Posted on by Dr. Francis Collins
It’s become increasingly clear that even healthy people with mild cases of COVID-19 can battle a constellation of symptoms that worsen over time—or which sometimes disappear only to come right back. These symptoms are part of what’s called “Long COVID Syndrome.”
Now, a new study of relatively young, healthy adult healthcare workers in Sweden adds needed information on the frequency of this Long COVID Syndrome. Published in the journal JAMA, the study found that just over 1 in 10 healthcare workers who had what at first seemed to be a relatively mild bout of COVID-19 were still coping with at least one moderate to severe symptom eight months later . Those symptoms—most commonly including loss of smell and taste, fatigue, and breathing problems—also negatively affected the work and/or personal lives of these individuals.
These latest findings come from the COVID-19 Biomarker and Immunity (COMMUNITY) study, led by Charlotte Thålin, Danderyd Hospital and Karolinska Institutet, Stockholm. The study, launched a year ago, enlisted 2,149 hospital employees to learn more about immunity to SARS-CoV-2, the coronavirus that causes COVID-19.
After collecting blood samples from participants, the researchers found that about 20 percent already had antibodies to SARS-CoV-2, evidence of a past infection. Thålin and team continued collecting blood samples every four months from all participants, who also completed questionnaires about their wellbeing.
Intrigued by recent reports in the medical literature that many people hospitalized with COVID-19 can have persistent symptoms for months after their release, the researchers decided to take a closer look in their COMMUNITY cohort. They did so last January during their third round of follow up.
This group included 323 mostly female healthcare workers, median age of 43. The researchers compared symptoms in this group following mild COVID-19 to the 1,072 mostly female healthcare workers in the study (median age 47 years) who hadn’t had COVID-19. They wanted to find out if those with mild COVID-19 coped with more and longer-lasting symptoms of feeling unwell than would be expected in an otherwise relatively healthy group of people. These symptoms included familiar things such as fatigue, muscle pain, trouble sleeping, and problems breathing.
Their findings show that 26 percent of those who had mild COVID-19 reported at least one moderate to severe symptom that lasted more than two months. That’s compared to 9 percent of participants without COVID-19. What’s more, 11 percent of the individuals with mild COVID-19 had at least one debilitating symptom that lasted for at least eight months. In the group without COVID-19, any symptoms of feeling unwell resolved relatively quickly.
The most common symptoms in the COVID-19 group were loss of taste or smell, fatigue, and breathing problems. In this group, there was no apparent increase in other symptoms that have been associated with COVID-19, including “brain fog,” problems with memory or attention, heart palpitations, or muscle and joint pain.
The researchers have noted that the Swedish healthcare workers represent a relatively young and healthy group of working individuals. Yet, many of them continued to suffer from lasting symptoms related to mild COVID-19. It’s a reminder that COVID-19 can and, in fact, is having a devastating impact on the lives and livelihoods of adults who are at low risk for developing severe and life-threatening COVID-19. If we needed one more argument for getting young people vaccinated, this is it.
At NIH, efforts have been underway for some time to identify the causes of Long COVID. In fact, a virtual workshop was held last winter with more than 1,200 participants to discuss what’s known and to fill in key gaps in our knowledge of Long COVID syndrome, which is clinically known as post-acute sequelae of COVID-19 (PASC). Recently, a workshop summary was published . As workshops and studies like this one from Sweden help to define the problem, the hope is to learn one day how to treat or prevent this terrible condition. The NIH is now investing more than $1 billion in seeking those answers.
 Symptoms and functional impairment assessed 8 Months after mild COVID-19 among health care workers. Havervall S, Rosell A, Phillipson M, Mangsbo SM, Nilsson P, Hober S, Thålin C. JAMA. 2021 Apr 7.
 Toward understanding COVID-19 recovery: National Institutes of Health workshop on postacute COVID-19. Lerner A, et al. Ann Intern Med, 2021 March 30.
COVID-19 Research (NIH)
Charlotte Thålin (Karolinska Institutet, Stockholm, Sweden)
Posted on by Dr. Francis Collins
Our nose does a lot more than take in oxygen, smell, and sometimes sniffle. This complex organ also helps us taste and, as many of us notice during spring allergy season when our noses get stuffy, it even provides some important anatomic features to enable us to speak clearly.
This colorful, almost psychedelic image shows the entire olfactory epithelium, or “smell center,” (green) inside the nasal cavity of a newborn mouse. The olfactory epithelium drapes over the interior walls of the nasal cavity and its curvy bony parts (red). Every cell in the nose contains DNA (blue).
The olfactory epithelium detects odorant molecules in the air, providing a sense of smell. In humans, the nose has about 400 types of scent receptors, and they can detect at least 1 trillion different odors .
But this is more than just a cool image captured by graduate student Lu Yang, who works with David Ornitz at Washington University School of Medicine, St. Louis. The two discovered a new type of progenitor cell, called a FEP cell, that has the capacity to generate the entire smell center . Progenitor cells are made by stem cells. But they are capable of multiplying and producing various cells of a particular lineage that serve as the workforce for specialized tissues, such as the olfactory epithelium.
Yang and Ornitz also discovered that the FEP cells crank out a molecule, called FGF20, that controls the growth of the bony parts in the nasal cavity. This seems to regulate the size of the olfactory system, which has fascinating implications for understanding how many mammals possess a keener sense of smell than humans.
But it turns out that FGF20 does a lot more than control smell. While working in Ornitz’s lab as a postdoc, Sung-Ho Huh, now an assistant professor at the University of Nebraska Medical Center, Omaha, discovered that FGF20 helps form the cochlea . This inner-ear region allows us to hear, and mice born without FGF20 are deaf. Other studies show that FGF20 is important for development of the kidney, teeth, mammary gland, and of specific types of hair [4-7]. Clearly, this indicates multi-tasking can be a key feature of a protein, not a trivial glitch.
The image was one of the winners in the 2018 BioArt Scientific Image & Video Competition, sponsored by the Federation of American Societies for Experimental Biology (FASEB). Its vibrant colors help to show the basics of smell, and remind us that every scientific picture tells a story.
 Humans can discriminate more than 1 trillion olfactory stimuli. Bushdid C1, Magnasco MO, Vosshall LB, Keller A. Science. 2014 Mar 21;343(6177):1370-1372.
 FGF20-Expressing, Wnt-Responsive Olfactory Epithelial Progenitors Regulate Underlying Turbinate Growth to Optimize Surface Area. Yang LM, Huh SH, Ornitz DM. Dev Cell. 2018;46(5):564-580.
 Differentiation of the lateral compartment of the cochlea requires a temporally restricted FGF20 signal. Huh SH, Jones J, Warchol ME, Ornitz DM. PLoS Biol. 2012;10(1):e1001231.
 FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Barak H, Huh SH, Chen S, Jeanpierre C, Martinovic J, Parisot M, Bole-Feysot C, Nitschke P, Salomon R, Antignac C, Ornitz DM, Kopan R. Dev. Cell. 2012;22(6):1191-1207
 Ectodysplasin target gene Fgf20 regulates mammary bud growth and ductal invasion and branching during puberty. Elo T, Lindfors PH, Lan Q, Voutilainen M, Trela E, Ohlsson C, Huh SH, Ornitz DM, Poutanen M, Howard BA, Mikkola ML. Sci Rep. 2017;7(1):5049
 Ectodysplasin regulates activator-inhibitor balance in murine tooth development through Fgf20 signaling. D Haara O, Harjunmaa E, Lindfors PH, Huh SH, Fliniaux I, Aberg T, Jernvall J, Ornitz DM, Mikkola ML, Thesleff I. Development. 2012;139(17):3189-3199.
 Fgf20 governs formation of primary and secondary dermal condensations in developing hair follicles. Huh SH, Närhi K, Lindfors PH, Häärä O, Yang L, Ornitz DM, Mikkola ML. Genes Dev. 2013;27(4):450-458.
Taste and Smell (National Institute on Deafness and Other Communication Disorders/NIH)
Ornitz Lab, (Washington University, St. Louis)
Huh Lab, (University of Nebraska Medical Center, Omaha)
BioArt Scientific Image & Video Competition, (Federation of American Societies for Experimental Biology, Bethesda, MD)
NIH Support: National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders
Posted on by Dr. Francis Collins
Our ability to distinguish the aroma of freshly baked bread from the sweet fragrance of a rose comes from millions of sensory neurons that line the upper nasal cavity. These so-called olfactory sensory neurons activate when the specific types of odor molecules to which they are attuned enter the nose, prompting them to send their sensory alerts onward to the brain, where we become aware of a distinctive scent.
If you look closely at the striking image above from a young mouse, the thin, fluorescently labeled lines (red, green, white) show the neuronal extensions, or axons, of olfactory sensory neurons. These information-conveying axons stretch right to left from the nose through the smell-mediating olfactory bulb (blue) in the forebrain of all vertebrates, ending in just the right spot (white, pink, or red).
But the axons presented here don’t belong to just any olfactory sensory neurons. They represent newly discovered “navigator” neurons, which are essential to forge life’s very first olfactory connections .
The image comes from a recent paper in the journal Neuron from an NIH-supported team led by C. Ron Yu, Stowers Institute for Medical Research, Kansas City, MO. Yu’s team offered the first hints of navigator neurons a few years ago when it showed that young mice could correct errors in their olfactory wiring only when those disruptions occurred within the first week of life .
After that, the mice had lifelong abnormalities in their sense of smell. The findings suggested that the olfactory sensory neurons present very early in life had a unique ability to blaze a trail to the brain to establish a coherent olfactory map.
The new study confirms that navigator neurons indeed have a unique molecular identity. During their short lives, they show more extensive axon growth compared to neurons that arise later. Their axons also travel a more circuitous route to the brain, as if exploring the neural tissue before settling on a path to their final destination. As olfactory neurons in older mice regenerate, they simply follow the trail blazed for them by those early scouts.
While the new findings involve mice, the researchers suspect similar processes are at work in humans too. That means images like this one aren’t just fascinating. They could help pave the way toward new approaches for reviving navigator neurons, potentially making it possible to forge new olfactory connections—and bring back the enjoyment of delightful aromas such as freshly baked bread or roses—in those who’ve lost the ability to smell.
 A population of navigator neurons is essential for olfactory map formation during the critical period. Wu Y, Ma L, Duyck K, Long CC, Moran A, Scheerer H, Blanck J, Peak A, Box A, Perera A, Yu CR. Neuron. 2018 Dec 5;100(5):1066-1082.
 A developmental switch of axon targeting in the continuously regenerating mouse olfactory system. Ma L, Wu Y, Qiu Q, Scheerer H, Moran A, Yu CR. Science. 2014 Apr 11;344(6180):194-197.
Smell Disorders (National Institute on Deafness and Other Communication Disorders)
Yu Lab (Stowers Institute for Medical Research, Kansas City, MO)
NIH Support: National Institute on Deafness and Other Communication Disorders
Posted on by Dr. Francis Collins
You’ve probably learned the hard way about how the grocery list can go out the window when you go shopping on an empty stomach. Part of the reason is that our sense of smell intensifies when we’re hungry, making the aroma of freshly baked cookies, fried chicken, and other tempting goodies even more noticeable. And this beautiful micrograph helps to provide a biological explanation for this phenomenon.
The image, which looks like something that Van Gogh might have painted, shows a thick mesh of neurons in a small cross section of a mouse’s olfactory bulb, a structure located in the forebrain of all vertebrates (including humans!) that processes input about odors detected by the nose. Here, you see specialized neurons called mitral cells (red) that can receive signals from the hypothalamus, a brain region known for its role in hunger and energy balance. Also fluorescently labeled are receptors that detect acetylcholine signals from the brain (green) and the nuclei of all cells in the olfactory bulb (blue).