infectious diseases
Persistence Pays Off: Recognizing Katalin Karikó and Drew Weissman, the 2023 Nobel Prize Winners in Physiology or Medicine
Posted on by Lawrence Tabak, D.D.S., Ph.D.
Last week, biochemist Katalin Karikó and immunologist Drew Weissman earned the Nobel Prize in Physiology or Medicine for their discoveries that enabled the development of effective messenger RNA (mRNA) vaccines against COVID-19. On behalf of the NIH community, I’d like to congratulate Karikó and Weissman and thank them for their persistence in pursuing their investigations. NIH is proud to have supported their seminal research, cited by the Nobel Assembly as key publications.1,2,3
While the lifesaving benefits of mRNA vaccines are now clearly realized, Karikó and Weissman’s breakthrough finding in 2005 was not fully appreciated at the time as to why it would be significant. However, their dogged dedication to gaining a better understanding of how RNA interacts with the immune system underscores the often-underappreciated importance of incremental research. Following where the science leads through step-by-step investigations often doesn’t appear to be flashy, but it can end up leading to major advances.
To best describe Karikó and Weissman’s discovery, I’ll first do a quick review of vaccine history. As many of you know, vaccines stimulate our immune systems to protect us from getting infected or from getting very sick from a specific pathogen. Since the late 1700s, scientists have used various approaches to design effective vaccines. Some vaccines introduce a weakened or noninfectious version of a virus to the body, while others present only a small part of the virus, like a protein. The immune system detects the weak or partial virus and develops specialized defenses against it. These defenses work to protect us if we are ever exposed to the real virus.
In the early 1990s, scientists began exploring a different approach to vaccines that involved delivering genetic material, or instructions, so the body’s own cells could make the virus proteins that stimulate an immune response.4,5 Because this approach eliminates the step of growing virus or virus protein in the laboratory—which can be difficult to do in very large quantities and can require a lot of time and money—it had potential, in theory, to be a faster and cheaper way to manufacture vaccines.
Scientists were exploring two types of vaccines as part of this new approach: DNA vaccines and messenger RNA (mRNA) vaccines. DNA vaccines deliver an encoded protein recipe that the cell first copies or transcribes before it starts making protein. For mRNA vaccines, the transcription process is done in the laboratory, and the vaccine delivers the “readable” instructions to the cell for making protein. However, mRNA was not immediately a practical vaccine approach due to several scientific hurdles, including that it caused inflammatory reactions that could be unhealthy for people.
Unfazed by the challenges, Karikó and Weissman spent years pursuing research on RNA and the immune system. They had a brilliant idea that they turned into a significant discovery in 2005 when they proved that inserting subtle chemical modifications to lab-transcribed mRNA eliminated the unwanted inflammatory response.1 In later studies, the pair showed that these chemical modifications also increased protein production.2,3 Both discoveries would be critical to advancing the use of mRNA-based vaccines and therapies.
Earlier theories that mRNA could enable rapid vaccine development turned out to be true. By March 2020, the first clinical trial of an mRNA vaccine for COVID-19 had begun enrolling volunteers, and by December 2020, health care workers were receiving their first shots. This unprecedented timeline was only possible because of Karikó and Weissman’s decades of work, combined with the tireless efforts of many academic, industry and government scientists, including several from the NIH intramural program. Now, researchers are exploring how mRNA could be used in vaccines for other infectious diseases and in cancer vaccines.
As an investigator myself, I’m fascinated by how science continues to build on itself—a process that is done out of the public eye. Luckily every year, the Nobel Prize briefly illuminates for the larger public this long arc of scientific discovery. The Nobel Assembly’s recognition of Karikó and Weissman is a tribute to all scientists who do the painstaking work of trying to understand how things work. Many of the tools we have today to better prevent and treat diseases would not have been possible without the brilliance, tenacity and grit of researchers like Karikó and Weissman.
References:
- K Karikó, et al. Suppression of RNA Recognition by Toll-like Receptors: The impact of nucleoside modification and the evolutionary origin of RNA. Immunity DOI: 10.1016/j.immuni.2005.06.008 (2005).
- K Karikó, et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Molecular Therapy DOI: 10.1038/mt.2008.200 (2008).
- BR Anderson, et al. Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic Acids Research DOI: 10.1093/nar/gkq347 (2010).
- DC Tang, et al. Genetic immunization is a simple method for eliciting an immune response. Nature DOI: 10.1038/356152a0 (1992).
- F Martinon, et al. Induction of virus-specific cytotoxic T lymphocytes in vivo by liposome-entrapped mRNA. European Journal of Immunology DOI: 10.1002/eji.1830230749 (1993).
NIH Support:
Katalin Karikó: National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke
Drew Weissman: National Institute of Allergy and Infectious Diseases; National Institute of Dental and Craniofacial Research; National Heart, Lung, and Blood Institute
The Prime Cellular Targets for the Novel Coronavirus
Posted on by Dr. Francis Collins
There’s still a lot to learn about SARS-CoV-2, the novel coronavirus that causes COVID-19. But it has been remarkable and gratifying to watch researchers from around the world pull together and share their time, expertise, and hard-earned data in the urgent quest to control this devastating virus.
That collaborative spirit was on full display in a recent study that characterized the specific human cells that SARS-CoV-2 likely singles out for infection [1]. This information can now be used to study precisely how each cell type interacts with the virus. It might ultimately help to explain why some people are more susceptible to SARS-CoV-2 than others, and how exactly to target the virus with drugs, immunotherapies, and vaccines to prevent or treat infections.
This work was driven by the mostly shuttered labs of Alex K. Shalek, Massachusetts Institute of Technology, Ragon Institute of MGH, MIT, and Harvard, and Broad Institute of MIT and Harvard, Cambridge; and Jose Ordovas-Montanes at Boston Children’s Hospital. In the end, it brought together (if only remotely) dozens of their colleagues in the Human Cell Atlas Lung Biological Network and others across the U.S., Europe, and South Africa.
The project began when Shalek, Ordovas-Montanes, and others read that before infecting human cells, SARS-CoV-2 docks on a protein receptor called angiotensin-converting enzyme 2 (ACE2). This enzyme plays a role in helping the body maintain blood pressure and fluid balance.
The group was intrigued, especially when they also learned about a second enzyme that the virus uses to enter cells. This enzyme goes by the long acronym TMPRSS2, and it gets “tricked” into priming the spike proteins that cover SARS-CoV-2 to attack the cell. It’s the combination of these two proteins that provide a welcome mat for the virus.
Shalek, Ordovas-Montanes, and an international team including graduate students, post-docs, staff scientists, and principal investigators decided to dig a little deeper to find out precisely where in the body one finds cells that express this gene combination. Their curiosity took them to the wealth of data they and others had generated from model organisms and humans, the latter as part of the Human Cell Atlas. This collaborative international project is producing a comprehensive reference map of all human cells. For its first draft, the Human Cell Atlas aims to gather information on at least 10 billion cells.
To gather this information, the project relies, in part, on relatively new capabilities in sequencing the RNA of individual cells. Keep in mind that every cell in the body has essentially the same DNA genome. But different cells use different programs to decide which genes to turn on—expressing those as RNA molecules that can be translated into protein. The single-cell analysis of RNA allows them to characterize the gene expression and activities within each and every unique cell type. Based on what was known about the virus and the symptoms of COVID-19, the team focused their attention on the hundreds of cell types they identified in the lungs, nasal passages, and intestines.
As reported in Cell, by filtering through the data to identify cells that express ACE2 and TMPRSS2, the researchers narrowed the list of cell types in the nasal passages down to the mucus-producing goblet secretory cells. In the lung, evidence for activity of these two genes turned up in cells called type II pneumocytes, which line small air sacs known as alveoli and help to keep them open. In the intestine, it was the absorptive enterocytes, which play an important role in the body’s ability to take in nutrients.
The data also turned up another unexpected and potentially important connection. In these cells of interest, all of which are found in epithelial tissues that cover or line body surfaces, the ACE2 gene appeared to ramp up its activity in concert with other genes known to respond to interferon, a protein that the body makes in response to viral infections.
To dig further in the lab, the researchers treated cultured cells that line airways in the lungs with interferon. And indeed, the treatment increased ACE2 expression.
Earlier studies have suggested that ACE2 helps the lungs to tolerate damage. Completely missed was its connection to the interferon response. The researchers now suspect that’s because it hadn’t been studied in these specific human epithelial cells before.
The discovery suggests that SARS-CoV-2 and potentially other coronaviruses that rely on ACE2 may take advantage of the immune system’s natural defenses. When the body responds to the infection by producing more interferon, that in turn results in production of more ACE2, enhancing the ability of the virus to attach more readily to lung cells. While much more work is needed, the finding indicates that any potential use of interferon as a treatment to fight COVID-19 will require careful monitoring to determine if and when it might help patients.
It’s clear that these new findings, from data that weren’t originally generated with COVID-19 in mind, contained several potentially important new leads. This is another demonstration of the value of basic science. We can also rest assured that, with the outpouring of effort from members of the scientific community around the globe to meet this new challenge, progress along these and many other fronts will continue at a remarkable pace.
Reference:
[1] SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Ziegler, CGK et al. Cell. April 20, 2020.
Links:
Coronaviruses (National Institute of Allergy and Infectious Diseases/NIH)
Human Cell Atlas (Broad Institute, Cambridge, MA)
Shalek Lab (Harvard Medical School and Massachusetts Institute of Technology, Cambridge)
Ordovas-Montanes Lab (Boston Children’s Hospital, MA)
NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences; National Heart, Lung, and Blood Institute
Capturing Viral Shedding in Action
Posted on by Dr. Francis Collins
You’ve probably seen some amazing high-resolution images of SARS-CoV-2, the novel coronavirus that causes COVID-19, on television and the web. What you might not know is that many of these images, including the ones shown here, were produced at Rocky Mountain Laboratories (RML), a part of NIH’s National Institute of Allergy and Infectious Diseases (NIAID) that’s located in the small Montana town of Hamilton.
The head of RML’s Electron Microscopy Unit, Elizabeth Fischer, was the researcher who took this portrait of SARS-CoV-2. For more than 25 years, Fischer has snapped stunning images of dangerous viruses and microbes, including some remarkable shots of the deadly Ebola virus. She also took some of the first pictures of the coronavirus that causes Middle East respiratory syndrome (MERS), which arose from camels and continues to circulate at low levels in people.
The NIAID facility uses a variety of microscopy techniques, including state-of-the-art cryo-electron microscopy (cryo-EM). But the eye-catching image you see here was taken with a classic scanning electron microscope (SEM).
SEM enables visualization of particles, including viruses, that are too small to be seen with traditional light microscopy. It does so by focusing electrons, instead of light, into a beam that scans the surface of a sample that’s first been dehydrated, chemically preserved, and then coated with a thin layer of metal. As electrons bounce off the sample’s surface, microscopists such as Fischer are able to capture its precise topology. The result is a gray-scale micrograph like the one you see above on the left. To make the image easier to interpret, Fischer hands the originals off to RML’s Visual Medical Arts Department, which uses colorization to make key features pop like they do in the image on the right.
So, what exactly are you seeing in this image? The orange-brown folds and protrusions are part of the surface of a single cell that’s been infected with SARS-CoV-2. This particular cell comes from a commonly studied primate kidney epithelial cell line. The small, blue spheres emerging from the cell surface are SARS-CoV-2 particles.
This picture is quite literally a snapshot of viral shedding, a process in which viral particles are released from a dying cell. This image gives us a window into how devastatingly effective SARS-CoV-2 appears to be at co-opting a host’s cellular machinery: just one infected cell is capable of releasing thousands of new virus particles that can, in turn, be transmitted to others.
While capturing a fixed sample on the microscope is fairly straightforward for a pro like Fischer, developing a sample like this one involves plenty of behind-the-scenes trial and error by NIAID investigators. As you might imagine, to see the moment that viruses emerge from an infected cell, you have to get the timing just right.
By capturing many shots of the coronavirus using the arsenal of microscopes available at RML and elsewhere, researchers are learning more every day about how SARS-CoV-2 enters a cell, moves inside it, and then emerges to infect other cells. In addition to advancing scientific knowledge, Fischer notes that images like these also hold the remarkable power to make an invisible enemy visible to the world at large.
Making SARS-CoV-2 tangible helps to demystify the challenges that all of us now face as a result of the COVID-19 pandemic. The hope is it will encourage each and every one of us to do our part to fight it, whether that means digging into the research, working on the front lines, or staying at home to prevent transmission and flatten the curve. And, if you could use some additional inspiration, don’t miss the NIAID’s image gallery on Flickr, which includes some of Fischer’s finest work.
Links:
Coronavirus (COVID-19) (NIH)
Rocky Mountain Laboratories (National Institute of Allergy and Infectious Diseases/NIH)
Elizabeth Fischer (National Institute of Allergy and Infectious Diseases/NIH)
NIH Support: National Institute of Allergy and Infectious Diseases
Creative Minds: Preparing for Future Pandemics
Posted on by Dr. Francis Collins
Jonathan Abraham / Credit: ChieYu Lin
Growing up in Queens, NY, Jonathan Abraham developed a love for books and an interest in infectious diseases. One day Abraham got his hands on a copy of Laurie Garrett’s The Coming Plague, a 1990s bestseller warning of future global pandemics, and he sensed his life’s calling. He would help people around the world survive deadly viral outbreaks, particularly from Ebola, Marburg, and other really bad bugs that cause deadly hemorrhagic fevers.
Abraham, now a physician-scientist at Brigham and Women’s Hospital, Boston, continues to chase that dream. With support from an NIH Director’s 2016 Early Independence Award, Abraham has set out to help design the next generation of treatments to enable more people to survive future outbreaks of viral hemorrhagic fever. His research strategy: find antibodies in the blood of known survivors that helped them overcome their infections. With further study, he hopes to develop purified forms of the antibodies as potentially life-saving treatments for people whose own immune systems may not make them in time. This therapeutic strategy is called passive immunity.
Lyme Disease: Gene Signatures May Catch the Infection Sooner
Posted on by Dr. Francis Collins
Caption: Borrelia burgdorferi. Immunofluorescent antibodies bind to surface proteins on the bacterium that causes Lyme disease, producing fluorescent yellow, red, and green hues.
Credit: National Institute of Allergy and Infectious Diseases
Each year, thousands of Americans are bitten by deer ticks.These tiny ticks, common in and around wooded areas in some parts of the United States, can transmit a bacterium into the bloodstream that causes Lyme disease. Those infected experience fever, headache, stiff necks, body aches, and fatigue. A characteristic circular “target” red rash can mark the site of the tick bite, but isn’t always noticed. In fact, many people don’t realize that they’ve been bitten, and weeks can pass before they see a doctor. By then the infection has spread, sometimes causing additional rashes and/or neurological, cardiac, and rheumatological symptoms that mimic those of other conditions. All of this can make getting the right diagnosis frustrating, especially in areas where Lyme disease is rare.
Even when Lyme disease is suspected early on, the bacterium is unusually slow growing and present at low levels, so it can take a while before blood tests detect antibodies to confirm the condition. By then, knocking out the infection with antibiotics can be more challenging. But research progress continues to be made toward improving the diagnosis of Lyme disease.
An NIH-supported team recently uncovered a unique gene expression pattern in white blood cells from people infected with the Lyme disease-causing bacterium Borrelia burgdorferi [1]. This distinctive early gene signature, which persists after antibiotic treatment, is unique from other viral and bacterial illnesses studies by the team. With further work and validation, the test could one day possibly provide a valuable new tool to help doctors diagnose Lyme disease earlier and help more people get the timely treatment that they need.
Happy New Year … and a Look Back at a Memorable 2015
Posted on by Dr. Francis Collins
A new year has arrived, and it’s going to be an amazing one for biomedical research. But before diving into our first “new science” post of 2016, let’s take a quick look back at 2015 and some of its remarkable accomplishments. A great place to reflect on “the year that was” is the journal Science’s annual Top 10 list of advances in all of scientific research worldwide. Four of 2015’s Top 10 featured developments directly benefited from NIH support—including Science’s “Breakthrough of the Year,” the CRISPR/Cas9 gene-editing technique. Here’s a little more on the NIH-assisted breakthroughs:
CRISPR Makes the Cut: I’ve highlighted CRISPR/Cas9 in several posts. This gene-editing system consists of a short segment of RNA that is attached to an enzyme. The RNA is preprogrammed to find a distinct short sequence of DNA and deliver the enzyme, which acts like a scalpel to slice the sequence out of the genome. It’s fast and pretty precise. Although CRISPR/Cas9 isn’t brand-new—it’s been under development as a gene-editing tool for a few years—Science considered 2015 to be “the year that it broke away from the pack.”
From Ebola Researchers, An Anthem of Hope
Posted on by Dr. Francis Collins
After watching this music video, you might wonder what on earth it has to do with biomedical science, let alone Ebola research. The answer is everything.
This powerful song, entitled “One Truth,” is dedicated to all of the brave researchers, healthcare workers, and others who have put their lives on the line to save people during the recent outbreak of Ebola virus disease. What’s more, it was written and performed by seven amazing scientists—one from the United States and six from West Africa.
NIH Ebola Update: Working Toward Treatments and Vaccines
Posted on by Drs. Anthony S. Fauci and Francis S. Collins
Credit: National Institutes of Health
Updated Oct. 22, 2014: The National Institutes of Health (NIH) today announced the start of human clinical trials of a second Ebola vaccine candidate at the NIH Clinical Center in Bethesda, MD. In this early phase trial, researchers from NIH’s National Institute of Allergy and Infectious Diseases (NIAID) are evaluating the vaccine, called VSV-ZEBOV, for its safety and ability to generate an immune response in healthy adults who receive two intramuscular doses, called a prime-boost strategy.
The Walter Reed Army Institute of Research is simultaneously testing the vaccine candidate as a single dose at its Clinical Trials Center in Silver Spring, MD. VSV-ZEBOV, which was developed by researchers at the Public Health Agency of Canada’s National Microbiology Laboratory, has been licensed to NewLink Genetics Corp. through its wholly owned subsidiary BioProtection Systems, both based in Ames, Iowa.
Early human testing of another Ebola vaccine candidate, co-developed by NIAID and GlaxoSmithKline, began in early September at the NIH Clinical Center. Initial data on that vaccine’s safety and ability to generate an immune response are expected by the end of 2014.
We are all alarmed by the scope and scale of the human tragedy occurring in West African nations affected by the Ebola virus disease epidemic. While the cornerstones of the Ebola response remain prompt diagnosis and isolation of patients, tracing of contacts, and proper protective equipment for healthcare workers, the National Institutes of Health (NIH), led by its National Institute of Allergy and Infectious Diseases (NIAID), is spearheading efforts to develop treatments and a vaccine for Ebola as quickly as possible.
For example, NIAID has supported and collaborated with Mapp Biopharmaceutical, Inc., San Diego, in its development of the product known as ZMapp, which has been administered experimentally to several Ebola-infected patients. While it is not possible at this time to determine whether ZMapp benefited these patients, NIAID is supporting a broader effort to advance development and clinical testing of ZMapp to determine if it is safe and effective. In addition, the U.S. Biodefense Advanced Research and Development Agency (BARDA) has announced plans to optimize and accelerate the manufacturing of ZMapp, which is in limited supply, to enable clinical safety testing to proceed as soon as possible.
Eradicating Ebola: In U.S. Biomedical Research, We Trust
Posted on by Dr. Francis Collins
Caption: Researcher inside a biosafety level 4 laboratory, which provides the necessary precautions for working with the Ebola virus.
Credit: National Institute of Allergy and Infectious Diseases, NIH
Updated August 28, 2014: Today, the National Institutes of Health (NIH) announced plans to begin initial human testing of an investigational vaccine to prevent Ebola virus disease. Testing of the vaccine, co-developed by NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and GlaxoSmithKline, will begin next week at the NIH Clinical Center in Bethesda, MD.
As the outbreak of Ebola Virus Disease continues to spread in West Africa, now affecting four countries in the region, I am reminded how fragile life is—and how important NIH’s role is in protecting it.
NIH research has helped us understand how Ebola initially infects people and how it spreads from person to person. Preventing this spread is currently our greatest defense in fighting it. Through research, we know that the Ebola virus is transmitted through direct contact with bodily fluids and is not transmitted through the air like the flu. We also know the symptoms of Ebola and the period during which they can appear. This knowledge has informed how we manage the disease. We know that the virus can be contained and eradicated with early identification, isolation, strict infection control, and meticulous medical care.
Print-and-Fold Origami Microscope for 50 cents
Posted on by Dr. Francis Collins
Caption: Here I am checking out the Foldscope at the White House Maker Faire on June 18. Very cool!
Credit: Manu Prakash, Stanford
When Stanford University bioengineer Manu Prakash traveled to a mosquito-infested rainforest in Thailand a couple of years ago, he visited a clinic with a sophisticated, $100,000 microscope that sat unused in a locked room. It was then Prakash realized that what global health workers really need is an ultra-low cost, simple-to-use, portable microscope that could be deployed in the field to diagnose disease—and he took it upon himself to develop one!
The result is the Foldscope, a ‘use and throwaway’ microscope that Prakash demonstrated last week at the first-ever Maker Faire at the White House. While I saw many amazing inventions and met many incredible inventors at this event, I came away particularly impressed by the practicality of this device and the ingenuity of its maker.
