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Category Archives: Genetic Medicine
January 08, 2021 -Using data from RNA sequencing, a team from the Icahn School of Medicine at Mount Sinai has detected three molecular subtypes of Alzheimers disease that could advance precision medicine treatments for the condition.
Alzheimers is the most common form of dementia, but it ranges in its biological and pathological manifestations. Researchers noted that there is a growing body of evidence suggesting that disease progression and responses to interventions differ significantly among Alzheimers patients.
While some patients have slow cognitive decline, others decline rapidly; some have significant memory loss and an inability to remember new information while others dont; and some patients experience psychosis or depression associated with Alzheimers while others dont.
Such differences strongly suggest there are subtypes of Alzheimers disease with different biological and molecular factors driving disease progression, said Bin Zhang, PhD, the lead author of the study, Director of the Center for Transformative Disease Modeling, and Professor of Genetics and Genomic Sciences at the Icahn School of Medicine.
RNA is a genetic molecule similar to DNA that encodes the instructions for making proteins. RNA sequencing is a technology that shows the presence and quantity of RNA in a biological sample like a brain slice.
To identify the subtypes of Alzheimers disease, researchers used a computational biology approach to understand the relationships among different types of RNA, clinical and pathological traits, and other biological factors that potentially drive the diseases progress.
The team analyzed RNA sequencing data of more than 1,500 samples across five brain regions from hundreds of deceased patients with Alzheimers disease and normal controls, and were able to identify three major molecular subtypes of Alzheimers disease. These subtypes were independent of age and disease stage, and were replicated across multiple brain regions in two cohort studies.
These subtypes correspond to different combinations of multiple dysregulated biological pathways leading to brain degeneration. Two neuropathological hall marks of Alzheimers disease, tau neurofibrillary tangle and amyloid-beta plaque, are significantly increased only in certain subtypes.
While many recent studies have shown that an elevated immune response may help cause Alzheimers, more than half of Alzheimers brains dont show increased immune response compared to normal, healthy brains. The analysis further revealed subtype-specific molecular drivers in Alzheimers progression in these samples.
The research also identified the correspondence between these molecular subtypes and the existing Alzheimers animal models used for mechanistic studies and for testing candidate therapeutics. This could partly explain why many drugs that succeeded in mouse models failed in human Alzheimers trials, which likely involved participants belonging to different molecular subtypes.
The subtyping described by the researchers was performed post mortem using the patients brain tissue. However, researchers said that if the findings were validated by future studies, the results could lead to the identification of biomarkers and clinical features in living patients associated with these molecular subtypes and earlier diagnosis and intervention.
Our systematic identification and characterization of the robust molecular subtypes of Alzheimers disease reveal many new signaling pathways dysregulated in Alzheimers and pinpoint new targets, said Zhang.
These findings lay down a foundation for determining more effective biomarkers for early prediction of Alzheimers, studying causal mechanisms of Alzheimers, developing next-generation therapeutics for Alzheimers, and designing more effective and targeted clinical trials, ultimately leading to precision medicine for the disease.
Going forward, studies should aim to advance the results found in this research to further achieve precision medicine for Alzheimers.
The remaining challenges for future research include replication of the findings in larger cohorts, validation of subtype specific targets and mechanisms, identification of peripheral biomarkers and clinical features associated with these molecular subtypes, Zhang concluded.
Wednesday, January 6, 2021
Using a recently developed DNA base-editing technique, researchers correct accelerating aging disorder.
Researchers have successfully used a DNA-editing technique to extend the lifespan of micewith thegenetic variationassociated withprogeria, a rare genetic disease that causes extreme premature aging in children and can significantly shorten their life expectancy. The studywas published in the journalNature, and was a collaboration between the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health; Broad Institute of Harvard and MIT, Boston; and the Vanderbilt University Medical Center, Nashville, Tennessee.
DNA is made up of four chemical bases A, C, G and T. Progeria, which is also known as Hutchinson-Gilford progeria syndrome, is caused by a mutation in the nuclear laminA(LMNA) gene in which one DNA base C is changed to a T. This change increases the production of the toxic protein progerin, which causes the rapid aging process.
Approximately 1 in 4 million children are diagnosed with progeria within the first two years of birth, and virtually all of these children develop health issues in childhood and adolescence that are normally associated with old age, including cardiovascular disease (heart attacks and strokes), hair loss, skeletal problems, subcutaneous fat loss and hardened skin.
For this study, researchers used a breakthrough DNA-editing technique calledbase editing, which substitutes a single DNA letter for another without damaging the DNA, to study how changing this mutation might affect progeria-like symptoms in mice.
"The toll of this devastating illness on affected children and their families cannot be overstated," said Francis S. Collins, M.D., Ph.D., a senior investigator in NHGRI's Medical Genomics and Metabolic Genetics Branch, NIH director and a corresponding author on the paper. "The fact that a single specific mutation causes the disease in nearly all affected children made us realize that we might have tools to fix the root cause. These tools could only be developed thanks to long-term investments in basic genomics research.
The study follows another recent milestone for progeria research, as theU.S. Food and Drug Administration approved the first treatment for progeriain November 2020, a drug called lonafarnib. The drug therapy provides some life extension, but it is not a cure. The DNA-editing method may provide an additional and even more dramatic treatment option in the future.
David Liu, Ph.D., and his lab at the Broad Institute developed the base-editing method in 2016, funded in part by NHGRI.
"CRISPR editing, while revolutionary, cannot yet make precise DNA changes in many kinds of cells," said Dr. Liu, a senior author on the paper. "The base-editing technique we've developed is like a find-and-replace function in a word processor. It is extremely efficient in converting one base pair to another, which we believed would be powerful in treating a disease like progeria.
To test the effectiveness of their base-editing method, the team initially collaborated with the Progeria Research Foundation to obtain connective tissue cells from progeria patients. The team used the base editor on theLMNAgene within the patients cells in a laboratory setting. The treatment fixed the mutation in 90% of the cells.
The Progeria Research Foundation was thrilled to collaborate on this seminal study with Dr. Collinss group at the NIH and Dr. Lius group at Broad Institute, said Leslie Gordon, M.D., Ph.D., a co-author andmedical director of The Progeria Research Foundation, which partially funded the study. These study results present an exciting new pathway for investigation into new treatments and the cure for children with progeria.
Following this success, the researchers tested the gene-editing technique by delivering a single intravenous injection of the DNA-editing mix into nearly a dozen mice with the progeria-causing mutation soon after birth. The gene editor successfully restored the normal DNA sequence of theLMNAgene in a significant percentage of cells in various organs, including the heart and aorta.
Many of the mice cell types still maintained the corrected DNA sequence six months after the treatment. In the aorta, the results were even better than expected, as the edited cells seemed to have replaced those that carried the progeria mutation and dropped out from early deterioration. Most dramatically, the treated mice's lifespan increased from seven months to almost 1.5 years. The average normal lifespan of the mice used in the study is two years.
As a physician-scientist, its incredibly exciting to think that an idea youve been working on in the laboratory might actually have therapeutic benefit, said Jonathan D. Brown, M.D., assistant professor of medicine in the Division of Cardiovascular Medicine at Vanderbilt University Medical Center. Ultimately our goal will be to try to develop this for humans, but there are additional key questions that we need to first address in these model systems.
Funding for the study was supported in part by NHGRI, the NIH Common Fund, the National Institute of Allergy and Infectious Diseases, the National Institute of Biomedical Imaging and Engineering, the National Institute of General Medical Sciences, the National Heart, Lung and Blood Institute and the National Center for Advancing Translational Sciences.
The National Human Genome Research Institute (NHGRI) is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at: https://www.genome.gov.
About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
NIHTurning Discovery Into Health
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DNA-editing method shows promise to treat mouse model of progeria - National Institutes of Health
By now, everyone has seen countless images of people receiving the COVID-19 vaccine. But once its injected into the upper arm, how does it actually interact with the body?
Dr. M. Fahad Khalid, chief of the Division of Hospital Medicine atPenn State Health Milton S. Hershey Medical Center, andDr. Mohammad Ali, an infectious diseases physician atPenn State Health Holy Spirit Medical Center, say while the vaccine doesnt contain any live COVID-19 virus, it teaches the human immune system to protect against it.
Both vaccines that received Emergency Use Authorization from the U.S. Food and Drug Administration (FDA) the Pfizer-BioNTech and Moderna vaccines are mRNA (messenger RNA) vaccines. They are not live viruses. Instead, they work by giving your body a blueprint to create a piece of the virus that causes COVID-19, called a spike protein.
Once you receive the vaccine, your cells machinery uses the mRNA instructions to make the spike protein. This protein is then displayed on the cell surface, and the immune system sees it and responds to it. While mRNA is a type of genetic code, it never enters the center (nucleus) of your cells. That means it never converts into DNA, Khalid said. The mRNA itself is destroyed by the cells after they produce the spike protein.
The spike protein the vaccines create is the same one found on the surface of the virus that causes COVID-19. However, the vaccines do not contain any live virus. The spike protein itself cannot cause an infection, Ali said.
Khalid and Ali also addressed many common questions people have about both vaccines:
The vaccines were approved quickly. Are they safe?Advances in vaccinology and vaccine production allowed pharmaceutical companies to create vaccines in months. However, both vaccines followed rigorous FDA guidelines, including the normal regimen of clinical trials and Phase 1, 2 and 3 trials. Their effectiveness is tremendous, Ali said. The flu vaccine is typically 40% to 60% effective, and the COVID-19 vaccines are 94% to 95% effective.
Do people get severe allergic reactions to the vaccine?The Centers for Disease Control and Prevention (CDC) reports a limited number of incidents where people experienced a severe allergic reaction (anaphylaxis) or reaction such as hives, swelling or wheezing. The CDC recommends against people taking the vaccine who had a prior severe allergic reaction to any ingredient in the COVID-19 vaccine. People who have had allergic reactions to other vaccines should ask their doctor about taking the COVID-19 vaccine. People with nonvaccine-related allergies food allergies, pet allergies, seasonal allergies are safe to get vaccinated, says the CDC.
Will the vaccine side effects be worse than getting COVID-19?Possible side effects, such as swelling or pain at the injection site, fever, headache or muscle pain, are temporary. Those side effects arent nearly as bad as severe cases of COVID-19, which can be fatal, Khalid said.
Do I need a vaccine if I already had COVID-19?Yes. Currently, the CDC recommends vaccination even in people who have had COVID-19 in the past. This is because we do not know how long immunity to the virus lasts after someone is infected.
Do I need to wear a mask after getting the COVID-19 vaccine?Yes, you must continue to wear a mask, practice social distancing and continue to wash your hands. The vaccine protects you from getting sick with COVID-19, but researchers still dont know if individuals can still get infected and transmit the virus to others.
Is there any kind of microchip tracking in the vaccines?No. The vaccine also will not cause infertility. Theres a lot of misinformation out there, Ali said. The most trustworthy resource for accurate information is the CDC website.
Alison Enimpah, a registered nurse who provided direct care for COVID-19 patients at the Milton S. Hershey Medical Center, was among the earliest group of health care workers to get vaccinated. Shell receive her second dose later this month. The vaccine adds a layer of reassurance that were making forward progress in keeping ourselves and our community safe during the pandemic, she said.
TheMedical Minuteis a weekly health news feature produced by Penn State Health. Articles feature the expertise of faculty, physicians and staff, and are designed to offer timely, relevant health information of interest to a broad audience.
DURBAN, South Africa Doctors and nurses at a South African hospital group noticed an odd spike in the number of Covid-19 patients in their wards in late October. The government had slackened its lockdown grip, and springtime had brought more parties. But the numbers were growing too quickly to easily explain, prompting a distressing question.
Is this a different strain? one hospital official asked in a group email in early November, raising the possibility that the virus had developed a dangerous mutation.
That question touched off a high-stakes genetic investigation that began here in Durban on the Indian Ocean, tipped off researchers in Britain and is now taking place around the world. Scientists have discovered worrisome new variants of the virus, leading to border closures, quarantines and lockdowns, and dousing some of the enthusiasm that arrived with the vaccines.
Britain has been particularly overwhelmed. Infections and hospitalizations have skyrocketed in recent weeks since that country discovered its own variant of the virus, which is more contagious than previous forms. By one estimate, the mutated virus is already responsible for more than 60 percent of new infections in London and surrounding areas.
The coronavirus has evolved as it made its way across the world, as any virus is expected to do. But experts have been startled by the pace at which significant new variants have emerged, adding new urgency to the race between the worlds best defenses vaccinations, lockdowns and social distancing and an aggressive, ever-changing foe.
The new variant pummeling Britain has already been found in about 45 countries, from Singapore to Oman to Jamaica, but many countries are effectively flying blind, with little sense of how bad the problem may be.
Long before the pandemic emerged, public health officials were calling for routine genetic surveillance of outbreaks. But despite years of warnings, many countries including the United States are conducting only a fraction of the genomic studies needed to determine how prevalent mutations of the virus are.
Denmark, which has invested in genetic surveillance, discovered the variant afflicting Britain in multiple Danish regions and recently tightened restrictions. The health minister compared it to a storm surge, predicting that it would dominate other variants by mid-February.
And as countries go looking, they are discovering other variants, too.
With the world stumbling in its vaccination rollout and the number of cases steeply rising to peaks that exceed those seen last spring, scientists see a pressing need to immunize as many people as possible before the virus evolves enough to render the vaccines impotent.
Its a race against time, said Marion Koopmans, a Dutch virologist and a member of a World Health Organization working group on coronavirus adaptations.
The vaccine alone will not be enough to get ahead of the virus: It will take years to inoculate enough people to limit its evolution. In the meantime, social distancing, mask-wearing and hand-washing coupled with aggressive testing, tracking and tracing might buy some time and avert devastating spikes in hospitalizations and deaths along the way. These strategies could still turn the tide against the virus, experts said.
We do know how to dial down the transmission of the virus by a lot with our behavior, said Carl T. Bergstrom, an evolutionary biologist at the University of Washington in Seattle. Weve got a lot of agency there.
Yet in the course of the pandemic, governments have often proven reluctant or unable to galvanize support for those basic defenses. Many countries have all but given up on tracking and tracing. Mask-wearing remains politically charged in the United States, despite clear evidence of its efficacy. Cities like Los Angeles have been gripped by a spike in cases linked to Christmas festivities, and national public health officials are bracing for surges elsewhere, driven by people who ignored advice and traveled during the holidays.
Much remains unknown about the new variants, or even how many are sprouting worldwide. Scientists are racing to sequence enough of the virus to know, but only a handful of countries have the wherewithal or commitment to do so with any regularity.
The rapid spread of the new variants is a reminder of the failings and missteps of major countries to contain the virus earlier. Just as China failed to stop travelers from spreading the virus before the Lunar New Year last year, Britain has failed to move fast enough ahead of the new variants spread. Britain lowered its guard during the holidays, despite a rise in cases now known to be linked to a variant. And just as China became a pariah early on in the pandemic, Britain now has the unfortunate distinction of being called Plague Island.
The spread of the variant lashing Britain has left some countries vulnerable at a time when they seemed on the brink of scientific salvation.
A case in point: Israel. The country, which had launched a remarkably successful vaccine rollout, tightened its lockdown on Friday after having discovered cases of the variant. About 8,000 new infections have been detected daily in recent days, and the rate of spread in ultra-Orthodox communities has increased drastically.
The variant discovered in Britain, known as B.1.1.7, has 23 mutations that differ from the earliest known version of the virus in Wuhan, China, including one or more that make it more contagious, and at least one that slightly weakens the vaccines potency. Some experiments suggest that the variant spreads more easily because mutations enable it to latch more successfully onto a persons airway.
Dr. Bergstrom and other scientists were surprised to see this more transmissible variant emerge, given that the coronavirus was already quite adept at infecting people.
While the exact order of vaccine recipients may vary by state, most will likely put medical workers and residents of long-term care facilities first. If you want to understand how this decision is getting made, this article will help.
Life will return to normal only when society as a wholegains enough protection against the coronavirus. Once countries authorize a vaccine, theyll only be able to vaccinate a few percent of their citizens at most in the first couple months. The unvaccinated majority will still remain vulnerable to getting infected. A growing number of coronavirus vaccines are showing robust protection against becoming sick. But its also possible for people to spread the virus without even knowing theyre infected because they experience only mild symptoms or none at all. Scientists dont yet know if the vaccines also block the transmission of the coronavirus. So for the time being, even vaccinated people will need to wear masks, avoid indoor crowds, and so on. Once enough people get vaccinated, it will become very difficult for the coronavirus to find vulnerable people to infect. Depending on how quickly we as a society achieve that goal, life might start approaching something like normal by the fall 2021.
Yes, but not forever. The two vaccines that will potentially get authorized this month clearly protect people from getting sick with Covid-19. But the clinical trials that delivered these results were not designed to determine whether vaccinated people could still spread the coronavirus without developing symptoms. That remains a possibility. We know that people who are naturally infected by the coronavirus can spread it while theyre not experiencing any cough or other symptoms. Researcherswill be intensely studying this question as the vaccines roll out. In the meantime, even vaccinated people will need to think of themselves as possible spreaders.
The Pfizer and BioNTech vaccine is delivered as a shot in the arm, like other typical vaccines. The injection wont be any different from ones youve gotten before. Tens of thousands of people have already received the vaccines, and none of them have reported any serious health problems. But some of them have felt short-lived discomfort, including aches and flu-like symptoms that typically last a day. Its possible that people may need to plan to take a day off work or school after the second shot. While these experiences arent pleasant, they are a good sign: they are the result of your own immune system encountering the vaccine and mounting a potent response that will provide long-lasting immunity.
No. The vaccines from Moderna and Pfizer use a genetic molecule to prime the immune system. That molecule, known as mRNA, is eventually destroyed by the body. The mRNA is packaged in an oily bubble that can fuse to a cell, allowing the molecule to slip in. The cell uses the mRNA to make proteins from the coronavirus, which can stimulate the immune system. At any moment, each of our cells may contain hundreds of thousands of mRNA molecules, which they produce in order to make proteins of their own. Once those proteins are made, our cells then shred the mRNA with special enzymes. The mRNA molecules our cells make can only survive a matter of minutes. The mRNA in vaccines is engineered to withstand the cell's enzymes a bit longer, so that the cells can make extra virus proteins and prompt a stronger immune response. But the mRNA can only last for a few days at most before they are destroyed.
But other experts had warned from the start that it would only be a matter of time before the virus became an even more formidable adversary.
Every situation we have studied in depth, where a virus has jumped into a new species, it has become more contagious over time, said Andrew Read, an evolutionary microbiologist at Penn State University. It evolves because of natural selection to get better, and thats whats happening here.
Much of the global response has focused on shutting out Britain, with a hodgepodge of national restrictions that harken back to the early reactions to the epidemic.
China has banned flights and travelers from Britain. Japan took an even harsher measure, banning entry to nonresident foreigners from more than 150 countries.
Others like India and New Zealand are allowing some flights from Britain but require passengers to have two negative tests one before departure and another after arrival. Australia is sticking with its policy of requiring hotel quarantines and testing for international travelers.
Experts say that countries should focus instead on ramping up vaccinations, particularly among essential workers who face a high risk with few resources to protect themselves. The longer the virus spreads among the unvaccinated, the more mutations it might collect that can undercut the vaccines effectiveness.
That is why, when the World Health Organization working group saw the first data on the variant circulating in South Africa on Dec. 4, everyone took notice.
Your next question immediately is: Can the vaccines still protect us if we get viruses with these mutations? said Dr. Koopmans, who was in the meeting.
For now, the answer seems to be yes, said Jesse Bloom, an evolutionary biologist at the Fred Hutchinson Cancer Research Center in Seattle. Dr. Koopmans agrees.
The variants that have emerged in South Africa and Brazil are a particular threat to immunization efforts, because both contain a mutation associated with a drop in the efficacy of vaccines. In one experiment, designed to identify the worst-case scenario, Dr. Blooms team analyzed 4,000 mutations, looking for those that would render vaccines useless. The mutation present in the variants from both Brazil and South Africa proved to have the biggest impact.
Still, every sample of serum in the study neutralized the virus, regardless of its mutations, Dr. Bloom said, adding that it would take a few more years before the vaccines need to be tweaked.
There should be plenty of time where we can be prospective, identify these mutations, and probably update the vaccines in time.
That sort of surveillance is precisely what led to the discovery of the new variants.
Liza Sitharam, a nurse and infectious disease specialist in coastal South Africa, was among those who first noticed a small cluster that was quickly bulging.
Wed have five cases and then itd double really quickly, she recalled. The raw numbers werent alarming, she said, but there was something just not looking right.
Her boss at the Netcare hospital group, Dr. Caroline Maslo, figured that with the countrys borders open, business travelers from German auto companies had perhaps brought in a European variant of the virus. She sought help from Tulio de Oliveira, a professor and geneticist at the Nelson Mandela School of Medicine in Durban who had studied viral variants during the first Covid-19 wave.
Soon, his lab was analyzing swabs, shipped on ice by courier overnight. On Dec. 1, he emailed a British scientist, Andrew Rambaut, and asked him to review some of his early findings: a series of strange mutations on the viruss outer surface.
Dr. de Oliveira, a Brazilian-South African scientist who sports long hair and a surfer vibe, shared his findings at a Dec. 4 meeting of the World Health Organization working group. All took notice because of the variants potential to disrupt the vaccines effectiveness.
Days later, Dr. de Oliveira recalled, Dr. Rambaut emailed him with a discovery of his own: British scientists had scoured their databases and found a similar but unrelated mutation that appeared linked to a cluster of infections in the county of Kent.
Coming two weeks before Christmas, Dr. de Oliveira immediately thought of the Lunar New Year early in the pandemic, when millions of people in China traveled far and wide for the holiday, some carrying the virus.
It was crystal clear, Dr. de Oliveira said in an interview. These variants will spread nationally, regionally and globally.
Dr. Rambaut and colleagues released a paper on the variant discovered in Britain on Dec. 19 the same day that British officials announced new measures. The variant had apparently been circulating undetected as early as September. Dr. Rambaut has since credited the South Africa team with the tip that led to the discovery of the variant surging in Britain.
Public health officials have formally recommended that type of swift genetic surveillance and information-sharing as one of the keys to staying on top of the ever-changing virus. But they have been calling for such routine surveillance for years, with mixed results.
The message was very clear, that this is the way surveillance has to go, said Dr. Josep M. Jansa, a senior epidemiologist at the European Centre for Disease Prevention and Control. Just as Covid-19 exposed flaws in the worlds pandemic plans a year ago, the hunt for new variants is exposing gaps in surveillance. Were learning, he said. Slowly.
Britain has one of the most aggressive surveillance regimens, analyzing up to 10 percent of samples that test positive for the virus. But few countries have such robust systems in place. The United States sequences less than 1 percent of its positive samples. And others cannot hope to afford the equipment or build such networks in time for this pandemic.
In Brazil, labs that had redirected their attention from Zika to the coronavirus had discovered a worrisome mutation there as early as this spring. But little is known about the variants circulating in the country, or how quickly they are spreading.
We just dont know because no one is either sequencing or sharing the data, said Dr. Nuno Faria at Imperial College and Oxford University who coordinates genomic sequencing projects with colleagues in Brazil. Genomic surveillance is expensive.
As the virus continues to mutate, other significant variants will almost certainly emerge. And those that make the virus hardier, or more contagious, will be more likely to spread, Dr. Read said.
The faster we can get the vaccines out, the faster we can get on top of these variants, he said. Theres no room for complacency here.
Matt Apuzzo reported from Durban, South Africa, and Brussels, Selam Gebrekidan from London, and Apoorva Mandavilli from New York. Reporting was contributed by Thomas Erdbrink; Melissa Eddy from Berlin; Isabel Kershner from Jerusalem; Manuela Andreoni from Rio de Janeiro; Christina Anderson from Stockholm; Amy Chang Chien and Amy Qin from Taipei, Taiwan; and Jennifer Jett and Tiffany May from Hong Kong.
Assaf Halevy, Founder and CEO of 2bPrecise
Electronic medical records (EMRs) are widely expected to serve as a cornerstone technology that drives the delivery of modern patient care.
But can the EMR alone support all the informatics capabilities required by an ever-evolving healthcare industry? The rapid growth of precision medicine, particularly the use of genetic and genomic information during clinical decision making, is a compelling example that functionality beyond the EMR is required. Not only does genomic data represent a category of information used differently than traditional clinical knowledge, but the volume of data generated through molecular testing alone also requires informatics and management of a higher magnitude than previously required.
The EMR is designed to reflect a snapshot (or collection of snapshots) in time: clinical summaries, annotated lab and test results, operation notes, etc. These are mostly stored as isolated documents, loosely coupled with the rest of the patient chart. They need to remain available for reference over time, in some instances, so providers can chart and contextualize ongoing trends and chronic conditions. However, these views are anchored in time and represent limited actionable value during clinical decision-making months, years, and decades later.
Genomic information, on the other hand, represents a patients life signature. DNA rarely changes over the course of an individuals lifetime. This means the results from germline testing a patients molecular profile conducted early in life are relevant, meaningful, and actionable during clinical decision making far into the future. They can also deliver insights exposing heritable proclivities that may be life-changing or life-saving for family members as well.
This recognition in and of itself alerts healthcare leaders that they need to adopt an advanced, more sophisticated strategy for data governance, management, and sharing than the approach traditionally applied to other clinical information systems, such as EMRs.
To be successful, healthcare organizations need an accelerator external to the EMR that is built on a data model unique to the management of molecular knowledge so test results and genomic insights can be used and shared across clinical specialties and care settings, as well as overtime. In addition, the rise of precision medicine requires an agile informatics platform that enables the cross-pollination of genomic data with clinical insights and ever-advancing discoveries in genomic science.
Consider these examples of how EMRs fall short of expectations for optimal use of genomic intelligence:
1. Studies have found that, despite ubiquitous availability of molecular tests, providers consistently fail to identify patients most at risk for heritable diseases. The Journal of the American Medical Informatics Association (JAMIA) recently released research showing that half the women meeting national guidelines for genetic screening are not getting the tests they need to determine their breast and ovarian cancer risk.
The reason? The full story of a patients risk for heritable cancer within their record often does not exist in a single location, says the JAMIA article. It is fragmented across entries created by many authors, over many years, in many locations and formats, and commonly from many different institutions in which women have received care over their lifetimes. In other words, no matter which EMRs they use, health systems routinely miss opportunities to improve care for patients they see. To achieve greater success, providers need tools that exceed EMR functionality and span multiple clinical systems.
2. Shortly after birth, Alexander develops a seizure disorder. The neonatologist orders a germline test to help her arrive at a precise diagnosis and begin targeted treatment. This approach is successful and Alexander thrives. In addition to genomic variants identifying the cause of his seizure disorder, the test results also contain information about other heritable risk factors, including cardiovascular disease.
Decades later, in the 70s, Alexander sees his primary care provider (PCP) with a rapid heartbeat and shortness of breath. After doing routine lab work, the PCP diagnoses congestive heart failure (CHF). If, however, the PCP had access to Alexanders genomic test results which remain as relevant and accurate as when he was an infant the PCP would have noted a variation that indicated the CHF was due to dilated cardiomyopathy, requiring a different treatment regime.
It is vital that health leaders immediately begin to plan an informatics strategy that accommodates genetic and genomic data while empowering providers to leverage these insights at the point of care as they make routine, yet critical, clinical decisions. As they evaluate their approach, they would do well to ask the following questions:
Which providers in my organization are already ordering genomic tests on their patients? How are test results being stored and managed and can they be easily shared with and accessed by others in the health system?
As the volume of genetic and genomic testing accelerates and it will how will we manage the volume of data generated? How will we apply consistent governance to the ordering process? How can we ensure results will be consumed as discrete data so our organization can optimize its value now and in the future?
What steps do we need to take so our precision medicine strategy remains current with changing science? Which informatics tools deliver access to up-to-date knowledge bases and clinical guidelines to ensure optimal medical decisions are made?
The advent of precision medicine represents a new standard of care for healthcare providers from coast to coast. Genetic and genomic information supplies a new data set that can be used to arrive at more accurate diagnoses sooner and more effective treatment faster. This, in turn, supports better outcomes, higher patient (and provider) satisfaction, and competitive differentiation for the health system adopting precision medicine first in its market.
But to capture this value, healthcare leaders must look beyond their legacy EMRs, recognizing that they were not developed nor do they have the capacity to properly handle the upcoming data revolution. Instead, industry innovators are looking for platforms agnostic to individual EMRs and integrated with molecular labs to address the next-generation demands of precision medicine.
About Assaf Halevy
Assaf Halevy is the founder and CEO of 2bPrecise, LLC, leading an international team dedicated to bridging the final mile between the science of genomics and making that data useful at the point of care. He joined Allscripts as senior vice president of products and business development in 2013 when the company acquired Israel-based dbMotion. An initial inventor and co-founder of dbMotion, Halevy helped develop the leading clinical integration and population health management platforms in the industry today.
With 13 patents pending in the areas of actionable clinical integration, interoperability, and precision medicine, Halevy leverages his industry expertise by evaluating strategic alliances and partnerships for U.S. and international markets. Halevy was invited to participate in several U.S. government activities and contribute to an HHS privacy committee task force. In 2016, he was part of a small selective group of executives invited to the White House by Vice President Joe Biden to discuss the future of interoperability.
After decades of work and mass vaccination campaigns that have spared millions of children from paralysis, the world is close to wiping out polio.
But a small number of outbreaks that have simmered in areas of low vaccination remain. And some happened after weakened virus in the oral polio vaccine, over time, moved around a community and regained the ability to cause disease. No other vaccines made with weakened live viruses have caused outbreaks of disease.
To stamp out vaccine-derived polio outbreaks, the World Health Organization has granted emergency use for a new polio vaccine. The oral vaccine got the go-ahead on November 13.
We are very, very enthusiastically looking forward to using this new vaccine, says medical epidemiologist Chima Ohuabunwo of Morehouse School of Medicine in Atlanta, who has worked on polio eradication in Africa for more than two decades. Along with continuing the crucial work of improving vaccination coverage in places where it is low, the new vaccine will hopefully take us to the finishing line of polio eradication.
Eight years after the WHOs 1980 declaration that the world was free of smallpox, the Global Polio Eradication Initiative launched to tackle polio. The disease was a promising candidate for eradication. An effective, easily administered and cheap vaccine was available. And poliovirus, which naturally infects only humans, doesnt hang around in other animals in between outbreaks.
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Most people who become infected with poliovirus dont feel sick, while some have flu-like symptoms. But about one in 200 become paralyzed for life. Although not a routine threat in the United States since the early 1950s (SN: 9/12/19), polio has continued to harm people, especially children, around the world.
In the late 1980s, wild poliovirus paralyzed more than 1,000 children each day, according to the Global Polio Eradication Initiative. Since then, thanks to widespread vaccination campaigns, cases have plummeted by more than 99 percent, and two of the three types of wild poliovirus have been eradicated. The last cases from type 2 and type 3 were reported in 1999 and 2012, respectively. Only wild poliovirus type 1 remains, and only in two countries: As of December 30, 56 cases were reported in Afghanistan and 83 in Pakistan caused by type 1, in 2020.
Much of this progress has been possible because of the oral polio vaccine. Its been the workhorse of the eradication campaign, says virologist and infectious disease physician Adam Lauring of the University of Michigan School of Medicine in Ann Arbor. Immunization with the oral vaccine has prevented more than 13 million cases of polio since 2000, according to WHO.
A big advantage of the oral vaccine, which is made of live but weakened poliovirus, is that it not only protects against paralysis it also can stop wild poliovirus from spreading in a community. Poliovirus moves from person to person when someone ingests water or food contaminated with virus-containing stool. The oral vaccine prevents wild poliovirus from multiplying in the gut and being passed on. (There is another, more expensive, injected polio vaccine with killed virus that prevents paralysis but not viral spread.)
While the oral vaccine has nearly wiped out wild poliovirus, it has a vulnerability. Weakened poliovirus in the vaccine has genetic changes that keep it from causing disease. As vaccine virus multiplies in the gut, it can lose key genetic changes, bringing it closer to behaving like wild poliovirus. And altered vaccine virus can be spread to others and establish community transmission, says biologist Raul Andino of the University of California, San Francisco School of Medicine. That can be a problem if not enough people have been immunized against polio.
More than 80 percent of children need to be vaccinated to keep poliovirus from spreading in a community. The first vaccine-derived polio outbreak to be detected occurred in the Dominican Republic and Haiti two decades ago, in areas with low vaccination. That allowed altered vaccine virus, shed in the stool of the immunized, to spread largely unchecked and, over time, return to a form that causes paralysis (SN: 8/10/04). The full process of vaccine virus reverting to disease-causing virus is rare and takes many months of moving around a community.
Today, vaccine-derived outbreaks are primarily found in Afghanistan, Pakistan and countries in Africa. Most of these outbreaks which have been responsible for more polio cases in the last few years than the remaining type of wild poliovirus are linked to vaccine virus type 2. Vaccination campaigns, which had used an oral vaccine containing weakened versions of all three types of poliovirus, switched to using a formulation with just types 1 and 3 in 2016.
However, the way to stop a type 2 vaccine-derived outbreak is with an oral vaccine containing only the weakened type 2 virus. And that has sparked new outbreaks, researchers reported in Science in April. It is this vicious circle, Lauring says. As of December 22, in 2020 there were 854 polio cases linked to the type 2 vaccine virus.
Hence the quest for a new and improved poliovirus type 2 oral vaccine, one that kept the good parts of the original but with tweaks to try to prevent problematic genetic changes. Its a wonderful vaccine, so we didnt want to change the characteristics that induce the bodys immune response, Andino says. The only thing we wanted to do is prevent the reversion to a disease-causing virus.
Andino and colleagues modified the type 2 vaccine virus in several places. The researchers altered a part of the viruss genetic instruction book, or genome, to make the virus less likely to develop a gatekeeper change: a first, critical step along the road to regaining the ability to cause disease.
Poliovirus can swap pieces of its genome with related viruses called enteroviruses. So the researchers moved a string of genetic letters the virus needs to make more copies of itself close to the gatekeeper modification. That way, if the vaccine virus was able to ditch that modification by way of a swap, it would lose this necessary string of genetic letters too, and die out.
Finally, the team tinkered with an enzyme that RNA viruses, including poliovirus, use to help replicate themselves. The enzyme is sloppy and can introduce a lot of genetic changes, Andino says. Thats advantageous for the viruses, which are continuously trying to adapt to a new environment, he says. Andino and colleagues modified this enzyme in the vaccine virus to introduce fewer mistakes, so the virus cannot evolve so quickly. The researchers described their improved oral polio vaccine in a study in Cell Host & Microbe in May.
The new oral polio vaccine was shown to be safe and to produce an immune response similar to that seen with the original vaccine in infants and children, researchers reported online December 9 in the Lancet. The hope is that the modifications will slow the evolution of the new vaccine virus such that it can end the existing outbreaks without creating new ones.
The vaccine-derived outbreaks are a significant, yet surmountable hurdle to polio eradication, says Ohuabunwo, and science is helping. But the key to ending polio is very high vaccination coverage. Obstacles including war, migrating populations, difficult terrain and lack of vaccine acceptance have created pockets of inaccessible children, he says.
Reaching all children requires engaging community leaders, providing culturally sensitive information and finding out how to meet other community needs, says Ohuabunwo. For example, while working in Nigeria, he and his colleagues made progress with nomadic populations. It meant sometimes combining vaccinating their children with vaccinating their animals. The nomads cattle would be immunized against brucellosis and anthrax bacterial infections. Protecting the animals also protected the nomads from these infections, he says, and motivated their cooperation towards having their children receive polio vaccine: a win-win.
Polio eradication has been a long journey, but were getting close, Ohuabunwo says. The new oral polio vaccine is another light in the tunnel.