Should greater attention be given to protein damage in chronic diseases such as Alzheimer’s and diabetes? One life scientist says “yes” and suggests changing how test developers view the cause of age-related and degenerative diseases
DNA and the human genome get plenty of media attention and are considered by many to be unlocking the secrets to health and long life. However, as clinical laboratory professionals know, DNA is just one component of the very complex organism that is a human being.
In fact, DNA, RNA, and proteins are all valid biomarkers for medical laboratory tests and, according to one life scientist, all three should get equal attention as to their role in curing disease and keeping people healthy.
Along with proteins and RNA, DNA is actually an “equal partner in the circle of life,” wrote David Grainger, PhD, CEO of Methuselah Health, in a Forbes opinion piece about what he calls the “cult of DNA-centricity” and its relative limitations.
Effects of Protein Damage
“Aging and age-related degenerative diseases are caused by protein damage rather than by DNA damage,” explained Grainger, a Life Scientist who studies the role proteins play in aging and disease. “DNA, like data, cannot by itself do anything. The data on your computer is powerless without apps to interpret it, screens and speakers to communicate it, keyboards and touchscreens to interact with it.”
“Similarly,” he continued, “the DNA sequence information (although it resides in a physical object—the DNA molecule—just as computer data resides on a hard disk) is powerless and ethereal until it is translated into proteins that can perform functions,” he points out.
According to Grainger, diseases such as cystic fibrosis and Duchenne Muscular Dystrophy may be associated with genetic mutation. However, other diseases take a different course and are more likely to develop due to protein damage, which he contends may strengthen in time, causing changes in cells or tissues and, eventually, age-related diseases.
“Alzheimer’s disease, diabetes, or autoimmunity often take decades to develop (even though your genome sequence has been the same since the day you were conceived); the insidious accumulation of the damaged protein may be very slow indeed,” he penned.
“But so strong is the cult of DNA-centricity that most scientists seem unwilling to challenge the fundamental assumption that the cause of late-onset diseases must lie somewhere in the genome,” Grainger concludes.
Shifting Focus from Genetics to Proteins
Besides being CEO of Methuselah Health, Grainger also is Co-Founder and Chief Scientific Advisor at Medicxi, a life sciences investment firm that backed Methuselah Health with $5 million in venture capital funding for research into disease treatments that focus on proteins in aging, reported Fierce CEO.
Methuselah Health, founded in 2015 in Cambridge, UK, with offices in the US, is reportedly using post-translational modifications for analysis of many different proteins.
How Does it Work?
“At Methuselah Health, we have shifted focus from the genetics—which tells you in an ideal world how your body would function—to the now: this is how your body functions now and this is what is going wrong with it. And that answer lies in the proteins,” stated Dr. David Grainger (above), CEO of Methuselah Health, in an interview with the UK’s New NHS Alliance. Click on this link to watch the full interview. [Photo and caption copyright: New NHS Alliance.]
This is how Methuselah Health analyzes damaged proteins using mass spectrometry, according to David Mosedale, PhD, Methuselah Health’s Chief Technology Officer, in the New NHS Alliance story:
- Protein samples from healthy individuals and people with diseases are used;
- Proteins from the samples are sliced into protein blocks and fed slowly into a mass spectrometer, which accurately weighs them;
- Scientists observe damage to individual blocks of proteins;
- Taking those blocks, proteins are reconstructed to ascertain which proteins have been damaged;
- Information is leveraged for discovery of drugs to target diseases.
Mass spectrometry is a powerful approach to protein sample identification, according to News-Medical.Net. It enables analysis of protein specificity and background contaminants. Interactions among proteins—with RNA or DNA—also are possible with mass spectrometry.
Methuselah Health’s scientists are particularly interested in the damaged proteins that have been around a while, which they call hyper-stable danger variants (HSDVs) and consider to be the foundation for development of age-related diseases, Grainger told WuXi AppTec.
“By applying the Methuselah platform, we can see the HSDVs and so understand which pathways we need to target to prevent disease,” he explained.
For clinical laboratories, pathologists, and their patients, work by Methuselah Health could accelerate the development of personalized medicine treatments for debilitating chronic diseases. Furthermore, it may compel more people to think of DNA as one of several components interacting that make up human bodies and not as the only game in diagnostics.
—Donna Marie Pocius
The Cult of DNA-Centricity
Methuselah Health CEO David Grainger Out to Aid Longevity
VIDEO: Methuselah Health, Addressing Diseases Associated with Aging
Understanding and Slowing the Human Aging Clock Via Protein Stability
Using Mass Spectrometry for Protein Complex Analysis
Access to vast banks of genomic data is powering a new wave of assessments and predictions that could offer a glimpse at how genetic variation might impact everything from Alzheimer’s Disease risk to IQ scores
Anatomic pathology groups and clinical laboratories have become accustomed to performing genetic tests for diagnosing specific chronic diseases in humans. Thanks to significantly lower costs over just a few years ago, whole-genome sequencing and genetic DNA testing are on the path to becoming almost commonplace in America. BRCA 1 and BRCA 2 breast cancer gene screenings are examples of specific genetic testing for specific diseases.
However, a much broader type of testing—called polygenic scoring—has been used to identify certain hereditary traits in animals and plants for years. Also known as a genetic-risk score or a genome-wide score, polygenic scoring is based on thousands of genes, rather than just one.
Now, researchers in Cambridge, Mass., are looking into whether it can be used in humans to predict a person’s predisposition to a range of chronic diseases. This is yet another example of how relatively inexpensive genetic tests are producing data that can be used to identify and predict how individuals get different diseases.
Assessing Heart Disease Risk through Genome-Wide Analysis
Sekar Kathiresan, MD, Co-Director of the Medical and Population Genetics program at Broad Institute of MIT/Harvard and Director of the Center for Genomics Medicine at Massachusetts General Hospital (Mass General); and Amit Khera, MD, Cardiology Fellow at Mass General, told MIT Technology Review “the new scores can now identify as much risk for disease as the rare genetic flaws that have preoccupied physicians until now.”
“Where I see this going is that, at a young age, you’ll basically get a report card,” Khera noted. “And it will say for these 10 diseases, here’s your score. You are in the 90th percentile for heart disease, 50th for breast cancer, and the lowest 10% for diabetes.”
However, as the MIT Technology Review article points out, predictive genetic testing, such as that under development by Khera and Kathiresan, can be performed at any age.
“If you line up a bunch of 18-year-olds, none of them have high cholesterol, none of them have diabetes. It’s a zero in all the columns, and you can’t stratify them by who is most at risk,” Khera noted. “But with a $100 test we can get stratification [at the age of 18] at least as good as when someone is 50, and for a lot of diseases.”
Sekar Kathiresan, MD (left), Co-Director of the Medical and Population Genetics program at Broad Institute at MIT/Harvard and Director of the Center for Genomics Medicine at Massachusetts General Hospital; and Amit Khera, MD (right), Cardiology Fellow at Mass General, are researching ways polygenic scores can be used to predict the chance a patient will be prone to develop specific chronic diseases. Anatomic pathology biomarkers and new clinical laboratory performed genetic tests will likely follow if their research is successful. (Photo copyrights: Twitter.)
Polygenic Scores Show Promise for Cancer Risk Assessment
Khera and Kathiresan are not alone in exploring the potential of polygenic scores. Researchers at the University of Michigan’s School of Public Health looked at the association between polygenic scores and more than 28,000 genotyped patients in predicting squamous cell carcinoma.
“Looking at the data, it was surprising to me how logical the secondary diagnosis associations with the risk score were,” Bhramar Mukherjee, PhD, John D. Kalbfleisch Collegiate Professor of Biostatistics, and Professor of Epidemiology at U-M’s School of Public Health, stated in a press release following the publication of the U-M study, “Association of Polygenic Risk Scores for Multiple Cancers in a Phenome-wide Study: Results from The Michigan Genomics Initiative.”
“It was also striking how results from population-based studies were reproduced using data from electronic health records, a database not ideally designed for specific research questions and [which] is certainly not a population-based sample,” she continued.
Additionally, researchers at the University of California San Diego School of Medicine (UCSD) recently published findings in Molecular Psychiatry on their use of polygenic scores to assess the risk of mild cognitive impairment and Alzheimer’s disease.
The UCSD study highlights one of the unique benefits of polygenic scores. A person’s DNA is established in utero. However, predicting predisposition to specific chronic diseases prior to the onset of symptoms has been a major challenge to developing diagnostics and treatments. Should polygenic risk scores prove accurate, they could provide physicians with a list of their patients’ health risks well in advance, providing greater opportunity for early intervention.
Future Applications of Polygenic Risk Scores
In the January issue of the British Medical Journal (BMJ), researchers from UCSD outlined their development of a polygenic assessment tool to predict the age-of-onset of aggressive prostate cancer. As Dark Daily recently reported, for the first time in the UK, prostate cancer has surpassed breast cancer in numbers of deaths annually and nearly 40% of prostate cancer diagnoses occur in stages three and four. (See, “UK Study Finds Late Diagnosis of Prostate Cancer a Worrisome Trend for UK’s National Health Service,” May 23, 2018.)
An alternative to PSA-based testing, and the ability to differentiate aggressive and non-aggressive prostate cancer types, could improve outcomes and provide healthcare systems with better treatment options to reverse these trends.
While the value of polygenic scores should increase as algorithms and results are honed and verified, they also will most likely add to concerns raised about the impact genetic test results are having on patients, physicians, and genetic counselors.
And, as the genetic testing technology of personalized medicine matures, clinical laboratories will increasingly be required to protect and distribute much of the protected health information (PHI) they generate.
Nevertheless, when the data produced is analyzed and combined with other information—such as anatomic pathology testing results, personal/family health histories, and population health data—polygenic scores could isolate new biomarkers for research and offer big-picture insights into the causes of and potential treatments for a broad spectrum of chronic diseases.
Forecasts of Genetic Fate Just Got a Lot More Accurate
Polygenic Scores to Classify Cancer Risk
Association of Polygenic Risk Scores for Multiple Cancers in a Phenome-Wide Study: Results from the Michigan Genomics Initiative
Polygenic Risk Score May Identify Alzheimer’s Risk in Younger Populations
Use of an Alzheimer’s Disease Polygenic Risk Score to Identify Mild Cognitive Impairment in Adults in Their 50s
New Polygenic Hazard Score Predicts When Men Develop Prostate Cancer
Polygenic Hazard Score to Guide Screening for Aggressive Prostate Cancer: Development and Validation in Large Scale Cohorts
UK Study Finds Late Diagnosis of Prostate Cancer a Worrisome Trend for UK’s National Health Service
New scientific insights from these studies represent progress in the effort to develop a clinical laboratory test that would enable physicians to diagnose Alzheimer’s Disease earlier and with greater accuracy
Most medical laboratory professionals are aware that, for more than 30 years, in vitro diagnostic (IVD) developers and pharmaceutical researchers have sought the Holy Grail of clinical laboratory testing—an accurate test for Alzheimer’s disease that is minimally-invasive and produces information that is actionable by clinicians at a reasonable cost. Such a test could spark a revolution in the diagnosis and treatment of this debilitating disease and would improve the lives of tens of thousands of people each year.
Now, two different research studies being conducted in Germany and Japan may have developed such tests that use blood samples. The tests detect specific biomarkers found in Alzheimer’s patients and one day could enable physicians to diagnose the disease in its preclinical stages.
German Test Identifies Amyloid-Beta Biomarker
The test under development at Ruhr University in Bochum, Germany, detects the presence of amyloid-beta, a component of amyloid plaque (AKA, amyloid-β plaques), which has consistently been found in Alzheimer’s patents, according to United Press International (UPI).
A healthy brain has amyloid-beta plaques, too. However, in a person with Alzheimer’s disease, the amyloid-beta is misfolded, formed like a sheet, and toxic to nerve cells, the researchers explained in a press release.
The test works with small amounts of blood plasma and employs an immuno-infrared-sensor, also developed at Ruhr University. The sensor measures the amounts of both pathological (the misfolded kind) and healthy amyloid-beta in the blood.
Amyloid plaques can start to form decades prior to the onset of Alzheimer’s symptoms, making them identifiable biomarkers that can be used as a “preselection funnel in two‐step diagnostics,” the researchers noted.
“The use of the immuno‐infrared‐sensor as an initial screening funnel to identify people who should undergo further diagnostics and eventually take part in clinical trials on therapeutics targeting Aβ misfolding might already be an important step forward because subjects with early AD stages are hard to identify,” the researchers note. “To our knowledge, there is today no other plasma test available, which has been tested both in an AD research cohort and in the general population.”
Klaus Gerwert, PhD, (left) Chair of Biophysics at Ruhr University in Bochum, Germany, and Dr. Katsuhiko Yanagisawa, PhD, (right) molecular biologist and Director of the Center for Development of Advanced Medicine for Dementia in Obu City, Japan, both lead research teams that developed tests for identifying amyloid-β biomarkers in early onset Alzheimer’s patients. More research must be conducted before these assays could be offered by clinical laboratories. (Photo copyrights: International Max Planck Research School in Chemical and Molecular Biology/Nagoya University School of Medicine.)
Another Blood Test Finds Amyloid-Beta
Interestingly, just a few months ahead of the German researchers’ paper, scientists at the Center for Development of Advanced Medicine for Dementia (CAMD) in Obu City, Japan, published their own paper on a similar blood test they developed that also identifies high levels of amyloid-beta in patients with Alzheimer’s.
However, according to a news release, the Japanese study involved the use of immunoprecipitation and mass spectrometry to measure amyloid-beta related fragments in the blood.
The study, which was published in Nature, involved 373 people: 121 Japanese in the discovery cohort set and 252 Australians in the validation data set. The test found amyloid-beta levels in the brain with 90% accuracy, The Scientist reported.
“These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-β burden at an individual level. These plasma biomarkers also have cost-benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening,” the researchers wrote in their paper.
Previous Alzheimer’s Research
These studies are not the first to seek biomarkers that could detect the early-onset of Alzheimer’s disease. In 2016, Dark Daily reported on two other studies: one conducted at Rowan University School of Osteopathic Medicine (RowanSOM) and another by IVD company Randox Laboratories. (See Dark Daily, “Two Different Research Teams Announce Tests for Alzheimer’s Disease That Could Be Useful for Clinical Laboratories after Clearance by the FDA,” November 30, 2016.)
Nevertheless, as of 2018, Alzheimer’s disease has impacted the lives of approximately 5.7 million Americans of all ages, according to the Alzheimer’s Association. And yet, doctors currently only have expensive positron emission tomography (PET) brain scans and invasive cerebrospinal fluid (CSF) analysis to identify the disease, generally in the latter stages of its development.
Thus, a less invasive, inexpensive test that accurately identifies biomarkers found in the majority of people during the early stages of the disease would be a boon to physicians who treat chronic neurodegenerative disease, medical laboratories that perform the tests, and, of course, the thousands of people each year who are diagnosed and suffer with this debilitating condition.
—Donna Marie Pocius
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Researchers Develop Potential Blood Test for Alzheimer’s Disease
Japan Researchers Develop Cheap and Easy Way to Diagnose Alzheimer’s
Two Different Research Teams Announce Tests for Alzheimer’s Disease That Could Be Useful for Clinical Laboratories After Clearance by the FDA
Low interest and a lack of diversity among study participants hinders research into one of America’s most fatal and costly chronic diseases
Finding enough people to participate in clinical laboratory trials for Alzheimer’s disease can be a daunting task for researchers. The shortage of participants has compelled scientists to develop innovative ways to locate volunteers for their studies. That includes “Swab-a-Palooza” events to make it easy for individuals to provide samples for this research and get speedy feedback about their ApoE.
“It’s all about recruitment now,” Stephen Salloway, MD, Director of Neurology and the Memory and Aging Program at Butler Hospital in Providence, R.I., and Professor of Clinical Neurosciences and Psychiatry at Brown Medical School, said in an article on the Biomedical Research Forum (BRF) website.
Some researchers are hunting online and offering free genetic testing to interested individuals to ensure they obtain the number of participants needed for their trials. Both the Alzheimer’s Prevention Registry (APR) and the Brain Health Registry (BHR) are using the Internet to compile listings of suitable participants.
The APR is dedicated to uniting Alzheimer’s researchers with individuals interested in participating in clinical trials. The Phoenix-based non-profit organization also educates the public on Alzheimer’s and prevention of the disease. The Brain Health Registry is a web-based research study led by medical researchers at the University of California, San Francisco. Participants complete online questionnaires and tests that provide researchers with information regarding an individual’s health, lifestyle, and cognitive function. The collected data is used to create a listing of potential participants for Alzheimer’s studies.
Using Genetic Testing to Recruit Alzheimer’s Study Participants
GeneMatch is a program led by the Banner Alzheimer’s Institute in the Phoenix area that is part of the APR. The purpose of this national program is to recruit participants for research on Alzheimer’s disease by using genetic testing to match qualified volunteers with research studies. According to their website, 80% of research studies on the disease aren’t completed on time due to a lack of volunteers.
Anyone can register to be part of GeneMatch as long as they live in the United States and are between the ages of 55 and 75. In addition, participants cannot have a diagnosis of cognitive impairment, Alzheimer’s, or dementia.
“We hold local swabbing parties, where the GeneMatch sign-up rate is 95%,” Pierre Tariot, MD, Internal Medicine and Psychiatry, and Director of Banner Alzheimer’s Institute, said in the BRF article. “Jeffrey Cummings calls them Swab-a-Paloozas.”
GeneMatch screens individuals for the Apolipoprotein E (ApoE) and the ApoE-e4 allele which increases the risk for Alzheimer’s disease and is associated with earlier onset of memory loss and other symptoms. At this time, it is not known how this allele is related to the risk of getting the disease, but researchers have discovered the brain tissue of affected individuals have an increased number of protein clumps called amyloid plaques. A buildup of these plaques may lead to the death of neurons and the presence of Alzheimer’s symptoms.
“I spend a lot of time in my community doing outreach. People are very interested and receptive,” said Salloway, who recently hosted a swabbing party for GeneMatch. “At events, I ask everyone to tell five other people about what they learned, and to host swabbing parties themselves.”
The DNA samples obtained by GeneMatch are analyzed by a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Over the past two years, GeneMatch has tested over 45,000 individuals for the ApoE-e4 allele and were able to identify 1,000 homozygote and 9,000 heterozygote carriers.
Lack of Diversity Among Study Participants
A paper published in September 2017 by Jeffrey Cummings, MD, Director of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, estimated the number of participants currently needed for Alzheimer’s research is over 55,000. Clinical trials for Alzheimer’s need volunteers who have little or no symptoms of the illness and locating such interested individuals can be complicated.
Jeffrey Cummings, MD (above), is Medical Director at Lou Ruvo Center for Brain Health in Las Vegas. In an interview with Drug Discovery and Development, Cummings said, “There is a huge problem of recruitment for many diseases throughout the nation. The problem goes beyond Alzheimer’s disease; there is a general lack of awareness by the public of either the availability or the importance of clinical trials.” (Photo copyright: Jerry Henkel/Las Vegas Review-Journal.)
Additional obstacles that face Alzheimer’s researchers are the lack of diversity among volunteers for their studies. The participants in GeneMatch are 78% female and there is little representation of African-American and Latino minorities.
“It’s not easy to get healthy individuals to join, and those who do are predominantly highly educated, white, and female,” Jessica Langbaum, PhD, Principal Scientist at Banner Alzheimer’s Institute, said in the BRF article. “That’s okay if the women are the health-info gatherers and send their men for trials, but it will be a problem if we cannot get men into studies.”
Delivering ApoE Genotype Results at Events
Technology that could help locate participants for Alzheimer’s research at open “Swab-a-Palooza” events include a small ApoE analyzer called the Spartan Cube. The small molecular diagnostic device, manufactured by Ottawa-based Spartan Bioscience, Inc., can deliver an ApoE genotype result in less than an hour. The gadget is perfect for outreach gatherings, as people can learn their ApoE genotype while at an event. At this time, the Spartan Cube is used only for research purposes and is not CLIA approved.
The paper by Cummings was a topic of discussion at the Clinical Trials on Alzheimer’s Disease (CTAD), which was held in November in Boston. The CTAD is an annual conference for Alzheimer’s disease researchers to meet and share information about the disease with each other. The 11th CTAD conference will take place in Barcelona, Spain, in October of this year.
More than five million people are living with Alzheimer’s disease in the United States and this number could reach 16 million by 2050, according to the Alzheimer’s Association. It is the sixth leading cause of death in the US and cost the nation $259 billion in 2017. It’s estimated that the costs associated with the disease could reach $1.1 trillion by 2050, which makes finding volunteers for research studies an important endeavor.
Don’t Be an Enrollment Loser: Throw Your Own Swab-a-Palooza!
Alzheimer’s Disease Drug Development Pipeline: 2017
A Cure for Alzheimer’s by 2025? An Interview with Jeff Cummings, MD
A university research team and a global diagnostics company simultaneously but independently unveil two new tests that accurately identify people predisposed to Alzheimer’s at earlier stages in the disease
Medical laboratory scientists and clinical pathologists have long awaited an accurate and clinically-useful test for the predisposition and early diagnosis of Alzheimer’s disease. Now comes pioneering efforts from two organizations that suggest real progress is being made.
One organization is an academic center and the other is an in vitro company. It was a research team at Rowan University School of Osteopathic Medicine (RowanSOM) that announced development of the first blood test to use the body’s own immune system to detect mild cognitive impairment (MCI), an early stage of Alzheimer’s disease.
Similarly, research scientists for Randox Laboratories unveiled to pathologists, clinical laboratory leaders, and others attending the American Association for Clinical Chemistry (AACC) Annual Scientific Meeting, how their biochip-based technology also could be used to detect elevated risk for Alzheimer’s disease. (more…)