spark investigation into whether poly ADP ribose polymerase (PARP) inhibitors could be used as an effective therapy.
Researchers of the study published in the journal Science Translational Medicine stated that they “demonstrate mutant IDH1-dependent PARP inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived glioma cells in culture and genetically matched tumor xenografts in vivo.”
According to the UHN press release, the next step in using the knowledge that BRCA1 and BRCA2 may indicate a more aggressive prostate cancer is for researchers to create a diagnostic tool that can be used to determine what type of prostate cancer a man has. They expect the process to take several years. “This work really gives us a map to what is going on inside a prostate cancer cell, and will become the scaffold on which precision therapy will be built,” Boutros stated in a Prostate Cancer Canada news release.
Unlocking Knowledge That Leads to Accurate Diagnoses and Treatments
Research that furthers precision medicine and allows clinicians to choose the most appropriate treatment for individuals shows how quickly scientists are applying new discoveries. Every new understanding of metabolic pathways that leads to a new diagnostic tool gives clinicians and the patients they treat more information about the best therapies to select.
For the anatomic pathology profession, this shows how ongoing research into the genetic makeup of prostate cancer is unlocking knowledge about the genetic and metabolic pathways involved in this type of cancer. Not only does this help in diagnosis, but it can guide the selection of appropriate therapies.
On the wider picture, the research at the Princess Margaret Cancer Centre is one more example of how scientists are rapidly applying new knowledge about molecular and genetic processes in the human body to identify new ways to more accurately diagnose disease and select therapies.
Genomics is quickly becoming the foundational disruptor technology on which many new and powerful clinical laboratory tests and procedures will be based
Genomics testing has become accessible, affordable, and in some instances, life-saving. Clinical laboratories and pathology groups are handling more genomic data each year, and the trend does not appear to be slowing down. Here are current trends in genomic research that soon could be bringing new capabilities to medical laboratories nationwide.
Improved Data Sharing
Sometimes genetic tests don’t translate into better outcomes for patients because medical labs are limited in how they can share genomic data. Thus, experts from various disciplines are seeking ways to integrate genomic data sharing into the hospital and laboratory clinical workflow in a form that’s easily accessible to doctors. (more…)
