2020 March
Getting Closer to a Blood Test for Alzheimer’s Disease?
Posted on by Dr. Francis Collins
As research on Alzheimer’s disease (AD) advances, a desperate need remains for an easy blood test to help diagnose the condition as early as possible. Ideally, such a test could also distinguish AD from other forms of dementia that produce similar symptoms. As published recently in Nature Medicine, an NIH-funded research team has designed a simple blood test that is on course to meet these criteria [1].
The latest work builds on a large body of work showing that one secret to predicting a person’s cognitive decline and treatment response in AD lies in a protein called tau. Using the powerful, but expensive, approach of PET scan imaging, we know that tau builds up in the brain as Alzheimer’s disease progresses. We also know that some tau spills from the brain into the bloodstream.
The trouble is that the circulating tau protein breaks down far too quickly for a blood test to offer a reliable measure of what’s happening in a person’s brain. A few years ago, researchers discovered a possible solution: test for blood levels of a slightly different and more stable version of the protein called pTau181 [2]. (The “p” in its name comes from the addition of phosphorus in a particular part of the protein’s structure.)
In the latest study, researchers in the lab of Adam Boxer, University of California, San Francisco, followed up further on this compelling lead. Boxer’s team measured pTau181 levels in blood samples from 362 people between the ages of 58 and 70. Those samples included 56 people with an Alzheimer’s diagnosis, along with 47 people with mild cognitive impairment and 69 healthy controls.
The researchers also included another 190 people diagnosed with frontotemporal lobar degeneration (FTLD). It is a relatively rare form of dementia that leads to a gradual decline in behavior, language, and movement, often in connection with a buildup of tau in the brain.
The study found that levels of pTau181 were roughly 3.5-times higher in the blood of people with AD compared to people without AD. Those with mild cognitive impairment due to underlying AD also showed an intermediate increase in blood levels of pTau181.
Importantly, people with FLTD had normal blood levels of pTau181. As a result, the blood test could reliably distinguish between a person with AD and a person with FLTD. That’s important because, while FLTD is a relatively rare condition, its prevalence is similar to AD in people under the age of 65. But both conditions have similar symptoms, making it often challenging to distinguish them.
The findings add to evidence that the new blood test can help in diagnosing AD and in distinguishing it from other neurodegenerative conditions. In fact, it does so with an accuracy that often rivals more expensive PET scans and more invasive cerebrospinal fluid tests, which are now the only reliable ways to measure tau.
There’s still plenty of work to do before this blood test is ready for a doctor’s office. But these initial findings are very promising in helping to simplify the diagnosis of this devastating condition that now affects an estimated 5.5 million Americans [3].
References:
[1] Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Thijssen EH, La Joie R, Wolf A, Strom A, Wang P, Iaccarino L, Bourakova V, Cobigo Y, Heuer H, Spina S, VandeVrede L, Chai X, Proctor NK, Airey DC, Shcherbinin S, Duggan Evans C, Sims JR, Zetterberg H, Blennow K, Karydas AM, Teunissen CE, Kramer JH, Grinberg LT, Seeley WW, Rosen H, Boeve BF, Miller BL, Rabinovici GD, Dage JL, Rojas JC, Boxer AL; Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) investigators. Nat Med. 2020 Mar 2.
[2] Plasma phospho-tau181 increases with Alzheimer’s disease clinical severity and is associated with tau- and amyloid-positron emission tomography. Mielke MM, Hagen CE, Xu J, Chai X, Vemuri P, Lowe VJ, Airey DC, Knopman DS, Roberts RO, Machulda MM, Jack CR Jr, Petersen RC, Dage JL. Alzheimers Dement. 2018 Aug;14(8):989-997.
[3] Alzheimer’s Disease Fact Sheet. National Institute on Aging, May 22, 2019.
Links:
Alzheimer’s Disease & Related Dementias (National Institute on Aging/NIH)
What Are Frontotemporal Disorders? (NIA)
Accelerating Medicines Partnership: Alzheimer’s Disease (NIH)
Adam Boxer (University of California, San Francisco)
NIH Support: National Institute on Aging; National Institute of Neurological Disorders and Stroke; National Center for Advancing Translational Sciences
Genomic Study Points to Natural Origin of COVID-19
Posted on by Dr. Francis Collins
No matter where you go online these days, there’s bound to be discussion of coronavirus disease 2019 (COVID-19). Some folks are even making outrageous claims that the new coronavirus causing the pandemic was engineered in a lab and deliberately released to make people sick. A new study debunks such claims by providing scientific evidence that this novel coronavirus arose naturally.
The reassuring findings are the result of genomic analyses conducted by an international research team, partly supported by NIH. In their study in the journal Nature Medicine, Kristian Andersen, Scripps Research Institute, La Jolla, CA; Robert Garry, Tulane University School of Medicine, New Orleans; and their colleagues used sophisticated bioinformatic tools to compare publicly available genomic data from several coronaviruses, including the new one that causes COVID-19.
The researchers began by homing in on the parts of the coronavirus genomes that encode the spike proteins that give this family of viruses their distinctive crown-like appearance. (By the way, “corona” is Latin for “crown.”) All coronaviruses rely on spike proteins to infect other cells. But, over time, each coronavirus has fashioned these proteins a little differently, and the evolutionary clues about these modifications are spelled out in their genomes.
The genomic data of the new coronavirus responsible for COVID-19 show that its spike protein contains some unique adaptations. One of these adaptations provides special ability of this coronavirus to bind to a specific protein on human cells called angiotensin converting enzyme (ACE2). A related coronavirus that causes severe acute respiratory syndrome (SARS) in humans also seeks out ACE2.
Existing computer models predicted that the new coronavirus would not bind to ACE2 as well as the SARS virus. However, to their surprise, the researchers found that the spike protein of the new coronavirus actually bound far better than computer predictions, likely because of natural selection on ACE2 that enabled the virus to take advantage of a previously unidentified alternate binding site. Researchers said this provides strong evidence that that new virus was not the product of purposeful manipulation in a lab. In fact, any bioengineer trying to design a coronavirus that threatened human health probably would never have chosen this particular conformation for a spike protein.
The researchers went on to analyze genomic data related to the overall molecular structure, or backbone, of the new coronavirus. Their analysis showed that the backbone of the new coronavirus’s genome most closely resembles that of a bat coronavirus discovered after the COVID-19 pandemic began. However, the region that binds ACE2 resembles a novel virus found in pangolins, a strange-looking animal sometimes called a scaly anteater. This provides additional evidence that the coronavirus that causes COVID-19 almost certainly originated in nature. If the new coronavirus had been manufactured in a lab, scientists most likely would have used the backbones of coronaviruses already known to cause serious diseases in humans.
So, what is the natural origin of the novel coronavirus responsible for the COVID-19 pandemic? The researchers don’t yet have a precise answer. But they do offer two possible scenarios.
In the first scenario, as the new coronavirus evolved in its natural hosts, possibly bats or pangolins, its spike proteins mutated to bind to molecules similar in structure to the human ACE2 protein, thereby enabling it to infect human cells. This scenario seems to fit other recent outbreaks of coronavirus-caused disease in humans, such as SARS, which arose from cat-like civets; and Middle East respiratory syndrome (MERS), which arose from camels.
The second scenario is that the new coronavirus crossed from animals into humans before it became capable of causing human disease. Then, as a result of gradual evolutionary changes over years or perhaps decades, the virus eventually gained the ability to spread from human-to-human and cause serious, often life-threatening disease.
Either way, this study leaves little room to refute a natural origin for COVID-19. And that’s a good thing because it helps us keep focused on what really matters: observing good hygiene, practicing social distancing, and supporting the efforts of all the dedicated health-care professionals and researchers who are working so hard to address this major public health challenge.
Finally, next time you come across something about COVID-19 online that disturbs or puzzles you, I suggest going to FEMA’s new Coronavirus Rumor Control web site. It may not have all the answers to your questions, but it’s definitely a step in the right direction in helping to distinguish rumors from facts.
Reference:
[1] The proximal origin of SARS-CoV-2. Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. Nat Med, 17 March 2020. [Epub ahead of publication]
Links:
Coronavirus (COVID-19) (NIH)
COVID-19, MERS & SARS (National Institute of Allergy and Infectious Diseases/NIH)
Andersen Lab (Scripps Research Institute, La Jolla, CA)
Robert Garry (Tulane University School of Medicine, New Orleans)
Coronavirus Rumor Control (FEMA)
NIH Support: National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute
Encouraging News for Kids with Neurofibromatosis Type 1
Posted on by Dr. Francis Collins
Amid all the headlines and uncertainty surrounding the current COVID-19 pandemic, it’s easy to overlook the important progress that biomedical research is making against other diseases. So, today, I’m pleased to share word of what promises to be the first effective treatment to help young people suffering from the consequences of a painful, often debilitating genetic disorder called neurofibromatosis type 1 (NF1).
This news is particularly meaningful to me because, 30 years ago, I led a team that discovered the gene that underlies NF1. About 1 in 3,000 babies are born with NF1. In about half of those affected, a type of tumor called a plexiform neurofibroma arises along nerves in the skin, face, and other parts of the body. While plexiform neurofibromas are not cancerous, they grow steadily and can lead to severe pain and a range of other health problems, including vision and hearing loss, hypertension, and mobility issues.
The good news is the results of a phase II clinical trial involving NF1, just published in the New England Journal of Medicine. The trial was led by Brigitte Widemann and Andrea Gross, researchers in the Center for Cancer Research at NIH’s National Cancer Institute.
The trial’s results confirm that a drug originally developed to treat cancer, called selumetinib, can shrink inoperable tumors in many children with NF1. They also establish that the drug can help affected kids make significant improvements in strength, range of motion, and quality of life. While selumetinib is not a cure, and further studies are still needed to see how well the treatment works in the long term, these results suggest that the first effective treatment for NF1 is at last within our reach.
Selumetinib blocks a protein in human cells called MEK. This protein is involved in a major cellular pathway known as RAS that can become dysregulated and give rise to various cancers. By blocking the MEK protein in animal studies and putting the brakes on the RAS pathway when it malfunctions, selumetinib showed great initial promise as a cancer drug.
Selumetinib was first tested several years ago in people with a variety of other cancers, including ovarian and non-small cell lung cancers. The clinical research looked good at first but eventually stalled, and so did much of the initial enthusiasm for selumetinib.
But the enthusiasm picked up when researchers considered repurposing the drug to treat NF1. The neurofibromas associated with the condition were known to arise from a RAS-activating loss of the NF1 gene. It made sense that blocking the MEK protein might blunt the overactive RAS signal and help to shrink these often-inoperable tumors.
An earlier phase 1 safety trial looked promising, showing for the first time that the drug could, in some cases, shrink large NF1 tumors [2]. This fueled further research, and the latest study now adds significantly to that evidence.
In the study, Widemann and colleagues enrolled 50 children with NF1, ranging in age from 3 to 17. Their tumor-related symptoms greatly affected their wellbeing and ability to thrive, including disfigurement, limited strength and motion, and pain. Children received selumetinib alone orally twice a day and went in for assessments at least every four months.
As of March 2019, 35 of the 50 children in the ongoing study had a confirmed partial response, meaning that their tumors had shrunk by more than 20 percent. Most had maintained that response for a year or more. More importantly, the kids also felt less pain and were more able to enjoy life.
It’s important to note that the treatment didn’t work for everyone. Five children stopped taking the drug due to side effects. Six others progressed while on the drug, though five of them had to reduce their dose because of side effects before progressing. Nevertheless, for kids with NF1 and their families, this is a big step forward.
Drug developer AstraZeneca, working together with the researchers, has submitted a New Drug Application to the Food and Drug Administration (FDA). While they’re eagerly awaiting the FDA’s decision, the work continues.
The researchers want to learn much more about how the drug affects the health and wellbeing of kids who take it over the long term. They’re also curious whether it could help to prevent the growth of large tumors in kids who begin taking it earlier in the course of the disease, and whether it might benefit other features of the disorder. They will continue to look ahead to other potentially promising treatments or treatment combinations that may further help, and perhaps one day even cure, kids with NF1. So, even while we cope with the COVID-19 pandemic, there are reasons to feel encouraged and grateful for continued progress made throughout biomedical research.
References:
[1] Selumitinib in children with inoperable plexiform neurofibromas. New England Journal of Medicine. Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, Weiss B, Kim A, Bornhorst M, Shah AC, Martin S, Roderick MC, Pichard DC, Carbonell A, Paul SM, Therrien J, Kapustina O, Heisey K, Clapp DW, Zhang C, Peer CJ, Figg WD, Smith M, Glod J, Blakeley JO, Steinberg SM, Venzon DJ, Doyle LA, Widemann BC. 18 March 2020. N Engl J Med. 2020 Mar 18. [Epub ahead of publication.]
[2] Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P1, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC. N Engl J Med. 2016 Dec 29;375(26):2550-2560.
Links:
Neurofibromatosis Fact Sheet (National Institute of Neurological Disorders and Stroke/NIH)
Brigitte Widemann (National Cancer Institute/NIH)
Andrea Gross (National Cancer Institute/NIH)
NIH Support: National Cancer Institute
To Beat COVID-19, Social Distancing is a Must
Posted on by Dr. Francis Collins
Even in less challenging times, many of us try to avoid close contact with someone who is sneezing, coughing, or running a fever to avoid getting sick ourselves. Our attention to such issues has now been dramatically heightened by the emergence of a novel coronavirus causing a pandemic of an illness known as COVID-19.
Many have wondered if we couldn’t simply protect ourselves by avoiding people with symptoms of respiratory illness. Unfortunately, the answer is no. A new study shows that simply avoiding symptomatic people will not go far enough to curb the COVID-19 pandemic. That’s because researchers have discovered that many individuals can carry the novel coronavirus without showing any of the typical symptoms of COVID-19: fever, dry cough, and shortness of breath. But these asymptomatic or only mildly ill individuals can still shed virus and infect others.
This conclusion adds further weight to the recent guidance from U.S. public health experts: what we need most right now to slow the stealthy spread of this new coronavirus is a full implementation of social distancing. What exactly does social distancing mean? Well, for starters, it is recommended that people stay at home as much as possible, going out only for critical needs like groceries and medicines, or to exercise and enjoy the outdoors in wide open spaces. Other recommendations include avoiding gatherings of more than 10 people, no handshakes, regular handwashing, and, when encountering someone outside of your immediate household, trying to remain at least 6 feet apart.
These may sound like extreme measures. But the new study by NIH-funded researchers, published in the journal Science, documents why social distancing may be our best hope to slow the spread of COVID-19 [1]. Here are a few highlights of the paper, which looks back to January 2020 and mathematically models the spread of the coronavirus within China:
• For every confirmed case of COVID-19, there are likely another five to 10 people with undetected infections.
• Although they are thought to be only about half as infectious as individuals with confirmed COVID-19, individuals with undetected infections were so prevalent in China that they apparently were the infection source for 86 percent of confirmed cases.
• After China established travel restrictions and social distancing, the spread of COVID-19 slowed considerably.
The findings come from a small international research team that included NIH grantee Jeffrey Shaman, Columbia University Mailman School of Public Health, New York. The team developed a computer model that enabled researchers to simulate the time and place of infections in a grid of 375 Chinese cities. The researchers did so by combining existing data on the spread of COVID-19 in China with mobility information collected by a location-based service during the country’s popular 40-day Spring Festival, when travel is widespread.
As these new findings clearly demonstrate, each of us must take social distancing seriously in our daily lives. Social distancing helped blunt the pandemic in China, and it will work in other nations, including the United States. While many Americans will likely spend weeks working and studying from home and practicing other social distancing measures, the stakes remain high. If this pandemic isn’t contained, this novel coronavirus could well circulate around the globe for years to come, at great peril to us and our loved ones.
As we commit ourselves to spending more time at home, progress continues to be made in using the power of biomedical research to combat this novel coronavirus. A notable step this week was the launch of an early-stage human clinical trial of an investigational vaccine, called mRNA-1273, to protect against COVID-19 [2]. The vaccine candidate was developed by researchers at NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and their collaborators at the biotechnology company Moderna, Inc., Cambridge, MA.
This Phase 1 NIAID-supported trial will look at the safety of the vaccine—which cannot cause infection because it is made of RNA, not the whole coronavirus—in 45 healthy adults. The first volunteer was injected this past Monday at Kaiser Permanente Washington Health Research Institute, Seattle. If all goes well and larger follow-up clinical studies establish the vaccine’s safety and efficacy, it will then be necessary to scale up production to make millions of doses. While initiating this trial in record time is reason for hope, it is important to be realistic about all of the steps that still remain. If the vaccine candidate proves safe and effective, it will likely take at least 12–18 months before it would be widely available.
In the meantime, social distancing remains one of the best weapons we have to slow the silent spread of this virus and flatten the curve of the COVID-19 pandemic. This will give our health-care professionals, hospitals, and other institutions more valuable time to prepare, protect themselves, and aid the many people whose lives may be on the line from this coronavirus.
Importantly, saving lives from COVID-19 requires all of us—young, old and in-between—to take part. Healthy young people, whose risk of dying from coronavirus is not zero but quite low, might argue that they shouldn’t be constrained by social distancing. However, the research highlighted here demonstrates that such individuals are often the unwitting vector for a dangerous virus that can do great harm—and even take the lives of older and more vulnerable people. Think about your grandparents. Then skip the big gathering. We are all in this together
References:
[1] Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2). Li R, Pei S, Chen B, Song Y, Zhang T, Yang W, Shaman J. Science. 16 March 2020. [Preprint ahead of publication]
[2] NIH clinical trial of investigational vaccine for COVID-19 begins. NIH News Release, March 16, 2020.
Links:
Coronavirus (COVID-19) (NIH)
COVID-19, MERS & SARS (National Institute of Allergy and Infectious Diseases/NIH)
Coronavirus (COVID-19) (Centers for Disease Control and Prevention, Atlanta)
NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences
How Our Brains Replay Memories
Posted on by Dr. Francis Collins
Note to my blog readers: the whole world is now facing a major threat from the COVID-19 pandemic. We at NIH are doing everything we can to apply the best and most powerful science to the development of diagnostics, therapeutics, and vaccines, while also implementing public health measures to protect our staff and the patients in our hospital. This crisis is expected to span many weeks, and I will occasionally report on COVID-19 in this blog format. Meanwhile, science continues to progress on many other fronts—and so I will continue to try to bring you stories across a wide range of topics. Perhaps everyone can use a little break now and then from the coronavirus news? Today’s blog takes you into the intricacies of memory.
When recalling the name of an acquaintance, you might replay an earlier introduction, trying to remember the correct combination of first and last names. (Was it Scott James? Or James Scott?) Now, neuroscientists have found that in the split second before you come up with the right answer, your brain’s neurons fire in the same order as when you first learned the information [1].
This new insight into memory retrieval comes from recording the electrical activity of thousands of neurons in the brains of six people during memory tests of random word pairs, such as “jeep” and “crow.” While similar firing patterns had been described before in mice, the new study is the first to confirm that the human brain stores memories in specific sequences of neural activity that can be replayed again and again.
The new study, published in the journal Science, is the latest insight from neurosurgeon and researcher Kareem Zaghloul at NIH’s National Institute of Neurological Disorders and Stroke (NINDS). Zaghloul’s team has for years been involved in an NIH Clinical Center study for patients with drug-resistant epilepsy whose seizures cannot be controlled with drugs.
As part of this work, his surgical team often temporarily places a 4 millimeter-by-4 millimeter array of tiny electrodes on the surface of the brains of the study’s participants. They do this in an effort to pinpoint brain tissues that may be the source of their seizures before performing surgery to remove them. With a patient’s informed consent to take part in additional research, the procedure also has led to a series of insights into what happens in the human brain when we make and later retrieve new memories.
Here’s how it works: The researchers record electrical currents as participants are asked to learn random word pairs presented to them on a computer screen, such as “cake” and “fox,” or “lime” and “camel.” After a period of rest, their brain activity is again recorded as they are given a word and asked to recall the matching word.
Last year, the researchers reported that the split second before a person got the right answer, tiny ripples of electrical activity appeared in two specific areas of the brain [2]. The team also had shown that, when a person correctly recalled a word pair, the brain showed patterns of activity that corresponded to those formed when he or she first learned to make a word association.
The new work takes this a step further. As study participants learned a word pair, the researchers noticed not only the initial rippling wave of electricity, but also that particular neurons in the brain’s cerebral cortex fired repeatedly in a sequential order. In fact, with each new word pair, the researchers observed unique firing patterns among the active neurons.
If the order of neuronal firing was essential for storing new memories, the researchers reasoned that the same would be true for correctly retrieving the information. And, indeed, that’s what they were able to show. For example, when individuals were shown “cake” for a second time, they replayed a very similar firing pattern to the one recorded initially for this word just milliseconds before correctly recalling the paired word “fox.”
The researchers then calculated the average sequence similarity between the firing patterns of learning and retrieval. They found that as a person recalled a word, those patterns gradually became more similar. Just before a correct answer was given, the recorded neurons locked onto the right firing sequence. That didn’t happen when a person gave an incorrect answer.
Further analysis confirmed that the exact order of neural firing was specific to each word pair. The findings show that our memories are encoded as unique sequences that must be replayed for accurate retrieval, though we still don’t understand the molecular mechanisms that undergird this.
Zaghloul reports that there’s still more to learn about how these processes are influenced by other factors such as our attention. It’s not yet known whether the brain replays sequences similarly when retrieving longer-term memories. Along with these intriguing insights into normal learning and memory, the researchers think this line of research will yield important clues as to what changes in people who suffer from memory disorders, with potentially important implications for developing the next generation of treatments.
Reference:
[1] Replay of cortical spiking sequences during human memory retrieval. Vaz AP, Wittig JH Jr, Inati SK, Zaghloul KA. Science. 2020 Mar 6;367(6482):1131-1134.
[2] Coupled ripple oscillations between the medial temporal lobe and neocortex retrieve human memory. Vaz AP, Inati SK, Brunel N, Zaghloul KA. Science. 2019 Mar 1;363(6430):975-978.
Links:
Epilepsy Information Page (National Institute of Neurological Disorders and Stroke/NIH)
Brain Basics (NINDS)
Zaghloul Lab (NINDS)
NIH Support: National Institute of Neurological Disorders and Stroke; National Institute of General Medical Sciences
First Virtual WALS Lecture
Posted on by Dr. Francis Collins
Finding Beauty in Cell Stress
Posted on by Dr. Francis Collins
Most stressful situations that we experience in daily life aren’t ones that we’d choose to repeat. But the cellular stress response captured in this video is certainly worth repeating a few times, so you can track what happens when two cancer cells get hit with stressors.
In this movie of two highly stressed osteosarcoma cells, you first see the appearance of many droplet-like structures (green). This is followed by a second set of droplets (magenta) and, finally, the fusion of both types of droplets.
These droplets are composed of fluorescently labeled stress-response proteins, either G3BP or UBQLN2 (Ubiquilin-2). Each protein is undergoing a fascinating process, called phase separation, in which a non-membrane bound compartment of the cytoplasm emerges and constrains the motion of proteins within it. Subsequently, the proteins fuse with like proteins to form larger droplets, in much the same way that raindrops merge on a car’s windshield.
Julia Riley, an undergraduate student in the NIH-supported lab of Heidi Hehnly and lab of Carlos Castañeda, Syracuse University, NY, shot this movie using the sophisticated tools of fluorescence microscopy. It’s the next installment in our series featuring winners of the 2019 Green Fluorescent Protein Image and Video Contest, sponsored by the American Society for Cell Biology. The contest honors the discovery of green fluorescent protein (GFP), which—together with a rainbow of other fluorescent proteins—has enabled researchers to visualize proteins and their dynamic activities inside cells for the last 25 years.
Riley and colleagues suspect that, in this case, phase separation is a protective measure that allows proteins to wall themselves off from the rest of the cell during stressful conditions. In this way, the proteins can create new functional units within the cell. The researchers are working to learn much more about what this interesting behavior entails as a basic organizing principle in the cell and how it works.
Even more intriguing is that similar stress-responding proteins are commonly altered in people with the devastating neurologic condition known as amyotrophic lateral sclerosis (ALS). ALS is a group of rare neurological diseases that involve the progressive deterioration of neurons responsible for voluntary movements such as chewing, walking, and talking. There’s been the suggestion that these phase separation droplets may seed the formation of the larger protein aggregates that accumulate in the motor neurons of people with this debilitating and fatal condition.
Castañeda and Hehnly, working with J. Paul Taylor at St. Jude Children’s Research Hospital, Memphis, earlier reported that Ubiquilin-2 forms stress-induced droplets in multiple cell types [1]. More recently, they showed that mutations in Ubiquilin-2 have been linked to ALS changes in the way that the protein undergoes phase separation in a test tube [2].
While the proteins in this award-winning video aren’t mutant forms, Riley is now working on the sequel, featuring versions of the Ubiquilin-2 protein that you’d find in some people with ALS. She hopes to capture how those mutations might produce a different movie and what that might mean for understanding ALS.
References:
[1] Ubiquitin Modulates Liquid-Liquid Phase Separation of UBQLN2 via Disruption of Multivalent Interactions. Dao TP, Kolaitis R-M, Kim HJ, O’Donovan K, Martyniak B, Colicino E, Hehnly H, Taylor JP, Castañeda CA. Molecular Cell. 2018 Mar 15;69(6):965-978.e6.
[2] ALS-Linked Mutations Affect UBQLN2 Oligomerization and Phase Separation in a Position- and Amino Acid-Dependent Manner. Dao TP, Martyniak B, Canning AJ, Lei Y, Colicino EG, Cosgrove MS, Hehnly H, Castañeda CA. Structure. 2019 Jun 4;27(6):937-951.e5.
Links:
Amyotrophic Lateral Sclerosis (ALS) (National Institute of Neurological Disorders and Stroke/NIH)
Castañeda Lab (Syracuse University, NY)
Hehnly Lab (Syracuse University)
Green Fluorescent Protein Image and Video Contest (American Society for Cell Biology, Bethesda, MD)
2008 Nobel Prize in Chemistry (Nobel Foundation, Stockholm, Sweden)
NIH Support: National Institute of General Medical Sciences
Prostate Cancer: Combined Biopsy Strategy Makes for More Accurate Diagnosis
Posted on by Dr. Francis Collins
Last year, nearly 175,000 American men were diagnosed with prostate cancer [1]. Most got the bad news after a blood test or physical exam raised concerns that warranted a biopsy of the prostate, a walnut-sized gland just below the bladder.
Traditional biopsies sample tissue from 12 systematically placed points within the prostate that are blind to tumor locations. Such procedures have helped to save many lives, but are prone to missing or misclassifying prostate cancers, which has led doctors both to over and under treat their patients.
Now, there may be a better approach. In a study of more than 2,000 men, NIH researchers and their colleagues recently found that combining the 12-point biopsy with magnetic resonance imaging (MRI)-targeted biopsy during the same session more accurately diagnoses prostate cancer than either technique alone [2].
The findings address a long-standing challenge in prostate cancer diagnostics: performing a thorough prostate biopsy to allow a pathologist to characterize as accurately as possible the behavior of a tumor. Some prostate tumors are small, slow growing, and can be monitored closely without treatment. Other tumors are aggressive and can grow rapidly, requiring immediate intervention with hormonal therapy, radiation, or surgery.
But performing a thorough prostate biopsy can run into technical difficulties. The 12-point biopsy blindly samples tissue from across the prostate gland, but it can miss a cancer by not probing in the right places.
Several years ago, researchers at the NIH Clinical Center, Bethesda, MD, envisioned a solution. They’d use specially designed MRI images of a man’s prostate to guide the biopsy needle to areas in the prostate that look suspicious and deserve a closer look under a microscope.
Through a cooperative research-and-development agreement, NIH and the now- Florida-based Philips Healthcare created an office-based, outpatient prostate biopsy device, called UroNav, that was later approved by the Food and Drug Administration. The UroNav system relies on software that overlays MRI images highlighting suspicious areas onto real-time ultrasound images of the prostate that are traditionally used to guide biopsy procedures.
The new technology led to a large clinical study led by Peter Pinto, a researcher with NIH’s National Cancer Institute. The study results, published in 2015, found that the MRI-targeted approach was indeed superior to the 12-point biopsy at detecting aggressive prostate cancers [3].
But some doctors had questions about how best to implement the UroNav system and whether it could replace the 12-point biopsy. The uncertainty led to a second clinical study to nail down more answers, and the results were just published in The New England Journal of Medicine.
The research team enrolled 2,103 men who had visible prostate abnormalities on an MRI. Once in the study, each man underwent both the 12-point blind biopsy and the MRI-targeted approach—all in a single office visit. Based on this two-step approach, 1,312 people were diagnosed with prostate cancer. Of that total, 404 men had evidence of aggressive cancer, and had their prostates surgically removed.
The researchers then compared the diagnoses from each approach alone versus the two combined. The data showed that the combined biopsy found 208 cancers that the standard 12-point biopsy alone would have missed. Adding the MRI-targeted biopsy also helped doctors find and sample the more aggressive cancers. This allowed them to upgrade the diagnosis of 458 cancers to aggressive and in need of more full treatment.
Combining the two approaches also led to more accurate diagnoses. By carefully analyzing the 404 removed prostates and comparing them to the biopsy results, the researchers found the 12-point biopsy missed the most aggressive cancers about 40 percent of the time. But the MRI-targeted approach alone missed it about 30 percent of the time. Combined, they did much better, underestimating the severity of less than 15 percent of the cancers.
Even better, the combined biopsy missed only 3.5 percent of the most aggressive tumors. That’s compared to misses of about 17 percent for the most-aggressive cancers for the 12-point biopsy alone and about 9 percent for MRI-targeted biopsy alone.
It may take time for doctors to change how they detect prostate cancer in their practices. But the findings show that combining both approaches will significantly improve the accuracy of diagnosing prostate cancer. This will, in turn, help to reduce risk of suboptimal treatment (too much or too little) by allowing doctors and patients to feel more confident in the biopsy results. That should come as good news now and in the future for the families and friends of men who will need an accurate prostate biopsy to make informed treatment decisions.
References:
[1] Cancer State Facts: Prostate Cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program.
[2] MRI-targeted, systematic, and combined biopsy for prostate cancer diagnosis. Ahdoot M, Wilbur AR, Reese SE, Lebastchi AH, Mehralivand S, Gomella PT, Bloom J, Gurram S, Siddiqui M, Pinsky P, Parnes H, Linehan WM, Merino M, Choyke PL, Shih JH, Turkbey B, Wood BJ, Pinto PA. N Engl J Med. 2020 Mar 5;382(10):917-928.
[3] Comparison of MR/ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. Siddiqui M, Rais-Bahrami, George AK, Rothwax J, Shakir N, Okoro C, Raskolnikov D, Parnes HL, Linehan WM, Merino MJ, Simon RM, Choyke PL, Wood BJ, and Pinto PA. JAMA. 2015 January 27;313(4):390-397.
Links:
Prostate Cancer (National Cancer Institute/NIH)
Video: MRI-Targeted Prostate Biopsy (YouTube)
Pinto Lab (National Cancer Institute/NIH)
NIH Support: National Cancer Institute; NIH Clinical Center
Time for Lunch
Posted on by Dr. Francis Collins
Discovering the Brain’s Nightly “Rinse Cycle”
Posted on by Dr. Francis Collins
Getting plenty of deep, restful sleep is essential for our physical and mental health. Now comes word of yet another way that sleep is good for us: it triggers rhythmic waves of blood and cerebrospinal fluid (CSF) that appear to function much like a washing machine’s rinse cycle, which may help to clear the brain of toxic waste on a regular basis.
The video above uses functional magnetic resonance imaging (fMRI) to take you inside a person’s brain to see this newly discovered rinse cycle in action. First, you see a wave of blood flow (red, yellow) that’s closely tied to an underlying slow-wave of electrical activity (not visible). As the blood recedes, CSF (blue) increases and then drops back again. Then, the cycle—lasting about 20 seconds—starts over again.
The findings, published recently in the journal Science, are the first to suggest that the brain’s well-known ebb and flow of blood and electrical activity during sleep may also trigger cleansing waves of blood and CSF. While the experiments were conducted in healthy adults, further study of this phenomenon may help explain why poor sleep or loss of sleep has previously been associated with the spread of toxic proteins and worsening memory loss in people with Alzheimer’s disease.
In the new study, Laura Lewis, Boston University, MA, and her colleagues at the Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston. recorded the electrical activity and took fMRI images of the brains of 13 young, healthy adults as they slept. The NIH-funded team also built a computer model to learn more about the fluid dynamics of what goes on in the brain during sleep. And, as it turns out, their sophisticated model predicted exactly what they observed in the brains of living humans: slow waves of electrical activity followed by alternating waves of blood and CSF.
Lewis says her team is now working to come up with even better ways to capture CSF flow in the brain during sleep. Currently, people who volunteer for such experiments have to be able to fall asleep while wearing an electroencephalogram (EEG) cap inside of a noisy MRI machine—no easy feat. The researchers are also recruiting older adults to begin exploring how age-related changes in brain activity during sleep may affect the associated fluid dynamics.
Reference:
[1] Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Fultz NE, Bonmassar G, Setsompop K, Stickgold RA, Rosen BR, Polimeni JR, Lewis LD. Science. 2019 Nov 1;366(6465):628-631.
Links:
Sleep and Memory (National Institute of Mental Health/NIH)
Sleep Deprivation and Deficiency (National Heart, Lung, and Blood Institute/NIH)
Alzheimer’s Disease and Related Dementias (National Institute on Aging/NIH)
NIH Support: National Institute of Mental Health; National Institute of Biomedical Imaging and Bioengineering; National Institute of Neurological Disorders and Stroke
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