Ricki Lewis

My blog posts around Thanksgiving are predictably dull: Turkey Genetics 101, The Peaceable Genomes of Pumpkins.

But 2020 is like no other year. Humanity is at war with the novel coronavirus SARS-CoV-2.

Images of overwhelmed hospitals and mobile morgues that dominated reporting from New York City in March are now coming from everywhere.

A mutation that's entered the US a few times from Europe doubled transmission rate without affecting severity, which is one reason why the percentage of fatal cases has fallen. Still, it's a huge absolute number, because of the fact that nearly 12 million Americans (as of today) have been infected. More than a quarter of a million have died.

And yet, some people still deny reality. Nurses tell of patients on their deathbeds still insisting that the pandemic is a hoax, that they're suffering from something else.

A Dangerous Meme

To continue reading, please go to my blog DNA Science at Public Library of Science, where this post first appeared.

The components of certain things are meant to remain mysterious. The ingredients of sausage. A burger's slimy secret sauce. The recipe for Coke or Kentucky Fried Chicken.

Researchers from Stanford University are tackling the make-up of another entity, something rather new to our world: the stuff retrieved from swabs shoved up nostrils to sample genetic material from SARS-CoV-2, the virus behind COVID-19. A swab actually samples much more than the virus's RNA, required for diagnosis.

Super Swabs

John Gorzynski and colleagues describe the "multi-omic data repositories" from deployed swabs in a preprint (not yet peer-reviewed) and at the recent virtual annual meeting of The American Society of Human Genetics.

"A single nasopharyngeal swab can reveal substantial host and viral genomic information in a high-throughput manner that will facilitate public health pandemic tracking and research into the mechanisms underlying virus-host interactions," they write.

That's a mouthful. I'll just call them super swabs.

Amplifying Viral Sequences

Extracting clues from the stuff on the swabs is a little like collecting evidence at a crime scene. Several things happen.

To continue reading, please go to my blog DNA Science at Public Library of Science, where this post first appeared.

In the early weeks of the pandemic, as patients overwhelmed New York City hospitals, the clinical characteristics of the most vulnerable quickly became apparent: many of the sickest people were older or had "co-morbidities" like diabetes, hypertension, or respiratory conditions.

As weeks became months and the symptom spectrum widened and worsened, researchers began to focus on "host risk factors" to explain the increasingly apparent variability in the COVID-19 experience. According to Jack Kosmicki, PhD, of Regeneron Genetics Center, at the recent American Society of Human Genetics virtual annual meeting:

"Genetics is one avenue to better understand why outcomes of COVID are so different. Some patients have so few symptoms that they don't realize they're infected, yet the other end of the extreme is requiring hospitalization, or death. Genetic risk factors might influence the likelihood of becoming infected or requiring hospitalization."

So far, very few genes have been linked to COVID-19. Other factors like socioeconomic status, exposure to the virus in the workplace or in crowded housing conditions, being of Black or Asian ancestry and non-genetic pre-existing conditions are more important.

To continue reading, please go to Genetic Literacy Project, where this post first appeared.

People with Down syndrome who contract COVID-19 face a fivefold increased risk for hospitalization and a tenfold increased risk for death compared with infected individuals who do not have the syndrome, researchers report in the Annals of Internal Medicine.

Since the pandemic began, public health and infectious disease experts have identified comorbidities that elevate the risk for serious complications or death from COVID-19. In the United Kingdom and the United States, Down syndrome hasn't been on that list. The authors of the new report argue that it should be.

Down syndrome might be associated with more severe COVID-19, owing to "the immune dysregulation, such as differences in T cell function," said first author Ashley Kieran Clift, MA, MBBS, clinical research fellow at the University of Oxford, Oxford, United Kingdom. "People with Down syndrome have a higher risk of pneumonia and viral respiratory tract infections, which may also apply to this novel coronavirus. They have high rates of other conditions that may make them more vulnerable, such as heart and lung disease. There could also be a role for their environment, such as living in care homes or other institutions."

 
The researchers analyzed data from a UK government-sponsored cohort study of 8.26 million adults older than 19 years. The data included information on COVID-19 test results; records of associated hospitalizations and deaths; whether or not a person also had Down syndrome; and information on age, sex, ethnicity, alcohol intake, smoking status, body mass index (BMI), comorbidities, and medications.

The cohort included 4053 people with Down syndrome. Of those, during the study period, from January 24 until June 30, 2020, 68 died ―39.7% of COVID-19, 25.0% of pneumonia or pneumonitis, and 35.3% of other causes. By contrast, among the 8,252,105 people who did not have Down syndrome, 41,685 died; the cause of death was listed as COVID-19 for 20.3%, pneumonia or pneumonitis for 14.4%, and other causes for 65.3%.

The hazard ratio (HR) for death related to COVID-19 was 10.39 (CI, 7.08 – 15.23) and for hospitalization, 4.94 (CI, 3.63 – 6.73) after adjusting for age, sex, ethnicity, BMI, dementia diagnosis, living in a care home, congenital heart disease, and other comorbidities and treatments. For individuals who had learning disabilities but not Down syndrome, the adjusted HR for COVID-19–related death was only 1.27 (CI, 1.16–1.40).

Corresponding author Julia Hippisley-Cox, MD, professor of clinical epidemiology and general practice, St. Anne's College, University of Oxford, said that although the study was observational and did not identify reasons for the elevated risk, "we feel that clinicians, policymakers, and other healthcare workers should be aware of potential risks. These findings could be used by healthcare workers within the context of other factors to have a more nuanced risk assessment for their patients." 

That might entail weighing the relative risks and benefits of measures that protect against infection vs the values of socialization in day care programs and physical and occupational therapies. It's a balancing act, Hippisley-Cox said.

Preston McCormack, MD, assistant professor or internal medicine and pediatrics at the University of Arkansas for Medical Sciences College of Medicine, Little Rock, Arkansas, agreed that caution is warranted in navigating care during this challenging time.

"It's well known that Down syndrome patients are at increased risk. However, with these data surfacing, it may be a good time to reassess how we plan to move forward," McCormack said. "The risk, even after adjustment for age, sex, and associated comorbidities, remains impressive and demands attention as we approach another viral season this fall and upcoming winter.

"The fact that most in this population require more frequent medical follow-up, therapy, and other ancillary services further compounds this risk," he continued. "The decision to restrict patients from these care providers will likely have to be determined on an individual basis, though it is imperative that we are continually informed of the risks vs benefits of these decisions. Without a doubt, we are unable to optimize therapy and socialization in this pandemic landscape. However, this expense is offset with minimization of significant risk quantified in this recent study."

Originally published at Medscape Medical News

Antibodies are supposed to be the good guys. The proteins, built of distinctive Y-shaped pieces, enter the bloodstream early in infection, pouring out from plasma cells. They then latch onto molecules festooning pathogens and alert natural killer cells, which release a torrent of cytokines and complement, which are the biochemical weapons of an immune response.

Fighting infection is a complex business.

In a mysterious phenomenon called "antibody-dependent enhancement," the proteins actually make matters worse, intensifying symptoms. When a vaccine elicits the errant antibodies, the backfiring is called "vaccine enhancement of disease." We know these reactions exist, but still do not completely understand them.

The turncoat antibodies can be coaxed to appear in test tube experiments, but are elusive in a patient who is getting sicker. That is, there's no clinical way to distinguish antibody-dependent enhancement from just a severe case of an infectious disease. And that can complicate analysis of a candidate vaccine. "Vaccine enhancement of disease" would show up in a clinical trial as more people receiving a vaccine getting sick than the participants getting placebo.

Reportedly that hasn't happened for the candidate COVID-19 vaccines, but the data won't be published until the phase 3 trials are completed.

To continue reading, please go to my blog DNA Science at Public Library of Science. 

As tens of thousands of people participate in phase 3 clinical trials on COVID-19 vaccine candidates, the focus is turning to the approval process: Will the approved vaccines be safe and effective? For how long? Has politics been injected into the process?

To reassure the public that the checks and balances that regulatory agencies have always had in place will prevail, Anthony Fauci, MD, Director of the National Institute of Allergy and Infectious Diseases, and Peter Marks, MD, PhD, director of the FDA's Center for Biologics Evaluation and Research, discussed the current state of the science with Howard Bauchner, MD, at JAMA Live Q+A webinars for the media on September 25 and October 5.

Their comments interweaved into a compelling narrative is like visiting with two scientific maestros.

To continue reading, go to Genetic Literacy Project, where this post first appeared.

Teaming treatments has long been a strategy to quell cancer, override mutations, and fight viruses. Will that be a winning strategy against SARS-CoV-2, the virus that causes COVID-19?

Surgery, chemo, and radiation are the traditional triple-punch against cancer, with more recent targeted therapies moving to the frontline. The same road has unfolded for cystic fibrosis (CF).

Fixing Errant Ion Channels

The first treatments for CF were simple: pounding on the chest to dislodge sticky mucus, sprinkling digestive enzymes on applesauce, and using old drugs to combat inflammation and infection.

The new CF drugs that have revolutionized treatment for most patients are small molecules that interact with the malformed ion channels that lie behind the disease. The channels are tiny tubes built of cells festooned with proteins that regulate the balance of water and salts in many body parts – hence the diverse symptoms of breathing difficulty, poor fat digestion, salty sweat, lung infections, and male infertility.

The new drugs work in three related ways.

To continue reading, go to my blog DNA Science, where this post first appeared. 

The European Medicines Agency has just recommended extending use of an existing drug, nitisinone (Orfadin), to treat alkaptonuria (AKU). AKU holds a special place in the history of genetics as the first "inborn error of metabolism" described. It affects one in 250,000 to one in a million people.

The route to impending approval took two decades, illustrating factors that make the quest to discover, develop, and deliver a treatment for a very rare disease so challenging. There's no "Operation Warp Speed" for the rare disease community. Sometimes there aren't even enough participants to carry out a clinical trial that is controlled, relying instead on comparisons to the natural history of a disease, or enrolling one patient at a time in an "N+1" study.

I last wrote about AKU in 2014, calling it "black pee disease." I'm happy to report now on the progress in Europe, but won't use that attention-grabbing descriptor, because it minimizes the severity.

A Peculiar Condition and an Astute Physician

To continue reading, go to my DNA Science blog at Public Library of Science.

To those who've never thought about volunteering to be intentionally infected to test a vaccine, the idea may at first seem a bit bonkers. But such "challenge" studies not only have a rich history, but nearly 40,000 people have already checked the box "I am interested in being exposed to the coronavirus to speed up vaccine development" at 1daysooner, a website and non-profit organization that launched in April.

Challenge studies go by other names: "controlled human infection models," "human viral challenge," and "purposeful infection." Dripping virus-tainted saltwater into a volunteer's nostrils enables researchers to track infection, and the immune system's response to it, right from the start. The approach complements phase 3 clinical "field" trials of efficacy that await natural infection in the community.

To continue reading, go to Genetic Literacy Project, where this post first appeared.

Drugs that restore the shape of the errant protein behind cystic fibrosis (CF) have, over the past eight years, helped the majority of patients, who have certain mutations. Gene-corrected stem cells might offer a "mutation agnostic" option to CF.

CF results from a glitch in a glycoprotein with the unwieldy name "cystic fibrosis transmembrane conductance regulator", or CFTR. The proteins normally fold into channels that regulate the flow of ions into and out of cells, controlling the balance of water and salts in linings and barriers of the respiratory tract, pancreas, intestines, and elsewhere. If the proteins can't fold correctly, or can't migrate to the cell's surface and then open and stay that way, the resulting ion imbalance allows too much water into lining cells and secretions thicken. CF symptoms ensue, such as difficulty breathing and digesting. The Cystic Fibrosis Foundation has a helpful video (see below) both on why CF develops and the promise of gene-editing.

The most common CF mutation, F508del, removes just one of the protein's 1,480 amino acids (a phenylalanine), and that's enough to wreck the ion channels. Ninety percent of patients have at least one F508del variant. Researchers have identified more than 2,000 variants in the CFTR gene, about 350 of which are pathogenic.

To continue reading go to The Niche, where this post first appeared.