The Scientific Observer Issue 31

A Green Approach To Upcycle Vegetable Waste HPV Is Not Just a Women's Health Issue ISSUE 31, OCTOBER 2023 Little Things AN INSPIRED SCIENTIST'S PURSUIT FOR A CANCER CURE The Sponsored by 2 CONTENT FROM THE NEWSROOM 05 ARTICLE HPV Is Not Just a Women’s Health Issue 07 Molly Campbell ARTICLE Four Spooky Sounding Halloween-Inspired Scientific Terms 10 Laura Elizabeth Lansdowne RESEARCH SPOTLIGHT A Green Approach To Upcycle Vegetable Waste 12 Daphne Ng FEATURE ARTICLE The Little Things: An Inspired Scientists Pursuit for a Cancer Cure 16 Anthony King ARTICLE Advances in Cancer Biology 21 Sarah Whelan ARTICLE Long COVID Research Is a Bit of a Mess 24 Leo Bear-McGuinness 10 24 16 FEATURE The Little Things: An Inspired Scientist's Pursuit for a Cancer Cure Anthony King iStock 3 EDITORS’ NOTE CONTRIBUTORS Have an idea for a story? If you would like to contribute to The Scientific Observer, please feel free to email our friendly editorial team. Anthony King Anthony King is a freelance science journalist who reports on a variety of topics in chemical and biological sciences, as well as science policy and health. Daphne Ng, PhD Daphne is the Assistant Director and Science Communication Lead at Nanyang Technological University. Laura Elizabeth Lansdowne Laura is the Managing Editor for Technology Networks. Leo Bear-McGuiness Leo is a Science Writer for Technology Networks. Molly Campbell Molly is a Senior Science Writer for Technology Networks. Sarah Whelan, PhD Sarah is a Science Writer for Technology Networks. Dear readers, Welcome to the 31st issue of Technology Networks’ monthly magazine, The Scientific Observer. In this issue, we're exploring the realm of oncology and the latest advances in cancer research. HPV infection is the most common sexually transmitted disease, and over one-third of men are infected with one or more strains considered to be “high risk”. Join Molly Campbell as she explores why HPV is often discussed in the context of women’s health, how transmission occurs and methods to prevent infection. This month’s feature article by Anthony King delves into the deeply personal and inspiring story of a scientist whose life's work has been galvanized by a tragic loss. As a child, Dr. Darrell Green witnessed the devastating impact of bone cancer when his dear friend Ben fell victim to the disease. His relentless quest to discover a cure is an emotional testament to the human spirit and the power of science. Join us as we follow the journey of this determined scientist who has turned his grief into a driving force for change. Also in this issue, Leo Bear-McGuinness provides an in-depth analysis of the current state of long COVID research. The COVID-19 global pandemic has left in its wake a baffling array of symptoms, affecting many survivors for months after the virus has run its course. Through the voices of those grappling with this enigmatic condition, and the scientists in pursuit of answers, you’ll gain a profound understanding of the challenges and hopes that surround long COVID research. And, of course, it wouldn't be October without a nod to the spooky and supernatural. Check out Laura Lansdowne’s fun dive into the “spookiest” sounding Halloween-inspired scientific terms. This, and much more, in issue 31 of The Scientific Observer. The Technology Networks Editorial Team A full slate of extremely high-quality recombinant proteins, antibodies, and CUSTOM development and production services www.sinobiological.com Sino Biological US Inc. (U.S.A.) Tel: +1-215-583-7898 Email: order_us@sinobiologicalus.com Sino Biological, Inc. (Global) Tel: +86-400-890-9989 Email: order@sinobiological.com 株式会社日本シノバイオロジカル (Japan) Tel: 044-400-1330 Email: order@sinobiological.co.jp Sino Biological Europe GmbH (Europe) Tel: +49(0)6196 9678656 Email: order_eu@sinobiologicaleu.com Comprehensive Solutions for Life Sciences Solutions covering phases from lead discovery to process development and clinical studies Multispecific Antibody Development Supporting the assessment of vaccine safety, immunogenicity, and protective efficacy Influenza Vaccine Development and Production Complete solutions covering each step from CAR development to CAR-T cell quality control CAR-T Therapy Development One-stop research support covering the entire CAR-NK development process CAR-NK Therapy Development Multi-dimensional efficacy evaluation system to accelerate antibody drug discovery In Vitro Efficacy Evaluation 5 FROM THE NEWSROOM 5 From the Newsroom FROM THE NEWSROOM National Museum of Health and Medicine, Otis Historical Archives New Contributed Photo Collection / Wikimedia Commons., iStock, Magda Pawluczuk/Unsplash A new study challenges the long-standing belief that the 1918 influenza pandemic disproportionately killed healthy young people. JOURNAL: The Proceedings of the National Academy of Sciences. The 1918 Flu Pandemic Did Not Disproportionately Kill Healthy Young People MOLLY CAMPBELL Gene variants inherited from Neanderthals are associated with a lower pain threshold in modern-day humans. JOURNAL: Nature. Genes From Neanderthals Linked to Lower Pain Threshold MOLLY CAMPBELL A new study has raised a “warning” that the hygiene hypothesis might not fully explain why allergies are on the rise. JOURNAL: Science Immunology. Hygiene Hypothesis Study Suggests More Microbes Might Not Be the Answer to Allergies RUAIRI J MACKENZIE 6 FROM THE NEWSROOM Johansen et al/Allen Institute for Brain Science, iStock Want to learn more? Check out the Technology Networks newsroom. A research consortium has published a flurry of papers detailing a “major step forward” in our knowledge of the human brain. World-First Human Brain Atlas Reveals New Cell Types RUAIRI J MACKENZIE A new study has detailed the potential of a new drug to mimic the beneficial effects of exercise in mouse models. The drug induced weight loss and improved endurance in obese mice, enabling them to run 50% further and lose 12% of their body weight. JOURNAL:Journal of Pharmacology and Experimental Therapeutics. Exercise-Mimicking Drug Helps Mice Lose Weight and Boost Endurance SARAH WHELAN A clinical trial has shown that ketamine nasal spray treatment led to higher rates of remission than standard intervention with the antipsychotic drug quetiapine in patients with treatment-resistant depression. JOURNAL: The New England Journal of Medicine. Ketamine Nasal Spray Sees Success in Trial for TreatmentResistant Depression SARAH WHELAN 7 iStock Human papillomavirus (HPV) is a group of related viruses that infect the skin and mucosal membranes. HPV infection is the most common sexually transmitted disease (STD) worldwide; nearly all sexually active men and women will be infected at some point during their lifetime according to the Centers for Disease Control and Prevention. While HPV is often discussed in the context of women’s health and cervical cancer risk, a recent study published in The Lancet Global Health found that over one-third of men aged 15 years and over are infected with at least one type of HPV. One in five men is infected with one or more types of HPV that are considered “high-risk” strains. “This statistic might be surprising to some, however, HPV affects both men and women, with a substantial impact on public health,” explains Christine Meyer, MD, practicing physician and founder of CMMD and Associates medical practice. Here, we explore how HPV viruses cause infection and – in some cases – cancer, and what the findings of the new study mean for HPV prevention efforts. HOW DOES HPV INFECT HUMAN CELLS? There are over 200 types of HPV that can be transmitted sexually, and individuals can be infected by more than one strain at the same time. “These viruses are categorized into low-risk and high-risk types based on their association with health problems,” says Meyer. Low-risk forms of HPV do not typically cause disease, but high-risk forms of HPV can lead to the development of various types of cancer. HPV is primarily transmitted through direct skin-to-skin contact. “The virus enters the body via breaks in the layer of cells (epithelial cells) which make up our skin and also the internal linings of our mouth, anus and vagina to name a few,” explains Dr. Gareth Nye, senior lecturer at the University of Chester, program lead for the BMedSci Medical Science Program and expert in maternal and fetal health. “Once the virus has bypassed this layer, it infects the cells leading to the virus being protected from our immune system. From here they can replicate and spread to neighboring cells, damaging the body’s cells as it does so.” THE HISTORY OF HPV AND CERVICAL CANCER RESEARCH Nowadays, the link between HPV and cervical cancer is well established. Its discovery dates back to the 1970s, when German virologist Harald zur Hausen went against the grain by proposing that HPV could be a causal agent behind this type of cancer. In pursuit of answers, he spent several years studying a variety of HPV strains and analyzing patient biopsies for HPV viral DNA. Ultimately zur Hausen discovered that patients with HPV16 and HPV18 were more likely to develop cervical cancer, a groundbreaking feat that earned him a share of the 2008 Nobel Prize in Physiology or Medicine. Over 95% of cervical cancer cases are due to HVP infection according to the World Health Organization, and HPV16 HPV Is Not Just a Women’s Health Issue MOLLY CAMPBELL 8 and HPV18 are found in ~70% of cancer biopsies worldwide. zur Hausen’s work paved the way for the first HPV cervical cancer vaccine, developed at the University of Queensland in Australia throughout the 1990s and approved for human use by the United States Food and Drug Administration in 2006. HPV IS A GLOBAL HEALTH ISSUE AFFECTING WOMEN AND MEN Extensive research has explored the epidemiology of HPV in women, perhaps owing to its association with cervical cancer. But over recent decades, HPV’s association with other types of cancer has been determined, including oropharyngeal cancer, anal cancer, penile cancer, vaginal cancer and vulvar cancer. An estimated 69,400 male cancer cases were attributed to HPV infections in 2018 alone, according to The International Agency for Research on Cancer. “While there are many studies conducted looking at HPV in women, very few address HPV in males and even fewer are conducted globally,” says Meyer. This is problematic as, without a complete understanding of HPV prevalence across men and women, data on the overall global disease burden and transmission risk is skewed. It also becomes increasingly challenging to create, implement and evaluate HPV and cancer prevention programs. The majority of existing studies on HPV prevalence in men – the last of which was published in 2011 – have been conducted in high-income countries, or in populations that are at an increased risk of HPV infection, such as men that have sex with men, men with HIV or HPV-symptomatic men, according to the authors of the new The Lancet Global Health study. The lead author of the work, Laia Bruni Coccoz, MD, is head of the Unit of Infections and Cancer Information and Interventions (UNIC-I) in the Cancer Epidemiology Research Program and coordinator of the Institute of Oncology/International Agency for Research on Cancer HPV Information Center. Alongside colleagues in the field, Coccoz aimed to provide updated and global data on HPV infection in men. The researchers conducted a systematic review and meta-analysis, analyzing studies on the prevalence of genital HPV infection in males that had been published between 1995–2022. Approximately 31% of men are infected with one strain of HPV, and 21% are infected with high-risk strains, the data suggests. Prevalence of HPV was higher in young adults, particularly those between 25–29 years old. “This statistic emphasizes the need for comprehensive HPV prevention strategies that include both genders. It highlights that HPV is not just a women's health issue but a broader public health concern, given its association with various cancers in men and women,” says Meyer. “It remains true that males remain key in the biology of this disease, and we should be considering them in all HPV prevention attempts including education and awareness. If more males understand the role they play, many more cases could be prevented,” adds Nye. “This study is a strong piece of research. The methods here involve combining the finding from other peer-reviewed sources and undertaking new analysis to gain a larger overview of the patterns of disease.” HOW CAN HPV BE DETECTED AND PREVENTED? Most often HPV infection does not cause noticeable symptoms, particularly in its early stages, which means those affected might not be aware of it. In some individuals, HPV might cause visible warts to form on the genitalia, the anus, mouth or throat, but this is not always the case. “The most reliable way to detect an HPV infection is through medical tests, such as pap smears for cervical HPV infections in women and specific HPV DNA tests,” Meyer explains. “Regular screening and healthcare check-ups are essential for identifying and managing HPV infections and associated health risks.” Currently, a simple screening test for HPV is lacking for men, which in Meyer’s opinion is further reasoning why The Lancet Global Health study is “so important.” As HPV infection is often symptomless, prevention is key, explains Nye: “Safe sex practices in particular are so important. Using condoms is a very good way of reducing the risk of infection. Avoiding the sharing of sex toys without through cleaning is also advised,” he says. “Anyone who is engaging in regular sexual activity either with multiple partners or a new partner should be getting regular sexual health screens to ensure infections of any kind are recognized as soon as possible. It’s also crucial if you do have an infection to tell recent partners, so they too can get tested and treated.” Beyond practicing safe sex, HPV vaccines are now available for both males and females. “These vaccines are most effective when administered before sexual activity begins, because they protect against the most common high-risk HPV types that can lead to cancer. HPV vaccination is recommended for adolescents and young adults,” says Meyer. Nye emphasizes that, though Coccoz and colleagues’ study is a stride forward for understanding HPV prevalence in men, further research is still warranted: “Although this is strong evidence, it is not current and newly undertaken research and so you can only take so much from the findings. This will become a solid basis for future studies targeting HPV spread around the world but for now, the findings should be taken very seriously,” he concludes. ⚫ HPV VACCINES The HPV vaccine is an example of a preventative vaccine, meaning it are designed to prevent, not treat, HPV infection. Current HPV vaccines use a combination of viruslike particles to trigger an immune response and the production of neutralizing antibodies against HPV. Disseminate Your Research With Us We know how important it is to disseminate your findings when working in research, but also what a challenge it can be to find opportunities beyond the conference hall. We want to address this! Technology Networks is spearheading a project to help researchers raise the profile of their work to a wider audience and increase coverage of the fantastic research papers out there that may not get the media attention they deserve. There is a lot of great research output and a very engaged audience that wants to hear about it, so share your work with us! Find Out More 10 iStock R esearchers spend their lives in pursuit of a scientific breakthrough. So, when that "eureka" moment finally arrives, of course it is tempting to give that groundbreaking discovery an absurd and memorable name. In honor of this year’s “spooky” season, we’re highlighting several Halloween-inspired scientific terms. GRIM REAPER The Grim Reaper, a striking skeletal figure, covered by a black cloak, clutching a scythe and set on harvesting human souls *shiver runs down spine*. Or perhaps your first thought was: weren’t grim and reaper those two genes discovered in 1994 in the Drosophila melanogaster fly? Indeed, they were. Twenty-four years ago, a team identified a strain of fly that was resistant to cell death. This strain possessed a homozygous genomic deletion (known as H99); grim and reaper were two of the three genes mapped to this deletion and were consequently identified as regulators of programmed cell death. More recently, sickle was identified, which appears to act in parallel with reaper and grim. Sickle is capable of inducing cell death when it is overexpressed in both mammalian and insect cells, and acts as an inhibitor of apoptotic protein antagonists. I can’t help but think “scythe” would have been a better choice if the plan was to stick to the Grim Reaper theme? THE HALLOWEEN GENES You are probably familiar with the Addams family, a supernatural black comedy film featuring a bizarre aristocratic family. But I’m guessing few of you will have heard of the “Halloween genes” a lesser-known family, of cytochrome P450 genes, which were discovered in the Drosophila melanogaster fly. The members include; the spook gene, the phantom gene, the disembodied gene (perhaps inspired by “Thing” – a disembodied hand?), the shadow gene, the spookier gene and the shade gene. Mutations in members of the Halloween gene family results in embryonic lethality – scary! ZOMBIE… GENE, PROTEIN OR CELL… YOU NAME IT, THEY HAVE TOO! Although none are officially termed “zombie” – cells, proteins and genes have all been referred to as “zomFour Spooky Sounding HalloweenInspired Scientific Terms LAURA ELIZABETH LANSDOWNE 11 iStock bie-like” by scientists, who have chosen to use the word to describe their characteristics or behaviors. Here we take a look at an example of each: ZOMBIE GENE PROTECTS ELEPHANTS FROM CANCER A study published in Cell Reports described how elephants have developed a way to resist cancer, by resurrecting a “zombie” gene called leukemia inhibitory factor 6 (LIF6), which can respond to damaged DNA and destroy cells that are destined to become cancer cells. LEUKEMIA ZOMBIE PROTEINS COULD BE THERAPEUTICALLY TARGETED The TRIB2 protein is a member of the Tribbles family of pseudokinase proteins, which are sometimes referred to as “zombie enzymes” as they are unable to catalyze chemical reactions. TRIB2 proteins can promote cell survival – a key hallmark of cancer, making them an attractive therapeutic target for cancer researchers. Using biochemical drug repurposing methods, a team have now identified compounds capable of degrading TRIB2 leading to cancer cell apoptosis. ZOMBIE CELLS IMPLICATED IN NUMEROUS AGE-RELATED DISEASES Reporting their findings in Nature, Mayo Clinic researchers show, using a mouse model of Alzheimer’s disease, that senescent “zombie” cells accumulate in the brain prior to cognitive loss. The researchers were able to reduce neuronal death, loss of memory, and tau protein aggregation by preventing the accumulation of the “zombie” cells. DRACULA As well as being a gothic horror novel published in 1897, dracula, also known as drc, is a gene found in the zebrafish that encodes ferrochelatase, an enzyme involved in the heme biosynthetic pathway. Researchers demonstrated using a Zebrafish model that draculam248 mutant embryos with a G»T transversion within the gene generate a premature stop codon. This resulted in both light-dependent hemolysis and liver disease phenotypes. Zebrafish drc mutant phenotypes are comparable to those seen in humans suffering from a specific type of porphyria known as erythropoietic protoporphyria (EPP). EPP causes severe photosensitivity, and is caused by either; mutation in the human ferrochelatase gene (FECH), or in some cases, mutation in the delta-aminolevulinic acid synthase-2 gene (ALAS2). Surely the name choice “dracula” must be inspired by the vampire-like symptoms – light-sensitivity, the gene’s impact on red blood cells? ⚫ 12 iStock A Green Approach To Upcycle Vegetable Waste Daphne Ng, PhD NANYANG TECHNOLOGICAL UNIVERSITY, SINGAPORE RESEARCH SPOTLIGHT Scientists at Nanyang Technological University (NTU) Singapore have devised an environmentally friendly method that turns vegetable waste into health and personal care products. Their approach could give vegetable waste a new lease of life and make the extraction of beneficial plant compounds more sustainable and cost effective. The study was published in Separation and Purification Technology. Research Spotlight iStock 12 13 iStock GIVING VEGETABLE WASTE A NEW LEASE OF LIFE Millions of tons of food waste are discarded annually around the world, with fruits and vegetables making up more than one third of it. Vegetable waste is generated at various stages of the food supply chain. Farmers often cut off the outer leaves as they are harvested for leafy vegetables like kale to sell aesthetically pleasing vegetables with no signs of damage or yellowing. When the vegetables reach the supermarket, large quantities are also rejected due to their size, shape or color imperfections. These practices result in the disposal of substantial amounts of edible vegetables. Vegetables contain many beneficial compounds that can also be extracted and added to food or cosmetics. Cruciferous vegetables such as kale are considered superfoods as they contain high levels of phytochemicals that have many health benefits. Organic solvents and pressurized carbon dioxide are commonly used to extract and recover these compounds from plants. However, these solvents are often toxic, volatile or not economically viable when used on an industrial scale. Solvents made from plant-based metabolites, called natural deep eutectic solvents (NADESs), could be safer alternatives for extracting phytochemicals. Unlike organic solvents, NADESs do not evaporate quickly and are biodegradable. They are also able to dissolve a wide range of natural products. EXTRACTING BENEFICIAL COMPOUNDS FROM VEGETABLE WASTE Researchers led by Prof. Hu Xiao from NTU’s School of Materials Science and Engineering, and a program director in the Nanyang Environment and Water Research Institute (NEWRI), tested the ability of NADESs with various formulations to extract phytochemicals from kale. First, the kale waste was blended into a paste or dried and ground into a powder (Figure 1). The researchers then mixed the kale paste (or powder) with their specially formulated NADES and stirred it at room temperature before filtering the mixture to extract the beneficial compounds. When the NADES mixture is allowed to stand, it naturally separates into layers, facilitating the easy extraction of phytochemicals from kale (polyphenols, carotenoids and chlorophylls) without heating, unlike current energy-intensive industrial methods (Figure 2). As heating is not required, the NTU method prevents the temperature-sensitive phytochemicals from degrading. The extraction process is quick and can be completed within 30 minutes. First author Dr. Lee Sze Ying, a research fellow at the Environmental Chemistry and Materials Program at NEWRI at the time of the study, said, “Our extraction approach is unique because it allows for the simultaneous recovery and separation of multiple valuable compounds from the RESEARCH SPOTLIGHT 13 Figure 1: Kale in various forms. Figure 2: The NADES (orange layer) and ethyl acetate solvents (green layer) can be added sequentially or simultaneously to extract various bioactive compounds from kale waste. NTU Singapore 14 iStock RESEARCH SPOTLIGHT vegetable waste in a single process without using heat.” The key findings of the study are: • The green solvent system gave the highest yield of polyphenols, more than two times higher than conventional methanol methods. • The polyphenol extract was stable in the new green solvent system, retaining 91.7% and 88.6% of the original contents after 30 days of storage at 4 and 25 ⁰C, respectively. • Other green solvents such as ethyl acetate can be added to the solvent mixture to obtain a polyphenol-rich extract and an extract rich in carotenoids and chlorophylls. GROWING INDUSTRIAL APPLICATIONS OF PLANT COMPOUNDS The researchers say that manufacturers can add the extract directly into the formula of their cosmetic products without further processing, reducing production time. Prof. Hu, the corresponding author, said, “The use of non-toxic and naturally derived solvents in our method makes it a food-safe technique. At the same time, our method preserves the potency of the extracted active ingredients, making it highly attractive for industry adoption. The extracted nutrients can be used for applications in personal care products, cosmetics, food supplements and even herbal medicinal ingredients.” However, one of the major limitations of using NADESs as solvents is that they are highly viscous, which hinders the diffusion of the compounds into the mixture, thus reducing extraction efficiency. To make NADESs less viscous and improve extraction efficiency, water is usually added to dilute the solvents during the extraction process. In the study, the researchers found that almost all bioactive compounds were more effectively recovered from the wet kale paste than the dried powder, as the water in the paste diluted the NADESs. This simplifies the extraction process as no additional water is required, and also removes the need for an energy-intensive step to dry the kale waste. Co-author Dr. Liang Yen Nan, senior research fellow, Environmental Chemistry and Materials Program at NEWRI, explained, “Our method essentially manipulates the chemical nature of NADES and other green solvents to maximize the extraction efficiency of the bioactive compounds found in kale. This approach induces simultaneous recovery of multiple phytochemicals from the kale and can easily be adapted for use in other types of vegetable and fruit wastes. Moreover, we have demonstrated that our approach remains viable even if we were to eliminate the energy-intensive freeze-drying of the kale waste, making our technology greener, cheaper and scalable for industry use.” SEEDING A SUSTAINABLE FUTURE FOR FOOD WASTE The team has filed a patent in Singapore for the innovation. For their next steps, the researchers are investigating if their newly developed method can extract beneficial compounds from other types of fruits and vegetables, like dragon fruit, spinach, lettuce and other medicinal plants. The team is exploring new partnerships to scale up their technology towards commercialization. ⚫ iStock 14 It’s simple, just choose the groups and click the bubble. Our Facebook groups allow you to keep up to date with the latest news and research and share content with like-minded professionals. With three diverse groups there is something for everyone. Hi. How are you? Have you seen our Facebook groups? Thanks! I’ll come join the conversation. Come join the Neuroscience, News and Research Group here. Discover the Analytical Science Network Group here. Explore The Science Explorer Group here. No I haven’t. Could you tell me more? Sounds great! How do I join? Anthony King iStock Little Things AN INSPIRED SCIENTISTS PURSUIT FOR A CANCER CURE The A CHILDHOOD TRAGEDY PUSHED THIS SCIENTIST TOWARD A REVOLUTIONARY BONE CANCER TREATMENT At 12 years of age, Darrell Green’s best friend began complaining of knee pain. Both Green and his friend, Ben, were avid footballers, playing for rival local teams in Thetford, Norfolk. The boy’s parents figured their son’s knee was a run-of-the-mill sports injury. But after a few weeks, the knee pain was still there, and Ben’s injured leg began to swell. “My friend was lucky in that the GP recognized quickly that something was not right,” recalls Dr. Green, now a researcher at the University of East Anglia. Tests confirmed a bone tumor and chemotherapy was quickly started. Ben ended up having an amputation yet, within months, the cancer was discovered to have spread to his lungs and he was told he was terminally ill. “Just before his 14th birthday, he passed away,” recalls Green. The harrowing experience stayed with Green, who has been striving to unearth a new drug to treat bone cancer. Treatment for the most common types of bone cancer in children, osteosarcoma and Ewing sarcoma, has not changed much since the late 1970s. Improvements in surgery mean that half of patients now survive to five years compared to the previous prognosis of three years. Yet there has been little sign of new therapies on the horizon. “There have been no successful clinical trials looking at targeted drugs in bone cancer,” says Green, frustrated by this lack of progress. Tragically, bone cancer is an extremely aggressive, mostly childhood disease. DISCOVERY Advances in Green’s lab this year, however, sparked hope and headlines that heralded a revolutionary new treatment. The Bone Cancer Research Trust in the UK welcomed it as what could be “the most important drug discovery in the field for more than 45 years.” Part of the advance happened when samples from patients at the Royal Orthopaedic Hospital in Birmingham revealed that a gene, RUNX2, was “switched on” in bone cancer and seemed implicated in its spread. “This isn’t the first time that RUNX2 has been implicated in bone cancer, but it is the first time that we could see how it operates and use that knowledge to develop a new medicine,” says Green. The idea that Green now has is that, in the future, doctors could give micro-RNAs to treat kids with bone cancer. These small pieces of RNA are our body’s way of dialing up or down the volume of genes, which are themselves the recipes for making proteins in the body. Proteins should be considered akin to biological robots and can carry out varied – and often unknown – molecular tasks. micro-RNAs could be introduced as a drug to damp down or turn the volume up on genes that make proteins suspected of encouraging or discouraging cancer. There is no quick fix for bone cancer. Around 600 people in the UK develop the disease each year. It is relatively uncommon, the research field is small and funds for investigating the disease are invariably in short supply – but Green is not discouraged. He is driven by witnessing his friend Ben’s traumatic disease. “I was personally affected by bone cancer, so I’m not going to be easily swayed by its difficulty,” he explains. As was the case for Ben, many children who develop a bone tumor are unfortunately faced with the cancer rapidly spreading to other parts of the body, especially the lungs. This is because the cells originate from mesenchymal stem cells that are naturally inclined to wander. One in three patients diagnosed with bone cancer will already have detectable metastasis – a cancer that has spread to another part of the body – by the time they are diagnosed. “We know that another one of those three will have undetectable metastasis that ends up relapsing later,” says Green, who has studied cancer progression and metastasis. Even the one-in-three diagnosed with localized disease only have a ~60% chance of still being alive in five years. This is yet another motivation for Green in his push to treat bone cancer. His scientific training has been steeped in investigating the outsized role of micro-RNAs, which can be just 22 nucleotide letters in length. “I’ve combined my interest in micro-RNAs with bone tumors,” says Green of his recent advance. In “I want to see a new treatment that is available to kids with bone cancer, because the treatments that my friend Ben received 21 years ago are the same treatments that are still being used today. This just isn’t good enough,” says Green. 17 18 order to understand the relevance of micro-RNAs, one needs to consider how our cells manufacture proteins. EMBRYO GENES REAWAKEN The blueprint for the string of amino acids that make up a protein is contained within the DNA of our chromosomes. This DNA must first be transcribed, letter-for-letter, as a messenger RNA (mRNA). The mRNA molecule then exits the nucleus and goes to a miniature protein factory (a ribosome) that translates the RNA code into a string of amino acids to make the protein. Some of these proteins may be anti-tumor machines, such as the p53 tumour suppressor, while others may promote cancers, such as HER2 in breast cancer. micro-RNAs work by matching up with letter sequences on mRNAs in a way that stops them from being made in the protein factories. This means that a tiny piece of RNA introduced into cells might shut down or dramatically curtail the production of a protein that is encouraging cancer. Indeed, the recent breakthrough in Green’s lab centers on RUNX2, a “master regulator” protein that directs and controls other proteins that are responsible for building the skeleton during embryo development, encouraging cells to move up and down the growing skeleton. “Cells moving from place to place as an embryo develops is quite normal, but is actually very dangerous once we are born,” Green explains. As a result, genes such as RUNX2 – which encodes the protein – are tuned down dramatically after birth. “We are thinking now that bone cancers somehow reactivate this embryonic gene and that is how the cancer cells move around the body,” says Green, explaining that the result of these peregrinations can be catastrophic. He knows of one patient in particular who underwent surgery to remove a large lung tumor, but surgeons were shocked to discover over 100 individual miniature tumors that had spread from the original tumour in bone. Green suspects that the RUNX2 master regulator is facilitating the spread of bone cancer throughout the body; yet his scientific sleuthing suggested that the problem starts even before that. THE LITTLE THINGS First, he and his team looked at differences in low-, medium- and highgrade bone cancer to see if there were clues as to what happens at the start of a cancer. Unfortunately, bone The University of East Anglia, Darrell Green Dr. Darrell Green at the Biomedical Research Centre, Norwich Medical School at the University of East Anglia. Darrell (right) pictured with his friend Ben (left) on a school trip in the late 1990s. 19 cancer is usually so aggressive that kids have advanced-stage tumors by the time they are diagnosed. The experiments revealed that levels of a molecule called micro-RNA 140, or miR-140, shot up in high-grade tumors, which in turn stoked up RUNX2 levels. The complexity did not stop there. This is a situation where a cell resembles highly intricate clockwork. While miR-140 and RUNX2 were elevated in high-grade tumors, there was a reduction in an RNA fragment known as tRF. Green believes that the heart of his mystery lies with such small fragments of RNA. As Sherlock Holmes said: “It has long been an axiom of mine that the little things are infinitely the most important.” A study of RUNX2 and tRF revealed a matching sequence. Green realized he had seen this sequence before; it is used as an anchor for another protein, YBX1, a well-known villain in driving cancers. “It became clear now that RUNX2 was just part of the story,” recalls Green, who revels in such complex biological riddles. Further experiments in the study revealed that YBX1 physically interacts with RUNX2. “We think that the [RNA fragment] is a ‘decoy’ that stops that interaction from happening,” says Green. “In a low-grade tumor, the RNA fragment binds YBX1 via the shared sequence and stops it from binding cancer-promoting proteins such as RUNX2.” But as is the case with most cancers, the tumor cells can find a way around the body’s defenses. “The RNA fragment is gotten rid of and switched off, and in its place, YBX1 is now free to bind and support cancer-causing molecules such as RUNX2,” Green explains. One solution to the puzzle is to introduce again the small fragment of RNA as a therapy to stop the master regulator from embryonic times being switched on. Or another approach, which attracted headlines earlier this year, is to block RUNX2 from sticking to the DNA using a hoped-for drug, named CADD522 When scientists administered this molecule three to five times a week to mice with bone cancer, the tumor’s size decreased, and metastasis-free survival increased. A group of scientists led by Professor Antonino Passaniti at the University of Maryland pursued the same strategy for breast cancer. Now, scientists in the US and the UK plan to pool their efforts and get the drug through all the necessary safety tests required before it can be tested in patients, says Green, though he is unable to name his collaborators at this stage. “There is a possibility that one day it could be just taken as a pill with a glass of water,” says Green – though he is not counting his chickens just yet. Getting from this promising place to crossing the finish line will be an uphill slog. “If everything goes smoothly, we could be testing this compound in patients in three years. But the reality is things will not run smoothly, and it is taking time to find funding,” says Green. As one might expect, he remains undaunted by the challenges ahead. “My drive in all of this isn’t to make money, become a millionaire and disappear on my yacht,” says Green. “I want to see a new treatment that is available to kids with bone cancer, because the treatments that my friend Ben received 21 years ago are the same treatments that are still being used today. This just isn’t good enough.” ⚫ Sophie Taylor, aged 5, who was at the heart of the “Take A Sophie” campaign to “Stick Your Tongue Out At Cancer”. Sophie and her family were invited to Dr. Green’s lab to see her tumour before it was molecularly profiled. Alex and Kirsty Taylor, iStock Six appeal QX600 Droplet Digital PCR System with more colors for greater multiplexing capabilities 21 iStock Cancer is defined as the uncontrollable division and proliferation of abnormal cells, leading to their dissemination and invasion of distant sites around the body. These cells form malignant tumors which spread and metastasize, destroying tissues and disrupting organ function. According to the World Health Organization (WHO), cancer is a leading cause of death worldwide. Almost one in six deaths were attributable to cancer in 2020, and the number of new cancer cases – the incidence rate – has been rising. Furthermore, recent estimates predict that as many as one in two people could develop a form of cancer in their lifetime. Nevertheless, scientists and researchers continue to develop sophisticated and innovative strategies to manage the growing disease burden caused by cancer. Research into cancer biology entails the study of intricate interactions between the genes, proteins and biological pathways that drive the growth and development of the disease. In essence, cancer biology is the study of what makes cancer cells different from normal cells in order to provide clues for how we might be able to treat it. With advancements in our knowledge of cancer, ever more effective treatments and technologies are being developed which is helping to increase survival rates. IMMUNOTHERAPY The immune system attacks cells that are “non-self ”, such as infected or cancerous cells. However, the immune system can struggle to keep pace with the proliferation of cancer cells and can have difficulty preventing tumor growth, as cancer cells employ several methods to evade detection and destruction by the immune system. In these cases, immunotherapies are designed to stimulate and augment the immune system’s ability to target cancer cells. In 2018, the Nobel prize in physiology or medicine was presented to Prof. James Allison and Prof. Tasuku Honjo for their contributions to immunoAdvances in Cancer Biology SARAH WHELAN 22 therapy research. Specifically, for their discoveries of programmed cell death protein 1 (PD-1) and its ligand PD-L1, as well as the development of neutralizing antibodies for these proteins that increase the anti-cancer capabilities of the immune system. Examples of immunotherapies include monoclonal antibodies, cytokines and immune checkpoint inhibitors. The first immune checkpoint inhibitor was the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab, approved by the FDA in 2011 for use in patients with advanced melanoma. However, many obstacles for the use of immunotherapies remain such as difficulties predicting which patients will respond to therapy, the development of resistance as well as high treatment costs. To this end, researchers continue to advance our knowledge of immunotherapies to overcome these complications. A recent advancement in this field came from researchers that demonstrated the overwhelming success of a new “immunoablative” immunotherapy in a small Phase 2 clinical trial. This treatment was designed to replace the need for surgery or chemoradiation for cancer treatment. Fourteen patients with DNA mismatch repair-deficient (MMRd), locally advanced rectal cancers were treated with dostarlimab (an anti-PD-1 antibody) every three weeks over a six-month period. Dostarlimab is already established as a treatment for metastatic MMRd colorectal cancer – therefore, the team hypothesized that dostarlimab for locally advanced disease may alter the requirements for additional therapy. All trial participants demonstrated a complete clinical response, whereby multiple imaging techniques revealed no signs of tumors after 6–25 months of follow-up. This supports the neoadjuvant use of similar therapies, i.e., treatment to first shrink the tumor prior to other major treatments such as surgery or radiation. Other advances include the development of a small synthetic molecule as an alternative to antibody-based immunotherapies. The use of monoclonal antibody therapies is limited due to their high cost in addition to their large size, which prevents them from reaching the less accessible areas within solid tumors. In this case, researchers used computer-aided drug design and bioinformatics approaches to develop small synthetic molecules that would inhibit PD-L1 as an alternative to therapeutic antibodies. Experimental data confirmed the final candidate molecule was effective at inhibiting PD-L1 in mice that expressed humanized T cells. The molecule requires further evaluation in cancer models, but if successful, could potentially be cheaper to produce than antibody therapies and could be suitable to take as an oral pill. AI/MACHINE LEARNING AI describes technologies designed to mimic human intelligence, simulated by machines and computer systems. Machine learning is an application of AI, designed to adapt algorithms and predictions based on experience. The use of AI tools in research and medicine can aid the identification of patterns across enormous datasets, helping to make decisions or predictions. For cancer, this could potentially assist with screening, diagnosis and establishing treatment plans. A recent study identified that, as of 2021, a total of 71 AI-based medical devices have been approved by the FDA in oncology-related fields. Most of these focus on radiology and pathology disciplines, with breast, lung and prostate cancers receiving the most benefit. To tackle the issue of low response rates to immune checkpoint inhibitors, researchers have used network-based machine learning to identify biomarkers that could indicate favorable immunotherapy responses. Their machine-learning algorithm analyzed the clinical outcomes of over 700 melanoma, gastric and bladder cancer patients alongside the transcriptomic analysis of their tumor tissue. The newly discovered biomarkers were able to successfully predict which patients would respond to immune checkpoint inhibitors – a breakthrough that could help the identification of patients ahead of treatment. Additionally, another research team have developed an AI they call “ikarus” which they demonstrated to be successful in differentiating between cancerous and healthy cells from single-cell sequencing data. In the study, ikarus was initially trained using data from colorectal and lung cancer cells, but the researchers later demonstrated it was also able to distinguish cancerous from healthy cells in liver and brain cancers. Advances in AI and cancer biology have also been made in the field of radiology. Cedars-Sinai researchers developed an AI that was able to identify individuals that would go on to develop pancreatic cancer from their CT scans taken years before they were ever diagnosed. Pancreatic cancer has some of the worst survival rates of any cancer type, with just two to 9 patients surviving five years after their diagnosis. Diagnosis of pancreatic cancer is frequently made With advancements in our knowledge of cancer, ever more effective treatments and technologies are being developed which is helping to increase survival rates. 23 iStock late due to its vague symptoms, which allows the cancer to advance into severe disease. Therefore, improving rates of early diagnosis may help to increase survival. With further study of its prediction capabilities, the AI could eventually be used to indicate the possibility of future pancreatic cancer for patients undergoing CT scans for other concerns. CANCER VACCINES The first vaccines used to prevent bacterial diseases were developed some 200 years ago. In modern research settings, cancer biologists have been using this knowledge to develop vaccines against cancer, though efforts to design and produce effective vaccines have proved challenging. Tumor antigens targeted by vaccines may not produce strong immune responses, or indeed tumor cells may mutate to evade destruction. Nevertheless, the COVID-19 pandemic has brought with it a new interest in mRNA vaccine technology that may help efforts to develop effective cancer vaccines which aim to stimulate or enhance anti-tumor immune responses. Most mRNA cancer vaccines are currently in Phase 2/3 trials and none to date have been approved by the FDA. Recently, a preclinical trial in mice demonstrated the efficacy of modified lipid nanoparticle “bubbles”. Other lipid nanoparticles, like those used in some COVID vaccines, can favor delivery of the vaccine to the liver, potentially resulting in inflammation. These newly developed lipid nanoparticles favored delivery of the vaccine into the lymphatic system, where immune cells are “trained”, to provoke a stronger immune response. The vaccine, which contained mRNA molecules encoding tyrosinase-related protein-2 (TRP-2), a tumor-associated protein expressed in melanoma, was tested in mouse models of the disease. The findings showed that increased delivery into the lymph by the modified lipid nanoparticles led to a stronger immune response. This significantly inhibited tumor growth, leading to a 40% complete response rate in combination with anti-PD-1 therapy. Another research team used a different method of development to produce an “off-the-shelf ” vaccine. Cancer vaccines often require tailoring to an individual patient’s neoantigens produced by their tumor. This treatment targeted MICA and MICB, stress proteins expressed in many cancer types in response to DNA damage, which flag damaged cells to be eliminated by the immune system. Cancer cells can evade this mechanism and cleave MICA/B from their surface to escape detection. The vaccine, which produces antibodies that bind to MICA/B, prevents the cleavage and loss of these proteins. Together, this strengthens the immune response from both T and NK cells against tumor cells, delivering a powerful “double-punch” that reduced the rate of metastasis in mouse models of melanoma and triple-negative breast cancer. TURNING TODAY'S DISCOVERIES INTO TOMORROW'S TREATMENTS Cancer biology is a diverse discipline which includes many other sub-fields such as genetics, cell biology, pharmacology and medicinal chemistry. Stepwise advances in these fields made over the past several decades have improved our knowledge of the biological processes underpinning cancer development. Together, these advances could enable the development of new and innovative technologies and therapies with the aim of turning today’s discoveries into tomorrow’s treatments. ⚫ 24 iStock “I couldn’t believe that this could happen to someone.” B ack in March 2020, as the COVID-19 pandemic descended over the world, Naïma was a busy tech worker, zipping around London, speaking to clients and jogging on the weekends. “I was very, very busy,” she says. “I did triathlons and [was] running 10Ks all the time. I was living a normal life, a full life.” Then, like every other person in the UK, her life came to a standstill as the country’s first lockdown began. Only, Naïma was even more sedentary than most; she was ill with COVID-19. “I had quite a few symptoms: headache, fever, full-body soreness, sore throat, a bit of a cough and I felt very weak,” she explains. “That lasted a couple of weeks.” It would have been easy to panic, contracting the very virus that had just shut down the world, but Naïma was relatively calm. “Because I was so fit, I wasn’t too worried,” she says. “The only real story that was happening was the hospitalizations. The line was: ‘Unless you have underlying conditions or you’re much older, you’ll be fine’.” And for a while she was, mostly. “I had this niggling sensation in my chest that would pop up every couple of days, just for a few seconds. And in those few seconds, I couldn’t breathe properly. But that didn’t develop into anything else for several months.” When it did, Naïma wasn’t just troubled with a tight chest; she was debilitated with palpitations and crippling fatigue. She could barely walk. “My world was turned upside down from that point in October, when those severe symptoms kicked in. I spoke to general practitioners; I said, ‘I can’t move at all. It feels like there are bricks on my chest and shooting pains that come whenever I get up’. They said, ‘You know, you’re so young and fit, but this sounds like a heart attack’.” It wasn’t. It was long COVID. Naïma was part of the first batch of people in the world to develop ongoing, disabling complications following an un-hospitalized COVID-19 infection. Unfortunately, she’s still ill, more than three years later. “It took me a couple of months to realize that this wasn’t going anytime soon. I was convinced I’d just wake up Long COVID Research Is a Bit of a Mess LEO BEAR-MCGUINNESS 25 and be fine. And, yeah, that obviously never materialized.” RESEARCH REQUIRED How could a fit and healthy 26-yearold go from running triathlons to being bed-bound for months, just from a passing viral infection? Why were she and people like her left with life-altering symptoms, while others could move on from their infections, seemingly unchanged? Back in 2020, no one had answers to these questions. No one really knew how to help those struggling with the illness. Research was desperately needed. And, as 2021 dawned, research arrived. The UK government awarded £18.5 million to four studies that set out to define long COVID. The European Union gave €27.9 million to a larger research initiative, known as ORCHESTRA, to study how COVID-19 was impacting people’s health. And in February 2021, the US National Institutes of Health (NIH) raised the bar and allocated $1.15 billion to research the causes of long COVID and its possible treatments. So, two and a half years later, what has been learned? Perhaps more importantly, have any treatments been produced? The short answers: a lot. And not quite. WHAT EXACTLY IS LONG COVID? To begin with, researchers set about defining long COVID as a starting point. Many understood the condition to involve persisting symptoms after a SARS-CoV-2 infection, but that was about it. They didn’t know exactly what these symptoms were or who they were affecting. To gather insights, they began profiling patients. “A lot of these patients were actually young and healthy, in their 20s and 30s,” says Dr. Ziyad Al-Aly, a clinical epidemiologist at Washington University. “And everybody at the time [in March 2020] was telling them that, ‘If you’re young and healthy, then SARS-CoV-2, it’s not a big deal; you’ll recover’. But weeks later, these people were not recovering. So we decided to research long COVID to try to understand what it is.” Al-Aly and his colleagues began by looking at patient medical records. They recently published two years’ worth of observations in Nature, comparing the medical data of 138,818 individuals who had a SARS-CoV-2 infection and 5,985,227 who hadn’t. There were some stark differences. Among the non-hospitalized, long COVID took away 80.4 disabilityadjusted life years (DALYs), a standard measure of disease burden, per 1,000 people. For comparison, others studies have estimated that chronic obstructive pulmonary disease costs between 3.6 and 6.7 DALYs per 1,000 people, for instance. Long COVID’s high disease burden is partly explained by its sheer number of possible symptoms; Al-Aly and his colleagues observed more than 80 within the medical records. These included atrial fibrillation, cardiac arrest, anemia, diabetes, fatigue, acute gastritis, myalgia, memory problems and peripheral neuropathy. Just over 30% of these sequalae remained “significant” in non-hospitalized patients for two years. “Long COVID is the long-lasting legacy of this pandemic,” Al-Aly says. Al-Aly’s study documented, in unprecedented detail, just how wide-ranging the effects of long COVID-19 can be. But what exactly is causing these symptoms? Parallel research has shed some light. One study found that long COVID patients had 100 times the levels of SARS-CoV-2-specific T cells normally seen in people who recovered from the virus – a finding that suggests the virus is still active in the bodies of people with long COVID, surviving in reservoirs, plaguing sufferers for months. Tiny blood clots have been found in patients – clots that could be blocking oxygen from reaching cells, starving patients of their energy. The brains of people with long COVID are also more active in certain areas than the brains of those without the post-viral illness – an observation that could explain the memory loss and confusion experienced by many with the condition. There’s a lot going on under the skin of long COVID patients, multiple etiologies affecting multiple organ systems. And this is where the field of long COVID research gets sticky, because highly variable diseases are difficult to study further. What kind of clinical researcher is best suited to the job? A cardiologist? A neurologist? An infectious disease specialist? Based off the mounting data, it seems like long COVID is a job for all three. This issue is partly why, more than three years on from when the illness was identified, long COVID research is still stuck in its characterization phase. Have a Google of “long COVID research” these days and one will still come across new papers decrying how blurry the definition of the disease is and arguing for more thorough studies to detail it better. But people with this condition can’t wait any longer for such preliminary studies. They’re desperate for interventional clinical trials now. “People “It’s been three years. This is a really long time to go without any hope.” 26 are hanging their hopes on these trials,” says Al-Aly. “They want them to be done yesterday. And yet we’re moving forward at a turtle’s pace.” Ironically, it’s the same kind of characterization research that demonstrates this desperation best. Almost one in five UK doctors responding to a recent BMJ survey said that they had lost their ability to work due to their post-COVID ill-health. A US study, published last year, estimated that long COVID potentially accounted for 15% of the country’s whole labor shortage. Even those who have managed to keep working through their illness report life-altering levels of fatigue (the most common symptom of long COVID), enough to rob them of their prior quality of life. One survey of patients at a long COVID clinic, published in BMJ Open this year, found that, on average, the patients’ fatigue scores were worse or similar to those of people with severe kidney disease. The respondents’ quality of life scores were also lower than those of people with stage four lung cancer. Most concerning of all, due to the toll of the illness, people with long COVID seem to be at a higher risk of suicide. One US patient-led survey found that 45% of respondents had experienced recent suicidal thoughts – more than 11 times the national average (4%). Sadly, these data are supported by a growing number of anecdotal reports within the long COVID patient community from grieving loved ones. So, with no approved treatments for the illness or standardized care plan – and a disease duration that can span over three years in certain cases – it’s perhaps no wonder people with long COVID are crying out for trials. Fortunately, a few have been greenlit. WHAT’S BEING TRIALED? In August 2023, there were 386 trials underway around the world relating to long COVID, according to the ClinicalTrials.gov database. A promising figure, one might think. Only 94 of those studies, however, were classed as interventional and were recruiting, and only 12 trials were testing pharmacological interventions; the rest were testing the effects of food supplements, psychological support, acupuncture and other non-drugs. What are the 12 drug trials testing, though? Well, one – led by Yale University – is studying whether Paxlovid (a COVID-19 antiviral made by Pfizer) could benefit people with long COVID, perhaps by eliminating any rogue remnants of SARS-CoV-2 that may still be lingering in their bodies. Another – led by a private US company – is seeing whether a novel drug designed to remove pro-inflammatory nucleic acids could reduce the levels of vascular inflammation observed in long COVID patients, thereby reducing their fatigue. But perhaps the most highly anticipated trial within the long COVID community is that undertaken by the relatively small biotech company Berlin Cures. The German start-up made headlines back in 2021 when it announced that it had effectively treated four people with long COVID with just a single infusion (per person) of its proprietary drug, BC 007. Encouraged by these initial results, the company has since launched a Phase 2 clinical trial of its neutralizing functional auto-antibody formula, which recently completed a Phase 2 open study for heart failure. “We know, and others have shown, that these functional auto-antibodies play a key role in the pathogenesis of various debilitating diseases,” says Oliver von Stein, Berlin Cures’ CEO. “Long COVID, we believe, is one of them, heart failure is potentially another.” To be included as a participant in the company’s trial, potential patients have to test positive for these pernicious auto-antibodies, so the Berlin Cures team can later test if a reduction in auto-antibody levels correlates with a reduction in fatigue (the prime symptom assessed by the study). Thanks to this level of rigor built into the trial, and the early results of BC 007, von Stein and his colleagues iStock 27 iStock are expecting promising results by the second half of next year – results that they hope will attract a new wave of investment for a Phase 3 trial and, beyond that, other trials for other maladies. “We are optimistic and expect good data from our ongoing Phase 2 study,” von Stein says. “And, if this is the case, this will provide a lot of momentum to tackle other diseases, similar conditions – for example, chronic fatigue syndrome.” THE “ME” IN THE ROOM Chronic fatigue syndrome – or myalgic encephalomyelitis (ME) – is the elephant in the long COVID room. For the past three years, much of the media and discussion around long COVID has treated the post-viral condition as an entirely new illness, a view that has been reflected in its research; scientists from around the world have scrambled to study the disease from scratch. But if ME had been studied more thoroughly — or even just believed — years ago, much of the foundational work of long COVID research may already have been achieved. That’s certainly the belief of many of those suffering from ME, who often live exceptionally stationary lives due to their condition. Some are bed-bound, quite literally, for decades. “Half of long COVID symptoms are basically equivalent to ME symptoms,” says Chris Ponting, a professor at the University of Edinburgh’s Medical Research Council Human Genetics Unit and lead investigator of its Decode ME project. If anyone is compensating for these “lost years of ME research”, it’s Ponting; he and his colleagues are currently conducting the largest study of ME ever undertaken. By analyzing the DNA samples of 25,000 patients, they hope to identify genetic markers that could underpin a person’s susceptibility to the disease. With that information in hand, they could then both validate the existence of the malady and identify targets for future drugs to treat it. “We anticipate that we’ll be able to find a bunch of places in our genomes that scream at us: immunology, or mitochondria or some neurological phenotype in the genome,” says Ponting. “Then, through joining up the dots, we can make an evidence-based, cogent explanation for what is going wrong.” It all sounds quite promising. But there’s an obstacle to follow-up studies, the same one that prevented ME research for decades: funding. “Our study was funded prior to the COVID-19 pandemic,” Ponting says. “There has not been further funding since then.” Contrary to the hopes of many in the ME community, the relative surge of interest in long COVID has not translated into a research boon for other fatigue-inducing, likely post-viral conditions, according to Ponting. “There has been a shift in the dial in acceptance of ME,” he notes, “which has not translated to substantial research funding that this disease deserves.” And unfortunately, at the tail end of 2023, it’s not just ME that’s being starved of vital research. The funding well for long COVID is drying up, too. GOODBYE, PANDEMIC, AND GOODBYE, RESEARCH GRANTS “All of these scientists, they’re back in the usual hurdles that scientists go through to try and get research up and running in this country. There is no sense of urgency at all,” says Even those who have managed to keep working through their illness report life-altering levels of fatigue. 28 iStock Margaret O’Hara, founder trustee of Long Covid Support, a UK-based charity supporting people with long COVID. O’Hara liaises with researchers on behalf of the charity. Two years ago, many of the scientists she spoke to were getting their funding from the UK’s National Institute for Health and Care Research (NIHR), which launched rounds of commission calls that were worth millions in 2021. Now those funding rounds are a distant memory. “Then NIHR said, ‘right, no more commission calls’,” says O’Hara. “’Long COVID’s not special anymore, and if you want money to research it, you [must] go through the usual channels – RFPB [Research for Patient Benefit] – and you compete with all the other diseases. So, what we find now is that [research grant applications] are just getting knocked back.” The situation seems much the same across the Atlantic. Remember that $1.15 billion the US NIH allocated to long COVID research? Well, it’s pretty much all been spent, largely on observational, characterization research, according to an analysis by STAT, and there’s been no announcement of any follow-up funding, despite calls from US researchers. Some long COVID studies in the country have since relied on charitable donations to keep going. Why has the money dried up? Fittingly, one could blame fatigue. There is a bitter feeling within the long COVID community that the rest of the world has grown tired of all things COVID and no longer wants to hear from – or fund studies affecting – those damaged by the virus. “We think there’s a bit of a message coming from the top to say, ‘Yeah, let’s downplay long COVID because, you know, COVID’s over,’” says O’Hara. Whether accurate or not, this sentiment that “the top” has lost interest in long COVID is a doubly frustrating one for those researching the disease because, right now, the field could really do with some leadership. LONG COORDINATION “[There is] no coherent approach to studying long COVID. No coherent strategy,” says Al-Aly. “I liken it to if you have a bunch of musicians, and everybody is singing their own tune, and there’s no conductor harmonizing all of this.” Al-Aly’s exasperation is shared by many of his fellow researchers. At a time of disappearing grants, many say the field needs a conductor – some governing body with a comprehensive, coordinated plan of action. “We think there should be a coordinated effort by UKRI [UK Research and Innovation] to say, ‘OK, long COVID is a disease of great interest and we need to coordinate responses,’” says O’Hara. “We need to put these scientists together so that they’re not all repeating the same thing.” O’Hara and her colleagues at Long Covid Support have been calling for this kind of managed response since 2020. The charity recently wrote to the UK government, recommending that it declare long COVID a public health emergency and prioritize research into treatments. These pleas have so far gone unheeded, which may be unsurprising given recent political revelations. In October 2020, when presented with the health department’s first guidance on long COVID, the then prime minister Boris Johnson scrawled “bo***cks,” in capitals, on the document. But this offensive dismissiveness from “the top” doesn’t mean a topdown research strategy, if coordinated by health departments and research funders, is an impractical suggestion, researchers insist. “The funders will say that’s up to the scientists to coordinate,” says Ponting. “And they would have a point; it has to be from the ground-up mostly rather than from the topdown. But top-down does work.” “The response to mad cow disease did come from the top,” he adds. “There have been international efforts on many different diseases going back 29 iStock decades, including polio. So, the answer that it is up to the scientists to organize ourselves in a competitive world, where we compete for funding because there’s so little of it, is missing part of what should happen, which is that we need coordination.” STUCK IN COVID LIMBO While all this disarray between researchers, funders and governments plays out, long COVID patients watch on, many despondent. Some are relatively new to the illness. Some have been coping with it for over three years with little improvement. Others have improved over time, gaining back enough physical capability to return to work. But this remission is fragile. According to a Long Covid Support survey of people who had recovered from the illness, 60% got long COVID again following a reinfection of COVID-19. This happened to Naïma, twice. “It’s very much a relapsing and remitting story,” she says. “I’ve had periods where I can work part-time, nearly full time. And then I’ve had periods where, right now, I can’t work at all because of a reinfection.” To protect herself from worsening symptoms, Naïma still practices strict infection protocols. She restricts her socializing. She wears a mask on public transport. She routinely tests for COVID-19 and asks others she sees to do the same. She’s still behaving like many people did in 2020. Without long COVID treatments, she can’t afford to change her habits. “I’ve been lucky in terms of my life beforehand,” she says. “I no longer feel that way. I live with fear every day of reinfection.” What does she make of the state of long COVID research, then? Does it give her hope for a return to a normal, fear-free future? Not quite. While she is part of a characterization study being conducted at Imperial College London, and is optimistic that such research will one day bear useful results, she says those who have been struggling with their long COVID for years need better outcomes now. “A lot of studies are moving on to: ‘who is getting this?’ I’m part of a study now with Imperial taking blood samples. It’s just [about] understanding: why are we so greatly impacted by this? Is there a specific gene that we have? I think that [answer] would really go a long way to understanding this. And then, of course, treatments for people who have been suffering now for years…” She pauses. “It’s been three years. This is a really long time to go without any hope.” “I think, because I’ve had improvement,” she adds. “I have more hope because I know that I do have better points and worse points. But some people have not had any good moments; they’ve been around for three years and had no improvement. I think we really need to be able to offer something to those people, to all of us.” ⚫ Those interested in following Naïma’s journey of long COVID recovery can subscribe to her Substack journal. For those living with long COVID, links to support groups and symptom management guides can be found at Long Covid Support. Those with ME can find similar support resources at ME Association. For those struggling with suicidal ideation in the UK, Papyrus and Samaritans offer 24/7 support. Those living in the US can call the 988 Suicide & Crisis Lifeline. 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